The Critical Importance of Timing in Secondary Stroke Prevention
In the management of minor ischemic stroke and high-risk transient ischemic attack (TIA), the introduction of dual antiplatelet therapy (DAPT) has been a paradigm shift in secondary prevention. Historical trials such as CHANCE and POINT established that combining aspirin with clopidogrel is superior to aspirin monotherapy in reducing the risk of recurrent events. However, the exact ‘window of opportunity’ during which DAPT provides its maximal benefit—and when that benefit begins to wane—has remained a subject of intense clinical debate. A newly published multicenter cohort study in the journal Stroke provides a granular look at the relationship between treatment initiation timing and clinical outcomes, suggesting a much narrower therapeutic window than previously emphasized.
Highlighting the Urgency of Treatment
The core findings of this research underscore three critical clinical points:
1. The Power of the First 24 Hours
Initiating DAPT within 24 hours of symptom onset remains the gold standard, associated with a 26% reduction in the risk of recurrent stroke, myocardial infarction, or death.
2. The 42-Hour Neutrality Point
The therapeutic benefit of DAPT appears to cross the null at approximately 42 hours. Beyond this point, the statistical advantage over monotherapy vanishes.
3. Risks of Late Initiation
Starting DAPT more than 72 hours after symptom onset may not only be futile but potentially harmful, with data suggesting a 25% increase in the risk of primary composite outcomes compared to monotherapy.
Study Design and Methodology: A Robust Multi-Center Analysis
The researchers utilized data from a prospective multicenter cohort involving 20 stroke centers between January 2011 and April 2023. The study included 41,530 patients (mean age 66.3 years; 62% male) who experienced a minor noncardioembolic ischemic stroke (defined as a National Institutes of Health Stroke Scale [NIHSS] score of 5 or less) or a high-risk TIA. All included patients presented within seven days of symptom onset.
Interventions and Grouping
The study compared in-hospital initiation of DAPT (typically aspirin and clopidogrel) versus monotherapy (aspirin or clopidogrel alone). Patients were stratified into three groups based on the time from symptom onset to hospital arrival: 0 to 24 hours, 24 to 72 hours, and over 72 hours.
Statistical Rigor
To account for the non-randomized nature of the cohort, the investigators employed inverse probability of treatment weighting (IPTW) based on propensity scores. This adjusted for a wide array of variables, including demographic factors, baseline clinical characteristics, vascular risk factors (hypertension, diabetes, etc.), stroke subtype, arterial status (stenosis), and prior antiplatelet use. The primary endpoint was a 90-day composite of recurrent stroke, myocardial infarction, and death.
Detailed Results: A Time-Dependent Efficacy Gradient
Among the 41,530 participants, 60.5% (25,112) received DAPT. The overall 90-day primary outcome occurred in 10.7% of the DAPT group compared to 11.6% in the monotherapy group. While the aggregate hazard ratio (HR) was 0.82 (95% CI, 0.77-0.87), the stratification by time revealed a striking gradient.
Immediate Initiation (0-24 Hours)
For patients reaching the hospital and starting therapy within the first day, the HR was 0.74 (95% CI, 0.69-0.79). This reinforces the current guidelines that emphasize immediate intervention.
Delayed Initiation (24-72 Hours)
For those starting between 24 and 72 hours, the HR rose to 1.00 (95% CI, 0.88-1.15), indicating no significant difference between DAPT and monotherapy.
Late Initiation (>72 Hours)
The most concerning finding was in the group arriving after 72 hours, where the HR was 1.25 (95% CI, 1.01-1.55). This suggests that late-stage escalation to DAPT might actually correlate with worse 90-day outcomes.
The Inflection Point
Using time-dependent analysis, the researchers identified that the benefit of DAPT crosses the null at approximately 42 hours post-symptom onset. This provides a more precise clinical target than the broad 24-to-48-hour windows often discussed in earlier literature.
Expert Commentary and Clinical Interpretation
The biological plausibility of these findings rests on the temporal nature of platelet activation and plaque stabilization. In the ultra-acute phase of a minor stroke or TIA, the risk of recurrent thromboembolism is at its peak due to unstable atherosclerotic plaques or active thrombogenic surfaces. DAPT serves to aggressively dampen this hyper-reactive state.
Why Does the Benefit Decline?
As time progresses from the index event, the ‘red-hot’ thrombus begins to stabilize. By 42 to 72 hours, the physiological priority shifts from preventing new thrombus formation to preventing hemorrhagic transformation of the infarcted tissue. Introducing intensive antiplatelet therapy after the period of peak recurrent risk may expose the patient to the risks of DAPT (such as bleeding) without the counterbalancing benefit of preventing a new ischemic event.
Comparison with Previous Trials
These findings align with and extend the results of the CHANCE and POINT trials. While those trials mandated recruitment within 24 hours (CHANCE) or 12 hours (POINT), this cohort study provides real-world evidence of what happens when those windows are missed. It suggests that the ‘urgency’ of DAPT is not just a recommendation but a biological necessity for efficacy.
Conclusion: Moving Toward an ‘Ultra-Acute’ Mentality
This study serves as a critical reminder to clinicians that in the realm of minor stroke and high-risk TIA, ‘time is brain’ applies not only to thrombolysis and thrombectomy but also to secondary prevention strategies. The window for DAPT is narrow; the maximum benefit is achieved within the first day, and the therapeutic advantage effectively expires by the end of the second day.
Practice Implications
Health systems should ensure that diagnostic protocols and pharmacy workflows allow for the immediate administration of DAPT once a noncardioembolic minor stroke or high-risk TIA is confirmed. For patients presenting beyond the 42-to-72-hour mark, clinicians should carefully weigh the lack of proven benefit of DAPT escalation against the potential risks, potentially favoring monotherapy in those late-presenting cases.
References
1. Shin J, Lee KJ, Kim CK, et al. Timing of Initiation and Efficacy of Dual Antiplatelet Therapy in Minor Stroke or High-Risk TIA. Stroke. 2026;57(1). doi:10.1161/STROKEAHA.125.053343.
2. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.
3. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225.
