What is the best choice of antithrombotic therapy for stroke prevention in a patient with rheumatic heart disease, an enlarged Left Atrium (LA), and a history of recurrent ischemic strokes, without evidence of clot in the Left Atrium (LA) or Left Atrial Appendage (LAA)?

Warfarin with Aspirin for Recurrent Stroke Prevention in Rheumatic Heart Disease

For this patient with rheumatic heart disease, LA enlargement (4.2 cm), and recurrent ischemic strokes despite no visible clot, warfarin therapy with a target INR of 2.5 (range 2.0-3.0) should be initiated, and if strokes recur on therapeutic warfarin, aspirin 81 mg daily should be added to the warfarin regimen. 1

Primary Recommendation: Warfarin Anticoagulation

Long-term warfarin therapy is the cornerstone of treatment for patients with rheumatic mitral valve disease who have experienced systemic embolism, regardless of whether atrial fibrillation is present. 1 The American Heart Association/American Stroke Association provides a Class IIa recommendation (Level of Evidence C) for warfarin with a target INR of 2.5 (range 2.0-3.0) in this population. 1

Why Warfarin is Indicated Despite No Visible Clot

• The presence of previous systemic embolism (recurrent ischemic stroke) is itself an absolute indication for anticoagulation in rheumatic mitral valve disease, independent of whether a clot is currently visible. 1 The American College of Chest Physicians provides a Grade 1A recommendation for VKA therapy when rheumatic mitral valve disease is complicated by previous systemic embolism. 1

• LA enlargement ≥4.2 cm (42 mm) exceeds the threshold for anticoagulation. 1 The guidelines recommend VKA therapy for LA diameter ≥55 mm even without prior embolism (Grade 2C), but this patient has both LA enlargement AND recurrent strokes, making the indication even stronger. 1

• Recurrent embolism occurs in 30-65% of patients with rheumatic mitral valve disease who have a history of previous embolic events, with 60-65% of recurrences developing within the first year. 1 This extraordinarily high recurrence risk mandates aggressive anticoagulation.

Management of Recurrent Strokes on Warfarin

If this patient experiences another ischemic stroke while on therapeutic warfarin (INR 2.0-3.0), adding aspirin 81 mg daily is the recommended next step. 1, 2 The American Heart Association provides a Class IIa recommendation (Level of Evidence C) for adding aspirin in patients with rheumatic mitral valve disease who have recurrent embolism despite warfarin therapy. 1

Critical Caveat About Aspirin

Antiplatelet agents should NOT be routinely added to warfarin initially to avoid additional bleeding risk. 1, 3 Aspirin is reserved specifically for breakthrough events on therapeutic anticoagulation, not as first-line combination therapy. 1

Why NOT Direct Oral Anticoagulants (DOACs)

DOACs (apixaban, rivaroxaban, dabigatran, edoxaban) are contraindicated in this patient because rheumatic mitral valve disease is considered "valvular" atrial fibrillation. 1 The 2021 AHA/ASA guidelines explicitly state that DOACs should not be used in patients with moderate to severe mitral stenosis or mechanical heart valves. 1 While this patient's mean pressure gradient of 8 mmHg suggests mild stenosis, rheumatic heart disease itself represents valvular pathology that was excluded from all major DOAC trials. 1, 4, 5

Practical Implementation Algorithm

Step 1: Initiate Warfarin Monotherapy

• Target INR: 2.5 (range 2.0-3.0) 1, 3, 6
• Check INR at least weekly during initiation, then monthly once stable 2, 7, 3
• Aim for time in therapeutic range (TTR) >65% 2, 7, 3

Step 2: Monitor for Recurrent Events

• If recurrent stroke occurs while INR is subtherapeutic (<2.0), optimize warfarin dosing first 2, 3
• Subtherapeutic INR significantly increases thromboembolism risk 2, 3

Step 3: Add Aspirin Only for Breakthrough Events

• If recurrent stroke occurs with documented therapeutic INR (2.0-3.0), add aspirin 81 mg daily 1, 2
• Continue warfarin at same target INR (2.0-3.0) 1
• Do NOT increase INR target to 3.0-3.5 in rheumatic heart disease 1, 3 (This higher target is reserved for mechanical prosthetic valves, not native valve disease)

Common Pitfalls to Avoid

Do not delay anticoagulation waiting for clot resolution on imaging. 1 The absence of visible clot does not negate the indication for anticoagulation when previous systemic embolism has occurred. 1

Do not use antiplatelet monotherapy (aspirin or clopidogrel alone). 1 Observational studies demonstrate that anticoagulation is far superior to antiplatelet therapy in reducing recurrent embolism in rheumatic mitral valve disease. 1

Do not target INR >3.0 in native valve disease. 1, 3 The higher INR target (2.5-3.5) is only for mechanical prosthetic valves or when left atrial thrombus is present and requires dissolution. 1

Monitor for bleeding complications, especially intracranial hemorrhage, which increases significantly when INR exceeds 3.5. 2, 7, 3 The risk of bleeding becomes clinically unacceptable once INR exceeds 5.0. 2, 7