Why is Dual Antiplatelet Therapy (DAPT) with aspirin and another antiplatelet agent, such as clopidogrel, only prescribed for 21 days in a patient who has suffered a cerebrovascular accident (CVA) or stroke?

Why DAPT is Limited to 21 Days After Stroke

Dual antiplatelet therapy (DAPT) is limited to 21 days after minor ischemic stroke or high-risk TIA because the benefit of preventing recurrent stroke is concentrated in the first 21 days, while continuing beyond this period provides no additional stroke prevention benefit but significantly increases the risk of major bleeding and intracranial hemorrhage. 1, 2

The Critical 21-Day Window

The evidence demonstrates a clear temporal pattern of benefit:

• Maximum efficacy occurs within the first 21 days, with pooled analysis of the CHANCE and POINT trials showing that 263 of 5016 patients (5.2%) on DAPT experienced major ischemic events versus 391 of 5035 (7.8%) on aspirin alone (HR 0.66,95% CI 0.56-0.77) during this period. 2

• After day 21, DAPT provides no additional benefit - from day 22 to day 90, there was no significant difference in stroke prevention between DAPT and single antiplatelet therapy. 2

• Meta-analyses confirm that short-term DAPT (≤30 days) reduces recurrent ischemic stroke by 35% (RR 0.65,95% CI 0.53-0.79), which is superior to long-term DAPT (>30 days; RR 0.72,95% CI 0.60-0.86). 3

The Bleeding Risk Trade-Off

The decision to stop at 21 days is driven by safety concerns that emerge with prolonged use:

• Long-term DAPT (beyond 90 days) increases major bleeding risk by 142% (RR 2.42,95% CI 1.37-4.30) without reducing recurrent ischemic stroke (RR 0.89,95% CI 0.79-1.02). 4

• Intracranial hemorrhage risk increases significantly with prolonged DAPT, particularly in older patients and those with more severe strokes. 1

• The bleeding risk begins to outweigh stroke prevention benefits as early as 21 days according to meta-analyses. 1

Evidence-Based Duration Recommendations

Current guidelines are explicit about the 21-day cutoff:

• The American Heart Association/American Stroke Association recommends exactly 21 days of DAPT (aspirin plus clopidogrel) for minor stroke or high-risk TIA, followed by transition to single antiplatelet therapy. 5, 6, 4

• An alternative regimen allows up to 30 days when using aspirin plus ticagrelor, but 21 days remains the primary recommendation for aspirin-clopidogrel combinations. 5, 6

• After 21 days, switch to single antiplatelet therapy with either aspirin 75-100 mg daily or clopidogrel 75 mg daily for long-term secondary prevention. 5, 6

Clinical Algorithm for DAPT Duration

Days 0-21:

• Initiate DAPT with loading doses (aspirin 160-325 mg + clopidogrel 300-600 mg) within 12-24 hours after excluding intracranial hemorrhage. 5, 4
• Continue maintenance doses (aspirin 81 mg + clopidogrel 75 mg daily). 5, 4
• This period captures the highest risk window for recurrent stroke when DAPT is most effective. 2

Day 21:

• Stop one antiplatelet agent and transition to monotherapy. 5, 6
• Choose either aspirin 75-100 mg daily OR clopidogrel 75 mg daily for indefinite continuation. 5, 6

Beyond Day 21:

• Continuing DAPT provides no additional stroke prevention benefit and increases bleeding complications. 1, 2
• The number needed to harm for major bleeding with prolonged DAPT is 284-330 patients. 4

Common Pitfalls to Avoid

• Do not extend DAPT beyond 30 days unless there is a separate indication (e.g., recent coronary stent), as this increases bleeding risk without improving stroke outcomes. 1, 6

• Do not continue DAPT indefinitely - this is a common error in clinical practice that significantly increases hemorrhagic complications. 1

• Older patients (≥70 years) and those with severe strokes are at particularly high risk for intracranial hemorrhage with prolonged DAPT and require strict adherence to the 21-day limit. 1

• Triple antiplatelet therapy should never be used, as the TARDIS trial showed no benefit and significantly increased bleeding risk. 1, 4

The Biological Rationale

The 21-day window corresponds to the period of highest thrombotic risk after acute cerebrovascular events:

• Early recurrent stroke risk is highest in the first 2-3 weeks following the index event, when platelet activation and thrombus propagation are most active. 2

• After 21 days, the acute thrombotic phase resolves, and the risk-benefit ratio shifts unfavorably as bleeding risk accumulates while stroke prevention benefit plateaus. 1, 2

• The number needed to treat to prevent one major ischemic event with DAPT is approximately 92 patients, but this benefit is concentrated in the first 21 days. 6