Antithrombotic Therapy for Stroke with Unknown Etiology
For an older adult with a stroke 10 years ago of unknown etiology, long-term antiplatelet monotherapy with clopidogrel 75 mg daily or aspirin 75-100 mg daily is recommended, with clopidogrel being the preferred choice. 1
Primary Recommendation: Antiplatelet Monotherapy
When stroke etiology remains unknown after thorough evaluation (cryptogenic stroke), the evidence strongly supports antiplatelet therapy over anticoagulation for long-term secondary prevention:
Antiplatelet therapy is recommended over oral anticoagulation for noncardioembolic ischemic stroke, which includes cryptogenic strokes where no definitive cardiac source has been identified 1
Preferred antiplatelet options include:
Clopidogrel is suggested over aspirin alone for superior stroke prevention with similar bleeding risk 1, 2
Why Not Anticoagulation?
The landmark WARSS trial definitively answered this question for cryptogenic stroke:
Warfarin showed no superiority over aspirin in patients with noncardioembolic stroke, including those with unknown etiology 1, 3
Antiplatelet therapy is recommended over oral anticoagulants (Grade 1B evidence) for noncardioembolic ischemic stroke 1
The bleeding risks of anticoagulation are not justified without a clear cardioembolic source such as atrial fibrillation 1
Critical Exclusions to Rule Out
Before accepting "unknown etiology," ensure the following have been adequately evaluated, as they would change management:
Atrial Fibrillation (Most Important)
If atrial fibrillation is discovered (including paroxysmal AF), oral anticoagulation with a direct oral anticoagulant (apixaban, dabigatran, edoxaban, or rivaroxaban) is strongly preferred over antiplatelet therapy 1
Extended cardiac monitoring may be warranted if not previously performed, as up to 30% of "cryptogenic" strokes are eventually found to have paroxysmal AF 1
Patent Foramen Ovale (PFO)
For patients aged 60 years or younger with PFO-attributed stroke, either antiplatelet or anticoagulant therapy is reasonable, though antiplatelet therapy is generally preferred unless there is evidence of venous thrombosis or hypercoagulable state 1
For patients over age 60 with incidental PFO, antiplatelet therapy alone is recommended as the PFO is likely incidental rather than causal 1
Other Cardiac Sources
Left ventricular thrombus or severe left ventricular dysfunction (ejection fraction <35%) may warrant anticoagulation, though the evidence is less robust 1
Mechanical heart valves or moderate-to-severe mitral stenosis require warfarin anticoagulation 1
Practical Implementation
For This Patient (10 Years Post-Stroke)
Since the stroke occurred 10 years ago, this is clearly about ongoing long-term secondary prevention:
Initiate or continue clopidogrel 75 mg daily as the preferred single antiplatelet agent 1, 2
Aspirin 75-100 mg daily is an acceptable alternative if clopidogrel is not tolerated or affordable 1
Do NOT use dual antiplatelet therapy (aspirin plus clopidogrel) for chronic secondary prevention, as the bleeding risk outweighs benefits beyond 21-90 days post-stroke 1, 4
Additional Risk Factor Management
Antiplatelet therapy alone is insufficient—aggressive risk factor modification is essential:
High-intensity statin therapy (atorvastatin or rosuvastatin) to reduce LDL-C by ≥50% 1
Blood pressure control with target <130/80 mmHg for most patients 1
Diabetes management with hemoglobin A1c target ≤7% 1
Lifestyle modifications including smoking cessation, regular physical activity, weight management, and Mediterranean-type diet 1
Common Pitfalls to Avoid
Do not empirically anticoagulate without a clear indication—the WARSS trial showed no benefit and increased bleeding risk 1, 3
Do not use long-term dual antiplatelet therapy (aspirin plus clopidogrel) for chronic secondary prevention—this increases bleeding without additional stroke prevention benefit beyond the first 21-90 days 1, 4
Do not assume the etiology is truly unknown without adequate cardiac monitoring and imaging—consider extended cardiac monitoring if not previously performed 1
Do not use aspirin doses >150 mg daily for long-term prevention, as higher doses increase bleeding without additional efficacy 1, 2