Approach to the newer anticoagulants Dr Melita Kenealy Consultant Haematologist
Pradaxa (dabigatran) STROKE OR SYSTEMIC EMBOLISM (SSE)• RE-LY trial Non-inferiority Superiority P value P value – >18,000 pts non valv Margin=1.46 Dabigatran 110 mg BID <0.001 0.30 vs. warfarin AF + RF cf warfarin Dabigatran 150 mg BID <0.001 <0.001 – Rate of stroke or sys vs. warfarin 0.50 0.75 1.00 1.25 1.50 Hazard ratio embolism (%/yr) Error bars = 95% CI; BID = twice daily. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876. • 1.54 (110mg), – similar major bleeding 1.11(150mg), 1.71(warfarin) • less ICH, less life threatening, more major GI bleed PFP stopped early due to bleeding concerns Criticisms – lack of stakeholder involvement
Xarelto (rivaroxaban)• ROCKET-AF (stroke and systemic embolism) – N=14,264 v warfarin – Noninf efficacy HR 0.79 (0.66-0.96) – Bleeding similar• EINSTEIN-DVT (acute sympto DVT) – N=3449 v clexane/warfarin 3-12mths – Noninferior efficacy HR 0.68 (0.44-1.04) – Similar major/sympt non-major bleeding rates 8% PFP about to be rolled out Have they learnt from others’mistakes??
PRADAXA (DABIGATRAN) XARELTO (RIVAROXABAN)ACTION Direct thrombin inhibitor Factor Xa inhibitorPK Peak 0.5-2h Peak 2-4h T1/2 12-17h Reduced bioavail fasting 85% renal excr T1/2 11-13h P-gp interactions Highly protein bound, predom renal 35% protein bound excretion, some metab CYP3A4, P-gp interactionsINDICATION Approved VTE proph (PBS) and Approved VTE proph (PBS), AF and nonvalv AF+RF treatment DVT/PEDOSE AF 150bd oral but reduce dose to AF 20mg/d (15mg CrCl30-50) 110bd if any other RF (age>75, DVT 15mgbd 3w then 20mg/d antiplt/NSAID CrCl 30-50) If CrCl 15-29ml/min 10mg/d CI if CrCl<30 VTE proph 10mg/d VTE proph 150-200mg/dMONITORING Not required BUT difficult. Not required but difficult APTT nonlinear, Rx x1.5-2.0 APTT, PT long but nonlinear TCT(sens,linear), Hemoclot Chromogenic antiXaPERIOP Mx CrCL>50 stop 2+ days *Withdraw 12-24hrs CrCl 30-50 stop 3-5d
Summary• New agents useful in subgroup of patients• No simple test to establish anticoagulant effect• Management of bleeding – Resuscitate, treat source, stop drug, call haematologist! – No effective means of reversal, but short t1/2