Should a patient with RHD and recurrent strokes on apixaban and aspirin be switched to warfarin with clexane overlap?

Anticoagulation Management for RHD with Recurrent Stroke on Apixaban

Yes, switch from apixaban to warfarin with enoxaparin (clexane) bridging for this patient with rheumatic heart disease (RHD) and recurrent strokes despite current anticoagulation. 1

Primary Recommendation: Switch to Warfarin

For patients with ischemic stroke or TIA who have rheumatic mitral valve disease, whether or not atrial fibrillation is present, long-term warfarin therapy with a target INR of 2.5 (range 2.0-3.0) is the recommended anticoagulation strategy. 1

• Direct oral anticoagulants (DOACs) including apixaban are not recommended for patients with valvular heart disease, specifically rheumatic mitral valve disease 1
• The 2021 AHA/ASA guidelines explicitly state that warfarin is recommended for valvular AF (moderate to severe mitral stenosis or mechanical heart valves), not DOACs 1
• Apixaban's FDA approval and clinical trials (ARISTOTLE, AVERROES) specifically excluded patients with valvular heart disease, making its use in RHD off-label and unsupported by evidence 2

Bridging Protocol with Enoxaparin

When switching from apixaban to warfarin, use enoxaparin bridging to maintain therapeutic anticoagulation during the transition period. 2

Step-by-step transition protocol:

1. Stop apixaban and begin enoxaparin at therapeutic doses (typically 1 mg/kg subcutaneously twice daily) at the time the next apixaban dose would have been due 2

2. Start warfarin concurrently with enoxaparin on day 1 of the transition 2

3. Continue enoxaparin until INR reaches therapeutic range (≥2.0) on two consecutive measurements at least 24 hours apart 3

4. Monitor INR at least every 2-3 days initially during the transition period 3

5. Discontinue enoxaparin once therapeutic INR is achieved and stable 2

Target INR and Monitoring

Maintain INR target of 2.5 (range 2.0-3.0) for patients with rheumatic mitral valve disease. 1, 3

• Check INR at least weekly during warfarin initiation 3
• Once stable (INR consistently in therapeutic range), reduce monitoring to at least monthly 3
• Aim for time in therapeutic range (TTR) >65% for optimal stroke prevention 3

Management of Recurrent Stroke on Warfarin

If the patient experiences recurrent embolism while receiving warfarin at therapeutic INR, adding low-dose aspirin (81 mg/d) is reasonable. 1, 3

• This represents intensification of therapy for breakthrough events 1
• However, antiplatelet agents should not be routinely added to warfarin initially due to increased bleeding risk (Class III recommendation) 1
• Only add aspirin if recurrent stroke occurs despite documented therapeutic anticoagulation 1, 3

Critical Pitfalls to Avoid

Do not continue apixaban in this patient with RHD. The current regimen has already failed with recurrent stroke, and apixaban lacks evidence for efficacy in rheumatic valvular disease 1, 2

Do not switch to another DOAC. Recent evidence shows that switching from one DOAC to another DOAC is associated with increased risk of recurrent ischemic stroke (aHR 1.62,95% CI 1.25-2.11, p<0.001) compared to continuing the same DOAC 4. More importantly, no DOAC is appropriate for rheumatic valvular disease 1

Do not switch to warfarin without bridging anticoagulation. Apixaban has a half-life of approximately 12 hours, and warfarin takes 5-7 days to achieve therapeutic effect 2. This gap leaves the patient vulnerable to recurrent embolic events during the highest-risk period 2

Do not delay anticoagulation for more than 3 days after the acute stroke. While older data suggested delaying anticoagulation for 3 days after cerebral embolism due to hemorrhagic transformation risk 5, current guidelines support earlier initiation with careful monitoring, particularly in patients with recurrent events 1

Discontinue Aspirin (Ecospirin)

Stop aspirin once warfarin is initiated. 1

• The combination of aspirin and warfarin significantly increases bleeding risk without additional benefit in RHD patients 1
• Aspirin should only be added back if recurrent embolism occurs despite therapeutic warfarin 1, 3

Why This Patient Failed Apixaban

The patient's recurrent strokes on apixaban likely reflect:

• Inappropriate drug selection: Apixaban is not indicated for rheumatic valvular disease 1, 2
• Inadequate anticoagulation intensity: RHD with mitral stenosis creates a hypercoagulable state that may require the more intensive anticoagulation achievable with warfarin 1
• Lack of evidence base: All DOAC trials excluded patients with significant valvular disease 2, 6