Approach to the newer anticoagulants

Dr Melita KenealyConsultant Haematologist

Pradaxa (dabigatran)

• RE-LY trial – >18,000 pts non valv

AF + RF cf warfarin– Rate of stroke or sys

embolism (%/yr) • 1.54 (110mg),

1.11(150mg), 1.71(warfarin)

– similar major bleeding • less ICH, less life

threatening, more major GI bleed

STROKE OR SYSTEMIC EMBOLISM (SSE)

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.

0.50 0.75 1.00 1.25 1.50

SuperiorityP value

Non-inferiorityP value

Hazard ratio

Dabigatran110 mg BIDvs. warfarin

<0.001 0.30

Mar

gin

=1.

46

<0.001Dabigatran150 mg BIDvs. warfarin

<0.001

PFP stopped early due to bleeding concernsCriticisms – 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 outHave they learnt from others’mistakes??

PRADAXA (DABIGATRAN) XARELTO (RIVAROXABAN)

ACTION Direct thrombin inhibitor Factor Xa inhibitor

PK Peak 0.5-2hT1/2 12-17h85% renal excrP-gp interactions35% protein bound

Peak 2-4hReduced bioavail fasting T1/2 11-13hHighly protein bound, predom renal excretion, some metabCYP3A4, P-gp interactions

INDICATION Approved VTE proph (PBS) and nonvalv AF+RF

Approved VTE proph (PBS), AF and treatment DVT/PE

DOSE AF 150bd oral but reduce dose to 110bd if any other RF (age>75, antiplt/NSAID CrCl 30-50) CI if CrCl<30VTE proph 150-200mg/d

AF 20mg/d (15mg CrCl30-50)DVT 15mgbd 3w then 20mg/dIf CrCl 15-29ml/min 10mg/dVTE proph 10mg/d

MONITORING Not required BUT difficult.APTT nonlinear, Rx x1.5-2.0TCT(sens,linear), Hemoclot

Not required but difficultAPTT, PT long but nonlinearChromogenic antiXa

PERIOP Mx CrCL>50 stop 2+ daysCrCl 30-50 stop 3-5d

*Withdraw 12-24hrs

Pradaxa peri-op

PRADAXA (DABIGATRAN) XARELTO (RIVAROXABAN)

REVERSAL None provenStop drug

Charcoal <2hDialysable

Can try:PlateletsAntifibrinolyticsFFPProthrombinexrFVIIa

None provenStop drug

Charcoal<8hNot dialysable

PTX reversed coag tests in healthy volunteers

Can try:PlateletsAntifibrinolyticsFFPProthrombinexrFVIIa

Management of bleeding

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