la profilassi antitrombotica nella fibrillazione atriale ... · interventi che non richiedono...

La profilassi antitrombotica nella fibrillazione atriale cosa

succede davvero in Italia

Lrsquoaspetto clinico

Simone Mininni

Atrial FibrillationTrends in US Deaths and Death Rates

0

10

20

30

40

50

60

70

80

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

0

10000

20000

30000

40000

50000

60000

70000

80000

Rate Count

[Wattigney WA et al AJE 2002 155819-26]

AF as an underlying or contributing cause rate per 100000 ages 45 years+ age-

adjusted to 2000 US standard population

Rate per 100000 Number of deaths

Calendar year

Etagrave ed FA (studio Framingham)

88481805 Prevalenza

di FA

80-8970-7960-6950-59

Range di etagrave (anni)

Wolf et al Stroke 1991

Incidence of Stroke in Hypertensive Subjects

in Relation to Atrial Fibrillation

No AF Paroxismal AF

(n=41)

Chronic AF

(n=20)

Verdecchia P Angeli F et al Hypertension 200341218-223

Avril 2007

Relative Risk Reduction of Stroke in Atrial

Fibrillation ndash Warfarin Compared with ASA1

1 Lip GYH et al BMJ 2002 325 1022ndash1025

ASA betterWarfarin better

ACTIVE W study

ASA + Clopidogrel as an alternative for warfarin

235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59

Ictus etagrave ed FA (studio Framingham)


STROKE RISK IN AF PATIENTS

Predittori clinici di stroke nella fibrillazione atrialeCHADSrsquo2 SCORE

Etagrave gt 75 anniIpertensioneDiabeteScompenso di cuorePrecedente stroke o TIA o IMA

CHA2DS2VASc score

bull Congestive heart failure

bull Hypertension

bull Agegt 75

bull Diabetes mellitus

bull StrokeTIAthrombo-embolism

bull Vascular disease

bull Age 65-74

bull Female sex

CHA2DS2VASc score

Congestive heart failure 1

Hypertension 1

Agegt 75 2

Diabetes mellitus 1

StrokeTIAthrombo-embolism 2

Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc

HAS-BLED bleeding risk score

Pisters The Euro HeartSurvey Chest 2010

gt 3 high risk attention both with ASA and OAT

Un farmaco insoddisfacente

ma senza alternative

il Warfarin

Oral anticoagulant drugs do not cut

tablets in quarters

Biron C Licznar P Hansel S Schved JF

Thromb Haemost 1999 Sep82(3)1201

Terapia anticoagulante un esercizio difficilissimo che puograve

fallire per minimi imprevisti

A B

Gli anticoagulanti hanno una finestra terapeutica molto

strettahellip

Complicazioni emorragiche

Anticoagulazione insufficiente

Io ne prendo frac14 3 volte al giorno

Io ne devo prendere 4 cp e frac12 a settimana quindi dal lunedigrave al giovedigrave 1 il venerdigrave frac12 e salto sabato e domenica

Dottore quanti pezzettini ne devo prendere

Hylek et al 1994 and 1996

Proper Therapeutic Range for INRINR Values with Stroke or Intracranial Bleed

EFFICACY AND SAFETY OF WARFARIN

Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150

100STROKE INTRACRANIAL BLEED

10

Warfarin

bull Variabilitagrave di effetto del Warfarin

circa il 600 (ci sono pazienti

che assumono frac14 di cp ed altri

che ne assumono 1 + frac12 )

ADJUSTED ODDS RATIOS FOR ASSOCIATION

BETWEEN USE OF ANTITHROMBOTIC DRUG AND

SERIOUS UPPER GASTROINTESTINAL BLEEDING

FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19

ASPIRINA E CLOPIDOGREL 74

ASPIRINA E TAO 53

TERAPIA ANTITROMBOTICA DELLA FA

WARFARIN RISCHIO TROMBOEMBOLICO DEL

18 ANNO GIUSTIFICA IL TRATTAMENTO

RELY il primo studio clinico in cui il gigante

(warfarin) esce ldquoridimensionatordquo

Camm J Oral presentation at ESC on Aug 30th 2009

RE-LYreg il primo studio clinico in cui

il gigante (warfarin) esce

ldquoridimensionato dopo 50 annirdquo

W vs placebo

W vs W bassa dose

W vs ASA

W vs ASA + clopidogrel

W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20

Meglio Warfarin Meglio altro trattamento

TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b

PRT-054021Ximelagatran

Dabigatran

Via orale Via parenterale

DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT

APC (drotrecogin alfa)

sTM (ART-123)

Weitz amp Bates J Thromb Haemost 2005

TTP889

I NAO

Stangier J Clin Pharmacokinet 200847285-295

Dabigatran etexilato (PRADAXA)

Stroke or systemic embolic events

Ruff C Lancet 2013

Dabigatran 150 mg bid

Rivaroxaban 20 mg od

Apixaban 5 mg bid

Edoxaban 60 mg od

Secondary efficacy and safety outcomes

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Stroke or systemic embolic events subgroups

Ruff C Lancet 2013

Major bleeding subgroups

Ruff C Lancet 2013

Funzione renale prima di iniziare la terapia con controlli nel tempo

NAO

bull Variabilitagrave di effetto massimo il

30 (la dose a paritagrave di etagrave non

deve essere modificata se la

funzione renale egrave buona)




NAO TALE LIMITE SCENDE ALLO 09 ANNO

(RISPETTO AL WARFARIN IL RISCHIO DI

EMORRAGIE INTRACRANICHE SI RIDUCE

DEL 30 ndash 70 )

CHA2DS2-VASc

Cosa succede nella vita reale

Pazienti 2016 Eventi

emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068

Moore et al Institute for safe medication practice 2017

Quale scegliere

Pazienti giagrave in Warfarin con eventi ischemici

Dabigatran 150 x 2 o Apixaban

Pazienti con insufficienza renale moderata e clearance

creatinina tra 15 e 49 Apixaban Rivaroxaban o

Edoxaban 30

Elevato rischio di sanguinamento Apixaban Edoxaban

o Dabigatran 110 x 2

Pazienti con scarsa compliance Rivaroxaban o

Edoxaban

NB

bull I NAO non sono quei farmaci che non

richiedono semplicemente il controllo

periodico dellrsquoINR

bull Sono un passo avanti che permettono

di curare meglio il nostro paziente ad

elevato rischio tromboembolico

Principali interferenze farmacologiche dei DOAC

Dabigatran

Cautela

Non indicata riduzione del dosaggio

Cautela

Dosaggio ridotto

Non raccomandati Controindicati

Atorvastatina Diclofenac

pantoprazolo clopidogrel digossina

amiodarone chinidina

claritromicina

Verapamil Dronedarone

carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante

percheacute induttori di

glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela

(aumentano lrsquoeffetto

anticoagulante

percheacute inibitoridi

glicoproteina-P e

citocromo 3A4)

Uso possibile ma

attenazione specie in

IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil

Azoli antiretrovirali

1 Colonna P et al G Ital Cardiol 2013 14(4) 295-3222 Hedbuchel H Verhamme P et al Eur Heart J (2013) doi 101093eurheartjeht134

NAO e interventi chirurgici- BREVE EMIVITA

- CARATTERISTICHE DEI PAZIENTI (FR etagrave storia di complicanze emorragiche farmaci concomitanti)

-TIPOLOGIA DI PROCEDURA CHIRURGICA

INTERVENTI CHE NON COMPORTANO UN IMPORTANTE RISCHIO EMORRAGICO eo quando una adeguata emostasi locale egrave applicabile (es alcune procedure odontoiatriche o interventi per cataratta o glaucoma) la procedura puograve essere effettuata nel momento in cui la concentrazione del NOAC egrave piugrave bassa (es 12 o 24 ore dopo lrsquoultima assunzione a seconda che sia una dose BID o una monosomministrazione)

INTERVENTI A MINORE RISCHIO di sanguinamento sospendere lrsquouso dei NOAC 24 oreprima della procedura nei pazienti con funzione renale normale

INTERVENTI A MAGGIOR RISCHIO di sanguinamenti sospendere 48 ore prima

Per gli interventi in cui si ha unrsquoemostasi rapida e completa i NOAC possono essere ripresi 6-8 ore dopo lrsquointervento

Interventi che non richiedono necessariamente la sospensione

dellrsquoanticoagulazioneInterventi a basso rischio emorragico Interventi ad alto rischio emorragico

Procedure odontoiatrichebullEstrazione da 1 a 3 dentibullChirurgia parodontalebullIncisione di ascessibullPosizionamento di impianti

Endoscopia con biopsia Anestesia spinale o epidurale puntura lombare diagnostica

OftalmologiabullInterventi per cataratta o glaucoma

Biopsia prostatica o vescicale Chirurgia Toracica

Endoscopia senza chirurgia Studi elettrofisiologici o ablazione con catetere a radiofrequenza per tachicardia SV e (inclusa ablazione sinistra via singola puntura trans-settale)

Chirurgia addominale

Chirurgia superficiale (es incisione di ascessi piccole escissioni dermatologiche etc)

Angiografia Chirurgia ortopedica maggiore

Impianto di pacemaker o ICD Biopsia epatica

Resezione prostatica transuretrale

Biopsia renale

Ablazione sincomplessa (es isolamento della vena polmonare VT ablation)

Heidbuchel H et al EHRA practical guide for use of NOAC Europace (2013) 15 625ndash651

NAO e interventi chirurgici

Mancata assunzione di una dose

Dabigatran1 Rivaroxaban2 Apixaban3

La dose dimenticata puograve ancora essere assunta fino a 6 ore prima dellassunzione della dose successiva dopo di che la dose dimenticata deve essere omessa

In caso di dimenticanza prendere Xareltoimmediatamente e proseguire il giorno seguente con lassunzione mono giornaliera abitualeXarelto puograve essere assunto indipendentemente dai pasti

In caso di dimenticanza di una dose prendere Eliquisimmediatamente e quindicontinuare con lassunzione due volte al giorno come in precedenza

1 Pradaxa Riassunto delle Caratteristiche del Prodotto

2 Xarelto Riassunto delle Caratteristiche del Prodotto

3 Eliquis Riassunto delle Caratteristiche del Prodotto

Grazie per lrsquoattenzione

Episodio di sanguinamento con i NAO Informazioni sulla gestione della terapia- dosaggio e tempo dallrsquoultima dose somministrata- terapie concomitanti - precedenti episodi emorragici - test di routine- misurazione dellrsquoattivitagrave anticoagulante- funzione renale

Emorragie lievi

bullOmissioneSospensione della terapia con NAO

bull Identificare la sede del sanguinamento

bull Emostasi locale

Emorragie moderate

bull OmissioneSospensione della terapia con NAO

bull Identificare la sede del sanguinamentobull Emostasi meccanica o chirurgicabull Mantenere la diuresibull Liquidibull Emazie concentratebull Concentrati piastrinici (se appropriato)bull Plasma fresco congelatobull Ac Tranexamico (come adiuvante)

bull Desmopressina (in casi particolari)bull Dialisi (per dabigatran)

Emorragie gravi



bull Desmopressina (in casi particolari)bull Dialisi (per dabigatran)bull PCCbull PCC attivatobull FVII attivato

1 Palareti G et al Expert Opin Pharmacother 2013 14(5)655-6672 Colonna P et al G Ital Cardiol 2013 14(4) 295-3223 Hedbuchel H Verhamme P et al Eur Heart J (2013) doi 101093eurheartjeht134

Gestione delle complicanze emorragiche con i NAO

Rivaroxaban

bull RECORD ndash REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE

bull Rivaroxaban 10 mg od will be compared with enoxaparin in over 10000 patients worldwide

ndash RECORD 1 THR 5 weeks therapy

ndash RECORD 2 THR 5 weeks vs 10ndash14 days enoxaparin

ndash RECORD 3 TKR 10ndash14 days therapy


Rivaroxaban

Rivaroxaban

Rivaroxaban

EINSTEIN DVT - Rivaroxaban

bull 3449 patients were randomized to either standard DVT treatmentmdashwith around five days of subcutaneous injection with an LMWH in this case enoxaparin followed by a vitamin-K antagonist of either warfarin or acenocoumarol titrated to maintain an international normalized ratio (INR) of 20 to 30mdashor rivaroxaban given as 15 mg twice a day for the first three weeks followed by 20 mg once a day

bull The primary efficacy outcome was the first symptomatic VTE event which occurred in 21 of those on rivaroxaban (n=1731) compared with 3 of those on usual care (n=1718) with a hazard ratio of 068 (95 CI 044-104) This met the criteria for noninferiority (plt00001)

August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)

Stroke or systemic embolic

event

16 36 046 (033ndash064)

Stroke embolic event MI or

vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)

bullVascular death 25 29 086 (064ndash116)

Cardiovascular

hospitalizations

118 149 079 (068ndash091)

Total death 34 44 079 (062ndash102)

AVERROES Primary and secondary end points

Connolly S European Society of Cardiology 2010 Congress August 31 2010 Stockholm Sweden

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)

Major bleeding 14 12 114 (074ndash175)

Clinical relevant nonmajor

bleeding

30 26 118 (088ndash158)

Minor bleeding 52 41 127 (101ndash161)

Fatal bleeding 01 01 084 (026ndash275)

Intracranial 04 03 109 (050ndash239)

AVERROES Bleeding events

Connolly S European Society of Cardiology 2010 Congress August 31 2010

Stockholm Sweden

Perchegrave la trombina egrave un obiettivo

eccellente

Forma amp stabilizza gli aggregati

Ulteriore produzione di trombina

Stimola la fibrinolisi

Attiva le piastrine

Dabigatran Farmacologia Clinica

Dabigatran etexilato profarmaco convertito a Dabigatran

Inibitore diretto della trombina legandosi ad un sito

specifico per la fibrina impedisce il legame fibrinogeno-

fibrina bloccando cosigrave lrsquoultimo gradino della cascata

coagulativa

Dabigatran etexilato in quanto inibitore reversibile si

dissocia dalla trombina lasciando una piccola quantitagrave di

trombina libera enzimaticamente attiva disponibile per la

normale emostasi

Farmacocinetica

- Rapidamente assorbito picco plasmatico 2 - 3 ore dopo la dose orale

- Biodisponibilitagrave orale circa 65

- Il cibo ritarda il tempo di picco lrsquoAUC non si modifica

- Legame con le proteine 25 - 30

- Steady-state raggiunto entro 3 giorni

- Semivita plasmatica 15 ore

- Ecreto immodificato con le urine per~80

- Il rimanente viene coniugato ed escreto per via biliare ed egrave attivo come

la forma non coniugata

- Escrezione rallentata e livelli plasmatici aumentati in caso di

insuffrenale (VFG lt50mlmin)

- Il Dabigatran egrave dializzabile

- Mancano per ora dati in etagrave avanzata e pediatrica

Dabigatran Warfarin

Prodrug Yes No

Time to Peak 2-3 hours 4 days

Bioavailability 65 100

Food-Peak Levels Decreased No Effect

Food-AUC No Effect Vitamin K

dependent

Elimination half-life 25 days 14-17 hours

Elimination altered in

renal dysfunction

Yes No


Hepatic Dysfunction

No Yes

Protein binding 25-30 995

Farmacodinamica

Il Dabigatran induce un aumento dose-dipendente di

aPTT (tempo tromboplastina parziale attivata)

INR TT(tempo di trombina) ECT (tempo di ecarina)

ed una correlazione stretta tra prolungamento della

coagulazione ematica e livelli plasmatici di dabigatran

La variabilitagrave interindividuale dei parametri di

coagulazione egrave bassa (coefficiente di variazione lt30)

Il Dabigatran non egrave un antagonista della vitamina K quindi il suo effetto

anticoagulante non deve essere monitorato routinariamente

Dopo dabigatran Lrsquo INR aumenta modestamente nei soggetti sani

Un prolungamento del aPTT correla linearmente con la radice quadrata

della concentrazione plasmatica

LrsquoECT (ecarin clotting time) egrave un test specifico che correla linearmente con

la concentarzione plasmatica del dabigatran ed egrave piugrave sensibile e preciso

del aPTT

Il tempo di Trombina (TT) egravemolto sensibile al dabigatran e aumenta in

proporzione alle concentrazioni plasmatiche di Dabigatran

Un rapporto TT ratio (vs controlli) di 10-20 indica livelli plasmatici terapeutici

di Dabigatran

Tuttavia al momento i dosaggi del TT non sono stati standardizzati

Reazioni Avverse

Dabigatran egrave ben tollerato per dosi orali fino a

600mgdie

Reazioni avverse si verificano nel 3 circa dei pazienti

Sono stati descritti nausea vomito stipsi febbre

ipotensione insonnia edema periferico anemia

vertigini diarrea e cefalea

Aumento moderato delle GOT (gt3 volte il limite della

normalitagrave) ha una frequenza del 2 circa dopo 12 mesi

Emorragia si verifica raramente (1 dei casi)

Interazioni Farmacologiche

Lrsquouso concomitante di aspirina altri inibitori delle piastrine

e FANS aumenta significativamente il rischio di

sanguinamento

La co-somministrazione di pantoprazolo riduce lrsquo AUC del

dabigatran del 30

Il Dabigatran non altera il metabolismo dei farmaci che

sono substrato dei maggiori isoenzimi del citocromo P-

450

DABIGATRAN ETEXILATE

bull Studi clinici

Dabigatran etexilate Phase III clinical program

Primary DVT prevention

VTE treatment SPAF

VTE secondary prevention

More then 27000 patients involved

RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY

RE-MODEL Efficacy Outcomes

Total VTE and all

cause mortality

Ev

en

t R

ate

(

)

Dabigatran etexilate

p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)


Eriksson BI et al JTH Accepted article online 28-Aug-2007

26

3835

0

1

2

3

4

5

220 mg 150 mg Enoxaparin

364

405377

0

10

20

30

40


p+ = 038

p+ = 082

P Value for non inferiority vs enoxaparin

+ P Value for difference vs enoxaparin

RE-MODEL Bleeding Outcomes

No fatal bleeding one critical organ bleed in each of the dabigatran dose groups

131315Major bleeding ()

667174Major bleeding plus clinically

relevant non-major bleeding ()

166165162Any bleeding ()

Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome


RE-NOVATE Objective and Design

Objective

bull To establish non-inferiority of two doses of dabigatran etexilate relative to enoxaparin

bull Design

bull Patients undergoing total hip replacement

ndash Dabigatran etexilate (150 mg or 220 mg) qd or enoxaparin 40 mg qd

ndash Double-blind with blinded outcome assessment (N=3494)

bull Primary outcome Total venous thromboembolism (VTE) and all-cause mortality

bull 105 centres in Europe Australia and South Africa

qd once dailyEriksson BI et al Lancet 2007 370 949-956

RE-NOVATE Study Design

Randomisation

EnoxaparinStart 12 hours

pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R

The evening before surgery qd once daily

Dabigatran and enoxaparin were given for 28ndash35 days after surgery

Central Adjudication of all efficacy and safety outcomes

Eriksson BI et al Lancet 2007 370 949-956

Total VTE and Death

p lt00001

p lt00001

RE-NOVATE Efficacy Outcomes

Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071



Bleeding Events During Treatment

Major bleeding Major + clinically relevant

non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)


Dabigatran etexilateDabigatran etexilate

220 mg

1

08

30

1117

1146

RE-NOVATE Safety Outcomes


ALT gt 3 x ULN and bilirubin gt

2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN

Any time during treatment and 3 month follow-up

n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163


RE-NOVATE Conclusions

bull Proved to be non-inferior to enoxaparin when administered for the

same duration for the prevention of VTE

bull Showed a low rate of bleeding comparable with enoxaparin

bull Showed no difference in the incidence of liver enzyme elevations or

ACS when compared with enoxaparin

bull Offered fixed oral dosing without coagulation monitoring

In patients undergoing total hip replacement both doses of

the oral direct thrombin inhibitor dabigatran etexilate given

for a median of 33 days


Studi nella Fibrillazione Atriale

Efficacia dello ximelagatran in pazienti confi brillazione atriale

Trial Ictus embolie sistemiche OR (95 CI) P

Ximelagatran (36 mg bid) Warfarin (INR 2 to 3)

SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study

Randomized Evaluation of Long-term

anticoagulant therapY

Dabigatran Compared to Warfarin in 18113 Patients with

Atrial Fibrillation at Risk of Stroke

Characteristic Dabigatran 110

mg

Dabigatran 150

mgWarfarin

Randomized 6015 6076 6022

Mean age (years) 714 715 716

Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321

Prior strokeTIA () 199 203 198

Prior MI () 168 169 161

CHF () 322 318 319

Baseline ASA () 400 387 406

Warfarin Naiumlve () 499 498 514

Stroke or Systemic Embolism

050 075 100 125 150

Dabigatran 110 vs Warfarin


Non-inferiorityp-value

lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331

Adverse events occurring in

gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin

Dyspepsia 118 113 58

Dyspnea 93 95 97

Dizziness 81 83 94

Peripheral edema 79 79 78

Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56

Nasopharyngitis 56 54 56

Diarrhea 63 65 57

Atrial fibrillation 55 59 58

Urinary tract infection 45 48 56

Upper respiratory tract

infection48 47 52

Effetti collaterali

Occurred more commonly on dabigatran plt0001

Conclusions

bull Dabigatran 150 mg significantly reduced stroke compared to warfarin with similar risk of major bleeding

bull Dabigatran 110 mg had a similar rate of stroke as warfarinwith significantly reduced major bleeding

bull Both doses markedly reduced intra-cranial and life-threatening hemorrhage

bull Both doses are free of liver and other major toxicity although they increase dyspepsia and GI bleeding

Conclusions

bull Both Dabigatran doses offer advantages over

warfarin

bull Dabigatran 150 is more effective and dabigatran

110 has a better safety profile

bull The availability of two effective doses with different

benefit risk profiles creates the potential to tailor

therapy to individual patient characteristics

Vantaggi del Dabigatran rispetto al Warfarin

1) profilo farmacocinetico prevedibile

2) rapido inizio dellrsquoeffetto

3) finestra terapeutica ampia

4) sommistrazione orale

5) non richiede controlli ematici periodici

aggiustamenti di dose diete costanti

6) poche interazioni farmacologiche

7) tollerabilitagrave buona

A QUANDO LA DISPONIBILITArsquo

bull A Food and Drug Administration panel unanimously recommended Monday that the FDA approve BoehringerIngelheim GmbHs blood-thinning drug Pradaxa The move likely places the company as the first to get a new type of drug on the US market to prevent strokes in patients with irregular heart rhythms

bull The FDAs cardiovascular and renal drugs advisory committee voted 9 to 0 in favor of approving dabigatran to reduce the risk of stroke and blood clots in patients with atrial fibrillation The FDA usually follows the advice of its panels and is expected to make a decision by about Oct 19

Wall street journal 21 settembre 2010

grazie dellrsquoattenzione

1

Completed Dabigatran Etexilate in Extended VTE Prevention After Hip

Replacement Surgery

Conditions Thromboembolism Arthroplasty Replacement Hip

2

Completed RE-MODEL Dabigatran Etexilate 150mg or 220mg od vs Enoxaparin 40mg od for Prevention of Thrombosis

After Knee Surgery

Conditions Arthroplasty Replacement Knee Thromboembolism

3

Recruiting Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous

Thromboembolism

Condition Thromboembolism

4

Completed Dabigatran Etexilate vs Enoxaparin in Prevention of VTE Post Total Knee

Replacement


5

Recruiting Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) With

Dabigatran Etexilate

Conditions Atrial Fibrillation Cerebrovascular Accident

6

Recruiting Secondary Prevention of Venous Thrombo

Embolism


7

Active not

recruiting

Long-Term Open-Label Follow-up Treatment of Pateints With a-Fib Who Have Been Previously Treated

With BIBR 1048


8

Recruiting A Study of BIBR 1048 in Prevention of Venous Thromboembolism in Patients With

TKR Surgery

Conditions Arthroplasty Replacement Knee Venous Thrombosis

Buone Feste

Anticoagulanti

Un gran numero drsquoindicazioni diverse

Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi

bull Protesi valvolari

bull Embolie cardiache

bull TVP post-operatoria

bull TVP rischio medico

Interventi vascolari

(angioplasticheendoprotesi)

Circolazione extracorporea

ndash Emodialisi

ndash Chirurgia cardiaca

ndash Supporto circolatorio artificiale

Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily

Enoxaparin 40mg SC daily

Total VTE and death 405 364 377

Proximal DVT andor

PE

38 26 35

Major bleeding 13 15 13

Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni

azione non selettiva a molti livelli

Vitamin Kantagonists

TM

VIIa

Xa

Cellular tissue factor

Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII

Soluble fibrinFibrinogen Fibrin (clot)

Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII

Intrinsic system Extrinsic system

XIIa

Vantaggi ipotetici

Terapia orale a dosi fisse

Non richiesto monitoraggio della coagulazione

Azione Immediata

Risposta anticoagulante piugrave prevedibile

Margini di sicurezza piugrave ampi

Meno variabilitagrave tra soggetti

Minime interazioni farmacologiche

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa Inhibition

Tissue

factor

Fibrinogen Fibrin clot

Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa

Selective Indirect Factor Xa inhibition

Tissue

factor

AntithrombinFondaparinux


Factor II

(prothrombin)

times

PETRO demographic data risk factors

0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9

Proportion with risk factor

Dabigatran With or Without Concomitant Aspirin Compared

With Warfarin Alone in Patients With Nonvalvular Atrial

Fibrillation (PETRO Study)

The American Journal of Cardiology November 2007

PETRO major and minor bleeding

Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients

dabigatran etexilate

(mg bid)

ASA

(mg)

Any bleeding

PETRO frequency of bilirubin elevations

00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation

dabigatran etexilate dose bid

PETRO PK and PD findings

bull Parameters measured at 1 4 and 12 weeks

ndash Pre-dose dabigatran etexilate concentrations

ndash Activated partial thromboplastin time (aPTT)

ndash Ecarin clotting time (ECT)

bull Trough plasma concentrations increased in proportion with dose

bull Close correlations between aPTT ECT and plasma concentrations were observed

bull Rapid onset of action and stable and predictable PK and PD profiles were observed

in patients with AF

bull PK and PD results indicate doses of 150 ndash 300 mg bid provide adequate

anticoagulation

PETRO

dabigatran etexilate dose

finding trial in

patients with atrial

fibrillation

PETRO design

bull Phase II warfarin-controlled 12 week study in AF patients

ndash Dose-finding

ndash Safety

ndash Effect of concomitant ASA

bull 502 patients

bull Open label vs warfarin (INR 20-30) study of dabigatran etexilate in stroke prevention

bull Blinded for dabigatran dose (50 150 and 300 mg bid)

bull Dabigatran doses matrixed with ASA (0 81 and 325 mg)

PETRO design ndash 12 weeks treatment

303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30

dabigatran etexilate dosing

mg bid

Number of randomized patients in each treatment group

Note per protocol DSMB curtailed treatment in the two 300 mg bid + ASA

groups due to bleeds

PETRO thromboembolic events

0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid

Event rateASA (yn)dabigatran etex dose

PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid

Event RateASA (yn)dabigatran etexilate

dose

PETRO discontinuations due to adverse

events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid

PETRO frequency of ALT elevations

01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary

bull Dabigatran etexilate without ASA is well tolerated in doses up to 300 mg bid

bull Dabigatran without ASA appears to have the same risk of bleeding as warfarin

bull Thromboembolic events were only seen in 50 mg bid dose

bull Transaminase elevations gt3 x ULN were observed in ~ 07 of dabigatran

treated patients over 3 months

bull There were no patients with concomitant elevations in bilirubin gt 2 x ULN

bull The overall results indicate that 150 mg bid dabigatran is effective and well

tolerated and should be carried forward into Phase III trials

RE-LY

bull Indication Stroke prevention in patients with AF

bull Location Worldwide

bull No patients 15 000

bull 1ordm efficacy endpoint Strokes + systemic embolic events

bull 1ordm safety endpoint Bleeding events intracerebral amp intracranial hemorrhage LFT elevations

RE-LY study design

20-24 months

treatment

R

Randomization

Warfarin INR 20 ndash 30

Dabigatran Dose A

Open label warfarin vs dabigatran etexilate non-inferiority (NIM

146) study in patients with atrial fibrillation

Dabigatran doses are blinded

Dabigatran Dose B

A Once-Daily Oral Direct Factor Xa Inhibitor

Rivaroxaban (BAY 59-7939) for

Thromboprophylaxis After Total Hip ReplacementEriksson et al Circulation 20061142374-2381

Rivaroxaban bid (THRTKR pooled)

Estimated rates calculated by logistic regression adjusted for study age and gender

Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40

DVT PE and all-cause mortalityMajor bleeding

Esti

mate

d i

ncid

en

ce r

ate

(

)

Rivaroxaban (mg total daily dose)

5

Activated partial thromboplastin time (aPTT) values with increasing

dabigatran plasma concentrations in individual patients following

dabigatran etexilate on day 4 (steady state) in BISTRO I

The relationship between patient ecarin clotting time (ECT) values and

dabigatran plasma concentrations 0ndash12 h (A) and gt100 h (steady state) (B)

after first administration of dabigatran etexilate following orthopaedic

surgery

K-H Liesenfeld et alBritish Journal of Clinical Pharmacology2006

(A)

(B)

Dabigatran etexilate groups Enoxaparin

50 mg bid 150 mg bid 300 mg qd 225 mg bid 40 mg qd

Patients with VTE () 285 174 166 131 240

Patients with DVT () 285 168 166 131 240

Composite proximal

DVTPE 50 40 21 17 56

BISTRO II randomized trial

Journal of Thrombosis and Haemostasis 3 103ndash1112005

DVT deep vein thrombosis VTE venous thromboembolism PE pulmonary embolism

Anticoagulanti

una storia lunga

unrsquoevoluzione lenta

Cronologia delle Opzioni Anticoagulanti

1916

Eparin

1950s 1990s 20021970s

Warfarin LMWHInibitori

selettivi del fattore Xa

Inibitori diretti della

trombina

Weitz J Hirsh J Chest 200111995S

0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]

[Nature Reviews Drug Discovery 2003211-12]

Antithrombotic Drug Market

Anticoagulanti Disponibili

NoParenteraleFondaparinox

SiOraleantagonisti Vitamina K

(warfarin)

SiParenteraleInibitori diretti trombina

NoParenteraleEparine a basso peso

molecolare

SiParenteraleEparina

Monitoraggio

Laboratorio

Via di

somministrazione

Caratteristiche drsquoun anticoagulante ideale - 1

bull Efficacia sicurezza

bull Inizio dellrsquoazione rapido

bull Farmacocinetica e farmacodinamica stabili e

prevedibili

bull Non soggetto ad interazioni

bull Misurazioni dei livelli ematici dellrsquoeffetto non

necessarie

bull Non tossico

bull Poco costoso

Caratteristiche drsquoun anticoagulante ideale -2

Problemi con il Warfarin

bull Dosi molto variabili e imprevedibili

bull Finestra terapeutica stretta

bull Interazioni farmacologiche multiple

bull Interazioni con alcuni cibi

bull Le controindicazioni escludono circa il 20 dei pazienti

bull Necessitagrave di Controlli ematici frequenti

bull Molto scomodo per i pazienti

bull Prezzo basso ma follow-up dei pazienti complesso e costoso

bull Bassa compliance

Warfarin nella Fibrillazione Atriale

Samsa et al Arch Intern Med 2000160967-973

INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65

Adeguatezza dellrsquo Anticoagulazione nei

Pazienti con FA nella Medicina di Base




Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Oral Anticoagulation is Often Contraindicated in

Atrial Fibrillation

1 Sudlow et al Lancet 1998 352 1167ndash1171

2 Brass LM et al Stroke 1997 28 2382ndash2389

3 Kalra et al Stroke 1999 30 1218ndash22 Heart 1999 82 570ndash574

4 Go et al Ann Intern Med 1999 131 927ndash934

1 2 3 4

Standard

contraindications to

warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years

Dutch bypass OA vs ASA Lancet 2000 335246

0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50

Distribution of Time in Each INR

RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR

Oral anticoagulant drugs do not cut tablets

in quarters

bull Biron C Licznar P Hansel S Schved JF

bull Thromb Haemost 1999 Sep82(3)1201

NUMERI PAZIENTI RANDOMIZZATI A NAO

bull Profilassi TEV in ortopedia maggiore 21845

bull Profilassi paziente medico

(ADOPT MAGELLAN) 6194

bull Trattamento TEV (RE-COVER I

EINSTEIN DVT PE EXTENSION) 6025

bull FA (RE-LY ROCKET-AF ARISTOTLE AVERROES)31080

bull SCA (APPRAISE II ATLAS ACS 2 TIMI-51) 14118

Dabigatran 150 mgx2

bullMaggiore efficacia vs TAO

bullStesso rischio di sanguinamento generale

bullMinor rischio di sanguinamento intracranico

Dabigatran 110 mgx2

bullStessa efficacia TAO

bullMinor rischio di sanguinamento generale


RISULTATI STUDIO RELY

Avril 2007

Dabigatran etexilate e glicoproteine-P

DDI = drugndashdrug interaction P-gp = P-glycoproteinDisclaimer Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries

Please check local prescribing information for further details Dec 2011

Amiodarone (moderato P-gp inibitore)

Verapamil (forte P-gp inibitore)

Dronedarone (forte P-gp inibitore)

Chinidina (forte P-gp inibitore)

Claritromicina (forte P-gp inibitore)

bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE

Dabigatran etexilato

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionTissue

factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

He et al ASH 2006 Lassen et al ASH 2006

N

N

NO

N O

NH2

O

O

NAO indicazioni e dosaggi

Prevenzione dellrsquoictus e dellrsquoembolia sistemica in pazienti con FANV e uno o piugrave fattori di rischio

bull Precedente ictus attacco ischemico transitorio o embolia sistemica (ES)bull FE lt 40 bull Insufficienza cardiaca sintomatica ge Classe 2 NYHAbull Eta ge 75 annibull Eta ge 65 anni associata con una delle seguenti condizioni diabete mellito coronaropatia o

ipertensione

Pradaxa 110x2bull gt 80 a

bull Uso concomitante di verapamil

bull Alto rischio emorragico

Valutazione individuale Rischio emorragicotrombotico in

bull etagrave 75-80

bull IRC CL cr 30-50 mlmin

bull Gastrite esofagite MRGE

Dabigatran Pradaxa 110x2 o 150x2

AIFA

RivaroxabanXarelto 20 CrCl gt 50mlminXarelto 15 CrCl 30-49 mlmin

Prevenzione dellrsquoictus e dellrsquoembolia sistemica nei pazienti adulti

affetti da FANV Permanente con uno o piugrave fattori di rischio

-insufficienza cardiaca congestizia

-ipertensione

-etagravege 75 anni

-diabete mellito

-pregresso ictus o TIA

AIFA

APIXABANELIQUIS5 mgx 2


affetti da FANV con uno o piugrave fattori di rischio


-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2

Pazienti con creatinina sierica ge 15 mgdL

associata ad una etagrave ge 80 anni o

ad un peso corporeo le 60 kg

Dentali F et al Circulation 20121262381-2391

Copyright copy American Heart Association Inc All rights reserved

EMORRAGIE MAGGIORI CON I NAO

- 14

INCIDENZA EMORRAGIE INTRACRANICHE

NAO VERSUS WARFARIN

Atrial FibrillationTrends in US Deaths and Death Rates

0

10

20

30

40

50

60

70

80

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

0

10000

20000

30000

40000

50000

60000

70000

80000

Rate Count

[Wattigney WA et al AJE 2002 155819-26]

AF as an underlying or contributing cause rate per 100000 ages 45 years+ age-

adjusted to 2000 US standard population

Rate per 100000 Number of deaths

Calendar year


88481805 Prevalenza

di FA

80-8970-7960-6950-59





No AF Paroxismal AF

(n=41)

Chronic AF

(n=20)


Avril 2007





ACTIVE W study


235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


88481805 Prevalenza

di FA

80-8970-7960-6950-59





No AF Paroxismal AF

(n=41)

Chronic AF

(n=20)


Avril 2007





ACTIVE W study


235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN



No AF Paroxismal AF

(n=41)

Chronic AF

(n=20)


Avril 2007





ACTIVE W study


235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Avril 2007





ACTIVE W study


235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

ACTIVE W study


235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

235992815

Rischio di

ictus

correlato

alla FA

80-8970-7960-6950-59






CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




CHA2DS2VASc score


bull Hypertension

bull Agegt 75




bull Age 65-74

bull Female sex

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

CHA2DS2VASc score


Hypertension 1

Agegt 75 2

Diabetes mellitus 1


Vascular disease 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

CHA2DS2-VASc






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN






il Warfarin


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


tablets in quarters





A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN



A B


strettahellip









Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN







Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Warfarin








FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




FARMACO OR

ASPIRINA 18

CLOPIDOGREL 12

COUMADIN 18

DIPIRIMAOLO 19


ASPIRINA E TAO 53










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN










W vs placebo

W vs W bassa dose

W vs ASA


W vs ximelagatran

W vs dabigatran 150

0 03 06 09 12 15 18 20


TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

EdoxabanLY517717

YM150

DU-176b


Dabigatran


DX-9065a

Rivaroxaban

Otamixaban

Xa

IIa

TFVIIa

X IX

IXaVIIIa

Va

II

FibrinaFibrinogeno

AT


sTM (ART-123)


TTP889

I NAO




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Major bleeding

Ruff C Lancet 2013



Apixaban 5 mg bid

Edoxaban 60 mg od


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Ruff C Lancet 2013


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Ruff C Lancet 2013


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


NAO











DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN







DEL 30 ndash 70 )

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

CHA2DS2-VASc



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN



emorragici

Emorragie

Apixaban 2183821 3148 014

Dabigatran 486176 1944 040

Edoxaban 23886 108 045

Rivaroxaban 2209216 15043 068


Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Quale scegliere





Edoxaban 30




Edoxaban

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

NB








Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Dabigatran

Cautela


Cautela

Dosaggio ridotto





claritromicina


carbamazepina

rifampicina

fenitoina

inibitori delle

proteasi

antiretrovirali

Azoli tracolimus

ciclosporina

AntiXa

Cautela

Interferenti ma uso

possibile

Cautela (riducono

lrsquoeffetto

anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile

Cautela


anticoagulante


glicoproteina-P e

citocromo 3A4)

Uso possibile ma


IRC e se rischio di

sanguinamento

Controindicati

Digossina

atorvastatina

midazolam

Rifampicina

fenobarbital

fenitoina

carbamazepina

ipericum

Fluconazolo

eritromcina

claritromicina

amiodarone

verapamil






















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN





















Biopsia renale














Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN











Emorragie lievi




Emorragie moderate




Emorragie gravi






Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Rivaroxaban







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN







Rivaroxaban

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Rivaroxaban

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Rivaroxaban




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




August 31 2010

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)


event

16 36 046 (033ndash064)


vascular death

41 62 066 (053ndash083)

bullMI 07 08 085 (048ndash150)


Cardiovascular

hospitalizations

118 149 079 (068ndash091)




Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Outcomes Apixaban

(n=2809)

Aspirin

(n=2791)

RR (95 CI)



bleeding

30 26 118 (088ndash158)






Stockholm Sweden


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


eccellente




Attiva le piastrine






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN






coagulativa




normale emostasi

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Farmacocinetica














Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Dabigatran Warfarin

Prodrug Yes No





dependent



renal dysfunction

Yes No


Hepatic Dysfunction

No Yes


Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Farmacodinamica















del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN








del aPTT




di Dabigatran


Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Reazioni Avverse


600mgdie











sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




sanguinamento


dabigatran del 30



450


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


bull Studi clinici



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN



VTE treatment SPAF



RENOVATE

REMODEL

REMOBILIZE

REMEDY

RESOLVE

RECOVER

PETRO

RELY


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Total VTE and all

cause mortality

Ev

en

t R

ate

(

)


p = 00003

p = 0017

Major VTE and VTE

related mortality

Ev

en

t R

ate

(

)



26

3835

0

1

2

3

4

5


364

405377

0

10

20

30

40


p+ = 038

p+ = 082









Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN







Enoxaparin

N=694


150 mg

N=703

220 mg

N=679Outcome



Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Objective


bull Design








Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Randomisation


pre-operatively

Start 1ndash4 hours

post-operatively

40 mg qd

75 150 mg qd

110 220 mg qd

Venography

Day 28ndash35

Follow-up

12ndash14 weeks

Dabigatran

etexilate

R





Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Total VTE and Death

p lt00001

p lt00001


Major VTE and Death

0

1

2

3

4

5

31

220 mg

43

150 mg

39

Enoxaparin


Eve

nt

Rate

(

)0

2

4

6

860

220 mg

86

150 mg

67

Enoxaparin


Eve

nt

Rate

(

)

10


p+ =033

p+ =071





non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN



non-major bleeding

0

1

2

3

20

220 mg

13

150 mg

16

Enoxaparin

Eve

nt

Rate

(

)

50

Enoxaparin

65

0

2

4

6

8

220 mg

60

150 mgE

ve

nt

Rate

(

)



220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

220 mg

1

08

30

1117

1146




2 x ULN - n

ALT gt 5 x ULN

ALT gt 3 x ULN


n

53

18

Enoxaparin

40 mg qd

0

1122

1154n

150 mg

1

15

29

1124

1163

















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN
















SPORTIF-III11 23 33 071 (048-107) 010

SPORTIF-V12 26 19 138 (091-210) 013

Total 25 25 098 (074-130) 094

I Precedenti

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

The RE-LY Study






mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


mg

Dabigatran 150

mgWarfarin



Male () 643 632 633

CHADS2 score

(mean)

0-1 ()

2 ()

3+ ()

21

326

347

327

22

322

352

326

21

309

370

321


Prior MI () 168 169 161

CHF () 322 318 319




050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


050 075 100 125 150




lt0001

lt0001

Superiorityp-value

034

lt0001

Margin = 146

HR (95 CI)

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

ALT or AST gt3x ULN

Years

Cu

mu

lati

ve

Ris

k

00

00

10

02

00

30

04

0 05 10 15 20 25

Dabigatran110

Dabigatran150

Warfarin

at RiskYear 05 10 15 20 25

D110D150

W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 1427

6022 5858 5708 4592 2906 1331


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


gt5 of any group

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin


Dyspnea 93 95 97

Dizziness 81 83 94


Fatigue 66 66 62

Cough 57 57 60

Chest pain 52 62 59

Arthralgia 45 55 57

Back pain 53 52 56


Diarrhea 63 65 57




infection48 47 52

Effetti collaterali


Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Conclusions





Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Conclusions


warfarin




















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN















1


Replacement Surgery


2


After Knee Surgery


3


Thromboembolism


4


Replacement


5




6


Embolism


7

Active not

recruiting


With BIBR 1048


8


TKR Surgery


Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Buone Feste

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Anticoagulanti


Trombosi acute

bull venose

bull arteriose

bull angina stabile

Profilassi








ndash Emodialisi



Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Clotting Cascade

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Dabigatran 150mg

daily

Dabigatran 220mg

daily



Proximal DVT andor

PE

38 26 35


Elevated LFTs

(ALTgt3X ULN)

37 28 40

RE-MODEL STUDY

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

I farmaci odierni



TM

VIIa

Xa


Ca2+

II

X

IXPS

PC PCa

XIIIa

XI

XII


Heparins

Xa

Va

PL

Ca2+

IXa

VIIIa

Ca2+

PL

IIa

XIa

VII


XIIa

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Vantaggi ipotetici



Azione Immediata





VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor


Factor II

(prothrombin)

Rivaroxaban

(BAY 59-7939) (oral)

LY517717 (oral)

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

VIIa

Xa

IXa

XIa

XIIa


Tissue

factor



Factor II

(prothrombin)

times


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


0

10

20

30

40

50

60

70

80

Hyperte

nsion

CAD

LVD

Age gt

75 ye

arsCHF

Diabete

s

Previ

ous TIA

Previ

ous stro

ke

71

61

33 3229

25

10 9







Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN






Warfarin300

15050

0

81

3250

10

20

30

40

50

Percent of patients


(mg bid)

ASA

(mg)

Any bleeding


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


00000gt5xULN

00000gt3xULN

00000gt2xULN

11

(68)

10

(60)

3

(29)

24

(56)

5

(71)

gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

Dabigatran

n=432

Warfarin

n=70

Elevation










in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN









in patients with AF


anticoagulation

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

PETRO


finding trial in


fibrillation

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

PETRO design


ndash Dose-finding

ndash Safety


bull 502 patients





303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


303327325

34362181

70105100590

30015050ASA

(mgday)

Warfarin

INR 20ndash

30


mg bid





0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


0070noWarfarin

0064yes

00105no300 mg bid

0069yes

00100no150 mg bid

21148yes

17159no50 mg bid


PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

PETRO major bleeds

0070noWarfarin

6464yes

00105no300 mg bid

0069yes

00100no150 mg bid

0048yes

0059no50 mg bid


dose


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


events

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

er

of

ev

en

ts

CVA

Bleeding

Stom

ach pain

dys

pepsia

ACS

chest pa

in

Worse

ning H

F dys

pne

aFa

tigue

Dia

rrhea

Dizz

iness

Warfarin

50 mg bid

150 mg bid

300 mg bid


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


01(06)01 (02)0gt5xULN

2(12)1(06)03 (07)0gt3xULN

3(19)3(18)06 (14)0gt2xULN

7(43)11(66)6 (57)24 (56)7 (10)gt1xULN

300 mg

n=161

150 mg

n=166

50 mg

n=105

dabigatran

n=432

Warfarin

n=70

Elevation


PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

PETRO summary









RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

RE-LY






RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

RE-LY study design

20-24 months

treatment

R

Randomization


Dabigatran Dose A




Dabigatran Dose B






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN






Efficacy p=039

Safety plt00001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40


Esti

mate

d i

ncid

en

ce r

ate

(

)


5







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN







surgery


(A)

(B)





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN





Composite proximal

DVTPE 50 40 21 17 56




Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Anticoagulanti

una storia lunga



1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


1916

Eparin

1950s 1990s 20021970s




trombina


0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

0

2

4

6

8

10

12

14

16

2001 2005 2010

developmental

antithrombotics

currently marketed

thrombolytics

currently marketed

antiplatelets

currently marketed

anticoagulants

Sale

s [

bil

lio

n $

]






(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




(warfarin)



molecolare


Monitoraggio

Laboratorio

Via di

somministrazione





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN





prevedibili



necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


necessarie

bull Non tossico

bull Poco costoso














INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN













INR sopra al

target

6

INR

Subterapeutico 13

INR nel

range ottimale

15

No warfarin

65






Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




Odds R

atio

050 60 80

INR

10 20 30 40 70

50

150


10


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Atrial Fibrillation





1 2 3 4

Standard


warfarin use in AF

patients gt65 years

Standard

contraindication to

OAC (including

ASA and NSAID)

Conventional

contraindication to

warfarin (ASA and

NSAID not

included)

Contraindications

to OAC in

randomly selected

AF patients aged

gt75 years


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


0

50

100

150

200

250

300

350

400

450

1 15 2 25 3 35 4 45 5 55 6 65 gt65

RANGE

50


RangeT

ime

in

IN

R C

lass (

pa

tie

nt-

ye

ars

)

INR


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


in quarters











Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN









Dabigatran 150 mgx2




Dabigatran 110 mgx2





Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

Avril 2007









bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

bull KETONAZOLO ev

bull CICLOSPORINA

bull TACROLIMUS

CONTROINDICAZIONE


VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN

VIIa

Xa

IXa

XIa

XIIa


factor


Factor II

(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

times


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN


Apixaban (Eliquis)


N

N

NO

N O

NH2

O

O




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




ipertensione





bull etagrave 75-80




AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN





-ipertensione

-etagravege 75 anni

-diabete mellito


AIFA

ELIQUIS

25 mgx 2







- 14


NAO VERSUS WARFARIN




- 14


NAO VERSUS WARFARIN


NAO VERSUS WARFARIN

la profilassi antitrombotica nella fibrillazione atriale ... · interventi che non richiedono...

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