1

Nove spoznaje o antikoagulacijskoj terapiji

Prof. Mijo Bergovec,FESC, FACC

Medicinski fakultet Sveučilišta u Zagrebu

XXVIII STRUČNI SASTANAK UDRUŽENJA KARDIOLOGA BiH

Orašje 7. aprila 2012.

2

Xa faktor i trombin imaju središnju ulogu u proces u koagulacije1,2

“ Zahvaljujući jedinstvenoj ulozi trombina u koagulacijskoj kaskadi, njegova inhibicija je ključna u uspješnoj antikoagulacijskoj

farmakoterapiji.”2

Inaktivirani Xa

InaktivranitrombinProtrombin

Fibrinogen Fibrin

Trombin(IIa)

XaX

AntitrombinIntrinzični(kontakt)

Ekstrinzičnii(tkivni faktor)

AntitrombinHeparin kofaktor II

1. Di Nisio M et al. N Engl J Med 2005; 353:1028–1040. 2. Gurm HS et al. Am Heart J 2005; 149(Suppl):S43–S53. 3. van Ryn J et al. Abstract accepted. Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Atlanta, GA, USA. May 2008.

3

In 1951 the failed attempted suicide of a navy In 1951 the failed attempted suicide of a navy recruit who had taken a large dose of rat poison recruit who had taken a large dose of rat poison led clinicians to discard dicumarol in favor of led clinicians to discard dicumarol in favor of warfarin.warfarin.

The first clinical study with warfarinThe first clinical study with warfarin was reported in 1955. In the same year, President was reported in 1955. In the same year, President Eisenhower was treated with warfarin following a Eisenhower was treated with warfarin following a heart attackheart attack

WarfarinWarfarin

Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdfScully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf

• Warfarin was launched as the ideal rat poison Warfarin was launched as the ideal rat poison in 1948. Although it was thought at first to be in 1948. Although it was thought at first to be too toxic for human usetoo toxic for human use

4

Warfarin vs. no Treatment or PlaceboWarfarin vs. no Treatment or Placebo

Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005

5

Therapeuticrange

1International normalized ratio

Odds

rati

o

2

15

8

10

5

01

3 4 5 6 7

20

5

ANTAGONISTI VITAMINA K IMAJU UZAK TERAPIJSKI PROZOR

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354& Eur Heart J 2006;27:1979–2030

Stroke

Intracranial bleed

VKAs = vitamin K antagonists

Gra

ph

rep

rod

uce

d w

ith

perm

issi

on

: ©

20

10

Am

eri

can

Colle

ge o

f C

hest

Ph

ysi

cian

s

6

Major Hemorrhage in First Yearof Warfarin Therapy

Hylek EM, et al. Circulation. 2007;115:2689-2696.

9 intracranial bleeds3 fatal8/9 age > 75

0 100 200 300 Days on Warfarin

Age > 80Age < 80

Pre

vale

nc

e o

f M

ajo

r H

em

orr

ha

ge

0.00

0.02

0.04

0.06

0.08

0.10

7

Intracerebralno krvarenje: najopasnija komplikacija antitrombotske terapije

>10% of intracerebral haemorrhages occur in patients on antithrombotic therapy

Intracerebral haemorrhages during anticoagulation can belife-threatening

Compared with placebo, antithrombotic therapy increases the riskof intracerebral haemorrhage:

~40% with Aspirin

~200% with warfarin (INR 2.0–3.0; increases to 0.3–0.6%/year)

7Hart RG et al. Stroke 2005;36:1588–93INR = international normalized ratio

8

terapija heparinom prekid th

24 h

4-5 dana

Varfarin(STAR 50 GODINA) INR 2.0

5-10 mg

oralni antikoagulans Haemostasis 1998

9

ZAŠTO SU POTREBNEPROMJENE ?

• NEZADOVOLJSTVO POSTOJEĆIM

• NOVA SAZNANJA

• ISKUSTVO

10

RADI TOGA POTREBNI SU NOVI LIJEKOVI

11

Key Steps in Coagulation Pathway

Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2

Intrinsic pathway Extrinsic pathway

1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.

Intrinsic pathway

1

50

Xa X

II

FibrinFibrinogen

Clot

Xa

Va

PL

Ca2+

IIa

VIIIa

Ca2+

PL

IXa

12

II a

13

New anticoagulant therapy

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150EdoxabanBetrixabanTAK 442

Dabigatran

ORAL PARENTERAL

DX-9065a

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates, J Thromb Haemost 2007

TTP889

1414 14

Search for NewAnti-Coagulants

Intrinsic Limb

Contact activation

Tissue factor released by damaged cells

X Xa

Thrombin

Fibrinogen Fibrin Cross-linked fibrin

XIII

XIIIa

VIIVIIa

Va V

Prothrombin (II)

Fibrin Degradation

Extrinsic Limb

FXa Inhibitors X

DTIsX

Edoxaban

Rivaroxaban

Apixaban

Edoxaban

Rivaroxaban

Apixaban

ENGAGE AF-TIMI 48

ROCKET

ARISTOTLE

ENGAGE AF-TIMI 48

ROCKET

ARISTOTLE

FXa InhibitorsFXa Inhibitors

Dabigatran RE-LY

Dabigatran RE-LY

DTIDTI

1515

CONFIDENTIAL 15

New Anticoagulants:Summary of Profile

Name Rivaroxaban Apixaban Dabigatran Edoxaban

Company Bayer/J&J BMS/Pfizer Boehringer Daiichi Sankyo

Time to Cmax 2-3 h 3 h 2 h 2 h

CYP Metabolism 32%3 15%10 none < 4%

Bioavailability > 40%2 43 – 46%10 4-5%12 > 45%

Transporters P-gp/BCRP3 P-gp P-gp12 P-gp

Protein binding 92-95%3,4 87%9 34-35%12 54%

Half life 5-9 h1,2 9-15 h6 14-17 h12 8-10 h

Renal Elimination

Total 66%Unchanged: 36%3,5

Total: 25 - 29%Unchanged:24%10

Total: 85%Majority unchanged12

Total: 35%Unchanged: 24%

Linear PK no yes unknown yes

1Kubitza D et al. Eur J Clin Pharmacol. 2005;61:873-880. 2Kubitza D et al. Clin Pharmacol Therap. 2005;78:412-421. 3FDA Briefing material. Available from URL: http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4417b1-01-FDA.pdf. 4Xarelto. Summary of Product Characteristics - EU. 2008. 5Weinz C et al. Drug Metab Dispos. 2009;37:1056-64. 6Frost C et al. J ThrombHemostas. 2007;5:suppl 2:P-M-664. 7Frost C et al. J Thromb Hemostas. 2007;5:suppl 2: P-M-665. 8Frost C et al. J ClinPharmacol. 2008;48:Abstract 142. 9He K et al. Blood. 2006;108: Abstract 910. 10Raghavan et al. Drug Metab Dispos. 200911

Gross & Weitz, CPT, 2009 12 CHMP Pradaxa Review15

16

Antikoagulacijsko liječenje bez određivanja INR

APIXABAN

DABIGRATRAN

EDOXABAN

RIVAROXABAN

17

Apixaban

Oral, direct, selective factor Xa inhibitor

Produces concentration-dependent anticoagulation

No formation of reactive intermediates

No organ toxicity or LFT abnormalities in chronic toxicology studies

Low likelihood of drug interactions or QTc prolongation

Good oral bioavailability

No food effect

Balanced elimination (~25% renal)

Half-life ~12 hrs

He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

Apixaban :Phase II Apropos – orthopaedic surgery

Botticelli – treatment

Adapt – advanced cancer

Appraise 1 – ACS

Apixaban : Phase III

Advance 1,2,3 – orthopaedic surgery

Adopt – medically ill

Aristotle -atrial fibrillation

Appraise 2 - ACS

20

Dabigatran for prevention of VTE after major orthopaedic surgery: results

Enoxaparin Dabigatran (150 mg)

Dabigatran (220 mg)

DVT, PE and all-cause mortality (%)

RE-NOVATE 6.7 8.6 p<0.0001*

6.0p<0.0001*

RE-MOBILIZE 25.3 33.7p=0.0009†

31.1p=0.02†

RE-MODEL 37.7 40.5p=0.0005*

36.4p=0.0345*

Major bleeding (%)

RE-NOVATE 1.6 1.3 2.0

RE-MOBILIZE 1.4 0.6 0.6

RE-MODEL 1.3 1.3 1.5

*Non-inferior to enoxaparin; †inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

21

R E L Y ®: Randomised Evaluation of Long term anticoagulant therapy

18,113 2 randomiziranih bolesnika kroz godine12 / 2005 – 03 / 2009964 centra u 44 zemlje

: Primarni cilj utvrditi jednaku djelotvornost dabigatran eteksilata u odnosu na warfarin

Rezultati su predstavljeni prvi puta na Kongresu Europskog društva kardiologa te objavljeni online u New England Journal of Medicine

- – RE LY opće informacije

22

- – RE LY dizajn studije

Atrijska fibrilacija sa ≥ 1 rizičnim faktorom Odsutnost kontraindikacija

R

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran eteksilat 110 mg (2 )x dnevno

N=6000

Dabigatran eteksilat 150 mg (2 )x dnevno

N=6000

23

- – RE LY rezultati studije

Dabigatran 150 mg vs. warfarin Statistički značajno smanjenje moždanih/sistemskih embolija

Statistički značajno smanjenje hemoragijskih moždanih udara

Statistički značajno smanjenje krvožilnih uzroka smrti

Usporediva učestalost velikih krvarenja

Značajno smanjenje ukupnog broja krvarenja, po život opasnih krvarenja i intrakranijalnog krvarenja

Dabigatran 110 mg v .s warfarin Usporediva učestalost moždanih/sistemskih embolija

Statistički značajno smanjenje hemoragijskih moždanih udara

Statistički značajno smanjenje velikih krvarenja

Značajno smanjenje ukupnog broja krvarenja, po život opasnih krvarenja i intrakranijalnog krvarenja

24

- – RE LY zaključci

U usporedbi s bolesnicima koji su dobro kontroliranim varfarinom, dabigatran eteksilat je pokazao:

Značajno smanjenje rizika od moždanog udara i sistemske embolije – uključujući hemoragijske moždane udare (150 – mg34%)Značajno manje krvarenja – uključujući po život opasno i

intrakranijsko krvarenje (110 – 21%)mgZnačajno smanjenje svih uzroka smrtnosti

“ ... dabigatran eteksilat u dozi od 150mg dva puta dnevno može spriječiti oko 3.000 moždanih udara

dnevno širom svijeta u usporedbi s dobro kontroliranim varfarinom. “

25

Rivaroxaban: oral direct Factor Xa inhibitor

Predictable pharmacology

High bioavailability

Low risk of drug–drug interactions

Fixed dose

No requirement for monitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

26

RIVAROXABAN Clinical programme overview: 50,000 patients to be enrolled

VTE prevention in hospitalized medically ill patients

Secondary prevention of acute coronary syndromes

Japanese Phase III study

Stroke prevention in atrial fibrillation

EINSTEIN-DVT

EINSTEIN-PE

EINSTEIN-EXT

ODIXa-DVT

EINSTEIN-DVT

VTE treatment

RECORD1

RECORD2

RECORD3

RECORD4

ODIXa-HIP1

ODIXa-HIP2

ODIXa-KNEE

ODIXa-OD-HIP

VTE prevention after major orthopaedic surgery

Phase III Phase II

>42,000~8,000

Oral rivaroxaban compared with subcutaneous enoxaparin for extended

thromboprophylaxis after total hip arthroplasty

28

RECORD1: summaryIn

cide

nce

(%)

Total VTE

Major bleeding

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

0

1

2

3

4

5

0.5% 0.3% 0.1% 0.3%

Symptomatic VTE

RRR 70%

2.0% 0.2%

Major VTE

RRR 88%

1.1%3.7%

Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis

with low molecular weight heparin after total hip arthroplasty

30

RECORD2: summary

Total VTE

Major bleeding

Major VTE

Inci

denc

e (%

)

0

2

4

6

10

8

9.3%

RRR 78.9%

2.0% 5.1% 0.1% 0.1%0.6%

RRR 87.8%RRR 80.1%

1.2% 0.2%

Symptomatic VTE

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery

32

RECORD3: summary

Total VTE

Major bleeding

20

Inci

den

ce (

%)

0

Major VTE

5

10

15

NS

RRR 49%

RRR 62%

Symptomatic VTE

Rivaroxaban 10 mg od

Enoxaparin 40 mg od

RRR 65%

0.5% 0.6%18.9% 9.6% 2.6% 1.0% 2.0% 0.7%

33

Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients

Alexander T Cohen

On behalf of the MAGELLAN Steering Committee and Investigators

3434

Patients ≥40 years hospitalized for acute medical illness with decreased level of mobility

Oral rivaroxaban 10 mg od 35±4 days

s.c. enoxaparin40 mg od 10±4 days

Day 35(31–39)

Oral placebo 35±4 days

Follow-up period

to Day 90

s.c. placebo 10±4 days

Ultrasonography on day 10±4

Ultrasonography on day 35±4

Primary efficacy outcome (non-inferiority)

Primary efficacy outcome (superiority)

Day 10(6–14)

8,101 patients randomized

MAGELLAN: clinical trial design

R

Day 90(83–97)

Cohen et al, 2011

3535

Primary efficacy outcome: Day 10*

* PP population, events up to Day 10 + 5 days; ‡includes cases where PE cannot be ruled out

Rivaroxaban (n=2,939)

Enoxaparin(n=2,993)

n % n %Primary efficacy outcome 78 2.7 82 2.7

Asymptomatic proximal DVT 71 2.4 71 2.4Symptomatic lower extremity DVT 7 0.2 6 0.2

Symptomatic non-fatal PE 6 0.2 2 <0.1 VTE-related death‡ 3 0.1 6 0.2

0.713 1.3340.968

Relative risk ratio

Superior Non-inferior

Inferior

p=0.0025 for non-inferiority (one-sided)

1.00 0 1.50

3636

Primary efficacy outcome: Day 35*

*mITT population, events up to Day 35 + 6 days; †4 confirmed fatal PEs

Rivaroxaban (n=2,967)

Enoxaparin/placebo(n=3,057)

n % n %Primary efficacy outcome 131 4.4 175 5.7

Asymptomatic proximal DVT 103 3.5 133 4.4Symptomatic lower extremity DVT 13 0.4 15 0.5 Symptomatic non-fatal PE 10 0.3 14 0.5 VTE-related death† 19 0.6 30 1.0

1.00 0

0.618 0.9620.771

Relative risk ratio

p=0.0211 for superiority (two-sided)

ARR 1.3%, RRR 22.9%

Superior Non-inferior

Inferior

3737

Summary

MAGELLAN met its primary efficacy endpoints Day 10: rivaroxaban was non-inferior to enoxaparin in reducing

the risk of VTE

Day 35: extended thromboprophylaxis rivaroxaban was superior to enoxaparin followed by placebo in reducing the risk of VTE

Overall bleeding rates were low, but significantly higher in the rivaroxaban arm across the entire study period

Rates of other adverse events, including liver and cardiovascular events, were similar in both arms

38

Rivaroxaban-Clinical Studies

- VTE Treatnent

- Atrial Fibrillation

ACS treatment

39

Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB

on behalf of the ROCKET AF Investigators

Rivaroxaban Once-daily oral direct factor Xa inhibition Compared

with vitamin K antagonism for prevention of stroke and Embolism

Trial in Atrial Fibrillation

40

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizeDouble Blind / Double Dummy

(n ~ 14,000)

Monthly MonitoringAdherence to standard of care guidelines

Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus

At least 2 or 3 required*

41

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate

1.71 2.16

42

Summary ROCKET AF

Efficacy:

Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism.

Rivaroxaban was superior to warfarin while patients were taking study drug.

By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.

Safety:

Similar rates of bleeding and adverse events.

Less ICH and fatal bleeding with rivaroxaban.

Conclusion:

Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

4343

Steering and Investigator Meeting Orlando, Florida

November 15, 2009

The Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation

ENGAGE AF-TIMI 48

EDOXABAN

44

DA LI SE MEĐU OVIM LIJEKOVIMA NALAZI

IDEALAN ANTIKOAGULACIJSKI LIJEK ?

II a

45

Najveći problem inhibitora Xa faktora i oralnih antitrombina:

NE POSTOJI ANTIDOT

potreban u slučaju komplikacija krvarenja!