What is the recommended treatment for a patient with Embolic Stroke of Undetermined Source (ESUS)?

Treatment of Embolic Stroke of Undetermined Source (ESUS)

Antiplatelet therapy, not oral anticoagulation, is the recommended treatment for patients with ESUS who do not have documented atrial fibrillation. 1, 2

Primary Treatment Strategy

The European Society of Cardiology explicitly states that initiation of oral anticoagulation in ESUS patients without documented atrial fibrillation is not recommended (Class III recommendation) due to lack of efficacy in preventing ischemic stroke and thromboembolism. 1, 2 This represents the highest quality, most recent guideline evidence available and supersedes earlier hypotheses that anticoagulation might be beneficial. 3, 4

Acute Phase Antiplatelet Therapy (First 21-90 Days)

For patients with minor stroke (NIHSS ≤3) or high-risk TIA:

• Initiate dual antiplatelet therapy (DAPT) with aspirin 81 mg daily plus clopidogrel 75 mg daily within 12-24 hours of symptom onset 2
• Administer loading doses: aspirin 160-325 mg and clopidogrel 300-600 mg at initiation 2
• Continue DAPT for 21-90 days, then transition to single antiplatelet therapy 2

Alternative DAPT regimen:

• Aspirin 75-100 mg daily plus ticagrelor 90 mg twice daily within 24 hours 2
• Loading doses: aspirin 300-325 mg and ticagrelor 180 mg 2
• Continue for 30 days before transitioning to single antiplatelet therapy 2

Long-Term Antiplatelet Therapy (After 90 Days)

Select one of the following single antiplatelet agents for indefinite use: 2

• Aspirin 50-325 mg daily, OR
• Clopidogrel 75 mg daily, OR
• Aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily

Do not continue dual antiplatelet therapy beyond 90 days due to increased hemorrhage risk without additional benefit. 2

Critical Diagnostic Imperative: Prolonged Cardiac Monitoring

Prolonged cardiac monitoring for atrial fibrillation detection is mandatory in all ESUS patients (Class I recommendation). 1, 2 This is the single most important diagnostic intervention because:

• Atrial fibrillation is the underlying mechanism in approximately 30% of ESUS patients 1, 2
• Detection probability increases from 2% at 1 week to over 20% by 3 years with implantable cardiac monitoring 1, 2
• If atrial fibrillation is detected, the patient requires anticoagulation instead of antiplatelet therapy 1, 2

The longer the monitoring duration, the higher the detection rate, with factors associated with increased AF detection including: advanced age, left atrial enlargement, cortical stroke location, and increased atrial premature beats. 1

Exception: Left Ventricular Injury Subgroup

In patients with ESUS and documented left ventricular injury, anticoagulation may be considered as it was associated with lower rates of recurrent stroke in observational data (adjusted HR 0.35,95% CI 0.16-0.77). 4 However, this finding requires validation in randomized trials and represents a small subgroup with limited evidence.

Essential Adjunctive Management

Beyond antithrombotic therapy, aggressive risk factor modification is critical: 2

• Blood pressure control: Target systolic BP <140 mmHg
• Lipid management: High-dose statin therapy
• Diabetes management: Aggressive glucose control
• Lifestyle modification: Smoking cessation and at least moderate physical activity

Evidence Base and Common Pitfalls

The recommendation against anticoagulation is based on two large randomized controlled trials (NAVIGATE ESUS and RE-SPECT ESUS) involving 13,970 patients, which demonstrated that direct oral anticoagulants did not reduce recurrent stroke compared to aspirin (RR 0.95% CI 0.83-1.08) but increased clinically relevant non-major bleeding (RR 1.52,95% CI 1.22-1.90). 3, 5 Real-world data from 2,328 patients confirmed no net benefit of anticoagulation over antiplatelet therapy. 4

Critical pitfall: Do not assume ESUS patients need anticoagulation based on the embolic mechanism alone—the evidence clearly shows no benefit and potential harm. 1, 3, 4

Recurrence risk: ESUS patients have an annual stroke recurrence rate of approximately 4-5% despite antiplatelet therapy, with higher risk in those with prior stroke/TIA (HR 2.03), current tobacco use (HR 1.62), diabetes (HR 1.28), and multiple acute infarcts on imaging (HR 1.49). 6, 7