Intravenous

Lepirudin

§   Half life 1 hour

§   Renal excretion

§   Dosed to aim APTT .15-2.0

Argatroban

§   Half life 45 min

§   Hepatic excretion

§   Treatment of choice in patients with HIT and renal failure

Bivalirudin

§        REPLACE 2 (2004)

§        Following angioplasty less bleeding and thrombocytopenia with similar rates of thrombosis compared with heparin

Oral

Ximelagatran

§   Orally absorbed

§   No need to measure levels

§   Multiple trials involving around 10,000 patients:

1.      Post TKR ximelagatran v warfarin – significant reduction in VTE and death

2.      Acute DVT ximelagatran v enoxaparin followed by warfarin – significant reduction in bleeding (1.3 v 2.2%) and mortality (2.3 v 3.4%)

3.      Prevention of stroke in AF (v warfarin) – equivalence

§   However – hepatotoxicity in 5% (rise in transaminases) and at least one death from hepatic failure

§   FDA refused approval in 2004 – Astrazeneca stopped marketing in 2006

Dabigatran

§        Oral thrombin inhibitor most advanced in clinical development

§        Plasma half life 14-17h

§        Absorption reduced by 30% by PPIs

§        Not dependant on P450, therefore drug interactions generally much less

§        Renal excretion

RE-NOVATE trial (Lancet 2007 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61445-7/fulltext)

§        Just under 3500 patients - post hip replacement - prophylaxis compared to enoxaparin

§        Similar efficacy (6%) in both arms and no significant difference in bleeding

§        Same rates of hepatitis

§        Approved April 2008 by the European Medicines Agency for VTE prophylaxis post THR and TKR.

RE-LY (NEJM 2009  http://content.nejm.org/cgi/content/abstract/361/12/1139)

§        Compared warfarin with 2 doses of dabigatran (110mg and 150mg twice daily) in 18,000 patients followed up for 2 years

§        Warfarin therapy was unblended whilst the two doses of dabigatran were blinded

RE-COVER (NEJM 2009 http://nejm.highwire.org/cgi/content/abstract/361/24/2342)

§        Compared warfarin with dabigatran 150mg twice daily in 1500 patients with acute venous thromboembolism

§        Patients were initially treated with parenteral anticoagulation in both treatment arms (ximelagatran had previously been shown to have a higher early rate of recurrent VTE compared to warfarin and enoxaparin).

§        Dabigatran non inferiror to warfarin in terms of the primary outcome (recurrence of VTE at 6 months)

§        3% of patients on dabigatran had dyspepsia