The document discusses two newer anticoagulants, Pradaxa (dabigatran) and Xarelto (rivaroxaban). It summarizes their mechanisms of action, indications, dosing, and monitoring. It notes that neither drug has a proven reversal agent. The summary emphasizes that these drugs are useful for certain patients but have no simple test to measure their effect. It advises that management of bleeding involves resuscitation, treating the source, stopping the drug, and contacting a hematologist, as the drugs cannot be readily reversed due to their short half-lives.

1. Approach to the newer
anticoagulants
Dr Melita Kenealy
Consultant Haematologist

2. 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

3. 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??

5. PRADAXA (DABIGATRAN) XARELTO (RIVAROXABAN)
ACTION Direct thrombin inhibitor Factor Xa inhibitor
PK 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 interactions
INDICATION Approved VTE proph (PBS) and Approved VTE proph (PBS), AF and
nonvalv AF+RF treatment DVT/PE
DOSE 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/d
MONITORING 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 antiXa
PERIOP Mx CrCL>50 stop 2+ days *Withdraw 12-24hrs
CrCl 30-50 stop 3-5d

6. Pradaxa peri-op

7. PRADAXA (DABIGATRAN) XARELTO (RIVAROXABAN)
REVERSAL None proven None proven
Stop drug Stop drug
Charcoal <2h Charcoal<8h
Dialysable Not dialysable
PTX reversed coag tests in healthy
volunteers
Can try:
Platelets Can try:
Antifibrinolytics Platelets
FFP Antifibrinolytics
Prothrombinex FFP
rFVIIa Prothrombinex
rFVIIa

8. Management of bleeding

9. 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