UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA

B. CosmiU.O. di Angiologia e Malattie della

Coagulazione“Marino Golinelli”

Policlinico S. Orsola-MalpighiBologna

Evolution of Venous Thromboembolism Prophylaxis

•1940s Early mobilization

•1940s Heparin

•1950s Warfarin

•1960s Dextrans

•1970s Low-dose heparin (LDH)

•1980s Low Molecular Weight Heparins (LMWH)

•1990s Parenteral direct thrombin inhibitor (DTI)

•(hirudin)

•2002 Fondaparinux (Pentasaccharide)

•2008 Oral direct thrombin inhibitors

•???? Oral Factor Xa Inhibitors

• Profilassi del TEV nei paz. chirurgici con i nuovi farmaci antitrombotici

• Profilassi meccanica

• Profilassi del TEV nel paz. medico

Obiettivi nello sviluppo di nuovi anticoagulanti

• effetto dose risposta prevedibile

• assenza interazioni con cibo e farmaci

• possibilità di somministrazione a dosi fisse senza monitoraggio di laboratorio

• semplificare terapia anticoagulante a lungo termine

Stadi della ricerca clinica con i nuovi anticoagulanti

• 1° stadio:

profilassi del tromboembolismo venoso in chirurgia ortopedica maggiore

• 2° stadio:

terapia del tromboembolismo venoso

• 3° stadio :

sindromi coronariche acute e fibrillazione atriale

I nuovi farmaci

Anticoagulanti:Indiretti (AT-mediati) Fondaparinux

IdraparinuxDiretti (anti IIa) Dabigatran

(anti Xa) RivaroxabanApixaban

PENTASACCHARIDESArixtra (fondaparinux) idraparinux (SanOrg34006)

O

C O O -

O M e

O MeO

O

OS O 3-

OS O 3-

OS O 3-O M e

OC O O -

O M e

O M e

O

OS O 3-

OS O 3-

OS O 3-

OO

O

O

OS O 3-

M eO

O M e

O M e

9 N a+

Arixtra®

SanOrg34006

• T1/2 suitable to treat o/week instead of o/d• More activity per mg administered

O

HO

OH

NHSO3Na

OSO3Na

O

COONa

OH

OH

O

OSO3Na

NHSO3Na

OSO3Na

O

OSO3Na

COONaOH

O

OH

NHSO3Na

OSO3Na

OMeOO

OO

10 Na+

Fondaparinux :The first of a new class of synthetic

selective inhibitors of factor Xa

• Five saccharide units

• Synthetic

• Highly selective for AT3

• Factor Xa inhibition

• No binding with plasma proteins

• No effect on platelet function

• No thrombocytopenia

Meccanismo d’azione del Pentasaccaride

Fondaparinux

• Molecular weight 1500 d• Rapid onset of action• Plasma half life 15-20 h • 1 administration/day• Renal elimination• No monitoring• No specific antidote available, but the

effects are reversed by F. VIIa

EFFICACIA DEL FONDAPARINUX NELLA PROFILASSI DELTROMBOEMBOLISMO VENOSO IN CHIRURGIA ORTOPEDICA

From first injection to day 11 - All treated patients

Patients WithFondaparinux

(N=3616)Enoxaparin NNH

(N=3621)

SAE 196 (5.4 %) 164 (4.5 %) 111

Fatal bleeding 0 1

Non-fatal bleeding incritical organ

0 1

Bleeding leading to re-operation

12 (0.33 %)

Bleeding withtransfusion ≥ 2 unitsand/or hemoglobindecrease ≥ 2g/dL

84 (2.3%) 52 (1.4 %) 111

Other Bleeding109 (3.01%) 99 (2.73%) 357

Serious adverse events and bleeding

9 (0.25 %) 125

Factor IIFactor II(Prothrombin)(Prothrombin)

FibrinogenFibrinogen

XII VII

X

XIIX

Direct Thrombin Inhibition

XIIaXIIa

ThrombinThrombin

VIIaVIIaXIaXIa

FibrinFibrin

IXaIXa

XaXa

Tissue Tissue FactorFactor

LepirudinLepirudinBivalirudinBivalirudinArgatrobanArgatroban

Ximelagatran (oral)Ximelagatran (oral) Dabigatran (oral)Dabigatran (oral)

Struttura del Dabigatran etexilateInibitore diretto della trombina, orale

Ingelheim/Germany, 27 March 2008

Boehringer Ingelheim today announced that the European Commission has granted marketing authorisation of the novel, oral direct thrombin inhibitor,

Pradaxa® (dabigatran etexilate) in all 27 EU member states.

It is anticipated that Pradaxa® will be launched in Germany and the United Kingdom in the coming weeks

Dabigatran etexilate versus enoxaparin for prevention ofvenous thromboembolism after total hip replacement:

a randomised, double-blind, non-inferiority trialBengt I Eriksson BI et al RE-NOVATE

Lancet 2007; 370: 949–56

• 3494 patients

• total-hip replacement were

• Randomized

• to one of two doses of dabigatran etexilate (220 mg or 150 mg once daily) or enoxaparin (40 mg sc once daily), given for one month.

• The primary efficacy outcome was the composite of total VTE (venographic or symptomatic) and death from all causes during treatment.

RE-NOVATE: Major results

End point Dabigatran 150 mg (%)

Dabigatran 220 mg (%)

Enoxaparin 40 mg (%)

Total VTE and death from all causes

8.6 6.0 6.7

Major bleeding

1.3 2.0 1.6

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous

thromboembolism after total knee replacement: the RE-MODEL randomized trial.

Eriksson BI et al. J Thromb Haemost. 2007 Nov;5(11):2175-7.

2076 patients dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Follow-up for 3 months

The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous

thromboembolism after total knee replacement: the RE-MODEL randomized trial.

Eriksson BI et al. J Thromb Haemost. 2007 Nov;5(11):2175-7.

End point Dabigatran 150 mg (%)

Dabigatran 220 mg (%)

Enoxaparin 40 mg (%)

Total VTE, and all-cause mortality (primary end point)

Major

Bleeding

40.5%

1.3%

36.4%

1.5%

37.7%

1.3%

“Dabigatran etexilate”

• Dose di

• 110 mg ( ½ cp) 1 - 4 h dopo chirurgia

• 220 mg/die

• 10 gg dopo protesi ginocchio

• 28-35 gg dopo protesi anca

• Se età > 75 aa o IRC moderata

• 150 mg

“Dabigatran etexilate”

• Studi in fase III (non-inferiorità verso TAO)

Re-COVER: TEV acuta, 5 gg LMWH poi random. (doppio cieco) a Dab. (150 mg x 2) o TAO x 6 mesi

Re-MEDY: prev. secondaria; dopo 3-6 m. di TAO, random., cieco; Dab. (150 mg x 2) o TAO x 18 mesi

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibition

Tissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixabanDU-176b

YM150LY517717

PRT-054021

×

Apixaban• A highly potent, oral, direct FXa inhibitor (Ki 0.08 nM)

– Follow-up to razaxaban (development halted due to bleeding concerns)

• Phase II study for VTE prevention after TKR: completed

– Double-blind; dose-ranging; three od and three bid apixaban doses; comparator enoxaparin and warfarin; target enrolment n=1202

• Phase II pilot study for VTE prevention in patients with advanced metastatic cancer: ongoing

Struttura del Rivaroxaban

A Once-Daily, Oral, Direct Factor Xa Inhibitor,Rivaroxaban (BAY 59-7939), for

Thromboprophylaxis After Total Hip ReplacementEriksson et al. Circulation. 2006;114:2374-2381

Rivaroxaban bid (THR/TKR pooled):

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

Efficacy: p=0.39

Safety: p<0.0001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40

DVT, PE, and all-cause mortalityMajor bleeding

Est

imat

ed in

cid

ence

rat

e* (

%)

Rivaroxaban (mg total daily dose)5

Rivaroxaban

• RECORD – REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE

• Rivaroxaban 10 mg od will be compared with enoxaparin in over 10,000 patients worldwide– RECORD 1: THR, 5 weeks therapy– RECORD 2: THR, 5 weeks vs 10–14 days enoxaparin– RECORD 3: TKR, 10–14 days therapy– RECORD 4: TKR, 10–14 days therapy

Rivaroxaban

Rivaroxaban

Rivaroxaban

RECORD 3: Major safety end points

Lassen M et al. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.

Outcome Rivaroxaban (%)

Enoxaparin (%)

p

Major bleed 0.6 0.5 NS

Any bleed 4.9 4.8 NS

Nuovi anticoagulanti: potenziali vantaggi

• Fondapar. Idrapar.rapida azione; no controllono HIT1 somm./die o 1/sett

• Altri anti-Xa o anti-IIaorali; no controllo rapida azione

Nuovi anticoagulanti: potenziali svantaggi

• No antidoti (eccetto SSR126517E)

• Difficile monitorare l’effetto (se emorragia)

• Non escludibili altri negativi effetti

• Breve tempo di emivita (vantaggi/svantaggi)

• Difficile controllare la compliance

• Costi

PROFILASSI MECCANICA

• Calze elastiche :

• prevenzione distensione venosa con riduzione stasi venosa nel polpaccio con miglioramento ritorno venoso

• CPI (compressione pneumatica intermittente; arto o solo piede) con manicotti gonfiabil ad intermittenza: solo paz. ospedalizzati

• Stimolano e mantengono flusso pulsatile nel circolo venoso profondo

• CPI aumentano velocità flusso in v. femorale comune dal 50 al 250% dei valori a riposo

ELASTIC COMPRESSION STOCKINGS FOR PREVENTION OF DEEP VEIN THROMBOSIS

(Amaragiri SV, Lees TA, Cochrane Review, Cochrane Library Issue 3, 2002)

• Nove studi clinici randomizzati ( sia paz. Chirurgici che medici)

CE da sole vs. controllo: TVP 13% vs. 27% RRR : 66%

• Sette studi clinici randomizzati (paz. Chirurgici)CE con altro metodo farmacologico:TVP 2% vs. 15% RRR: 76%

• Nessuno studio ha incluso paz a basso rischio

• In associazione alla profilassi farmacologica se:- sindrome varicosa- insufficienza venosa cronica- alto rischio

Intermittent pneumatic compression and deep vein thrombosis prevention.

A meta-analysis in postoperative patients.Urbankova et al. T& H, 2005; 2005 Dec;94(6):1181-5

RCT of IPC versus no prophylaxis,

2,270 patients in 15 eligible studies:

1,125 and 1,145 in the IPC and no prophylaxis group, respectively.

The included studies formed a total of 16 treatment groups and were conducted in orthopedic (5), general surgical (4),oncologic (3), neurosurgical (3) and urologic (1) patient populations.

In comparison to no prophylaxis, IPC devices reduced the risk of DVT by 60%(relative risk 0.40, 95% CI 0.29 - 0.56; p < 0.001).

• Foot pump livelli di compressione maggiori per aumentare flusso in v. femorale, più efficaci se utilizzate in combinazione con CE vs. CE sole

• Pochi confronti tra i vari apparecchi

• Non chiaro momento inizio e durata ottimali

• Compliance del paz.

• CPI > efficacia di CE in pz. A alto rischio in combinazione con anticoagulanti o se anticoagulanti controindicati

Hull RD et al. EXCLAIM 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.

Efficacy outcomes during extended-duration enoxaparin

therapy in high-risk nonsurgical patients End points Outcome,

extended prophylaxis, n=2052 (%)

Outcome, placebo, n=2062 (%)

RR reduction (%)

p

VTE events* 2.8 4.9 44 0.0011

Symptomatic VTE

0.3 1.1 73 0.0044

Asymptomatic VTE

2.5 3.7 34 0.0319

*Primary efficacy end point: composite of asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. Asymptomatic DVT was defined by compression ultrasonography, which was routinely performed. VTE=venous thromboembolismRR=relative risk

Safety outcomes during extended-duration randomized

therapy in high-risk nonsurgical patients

Hull RD et al. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.

End point Extended enoxaparin prophylaxis, n=2052 (%)

Placebo, n=2062 (%)

p

Total bleeding events*

5.7 3.8 0.007

Major bleeding events

0.6 0.15 0.019

Minor bleeding events

5.2 3.7 0.024

*Primary safety end point