Guideline: Starting dual antiplatelet therapy 24 h after high-risk TIA or minor ischemic stroke is recommended

Abstract

Guideline scope Early use of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel vs single-agent therapy after high-risk transient ischemic attack (TIA) or minor ischemic stroke. Guideline development methods An international expert panel developed recommendations based on a systematic review {with searches done to July 2018}* that included 3 randomized controlled trials (RCTs) (n =10447, mean age 62 to 68 y, 53% to 66% men, {follow-up 90 d}*). The RCTs compared aspirin plus clopidogrel with aspirin alone in patients with minor ischemic stroke (National Institutes of Health Stroke Scale score 3 in 3 RCTs) or high-risk TIA (ABCD2 scale score 4 in 2 RCTs, not defined in 1 RCT) enrolled 12 (1 RCT) or 24 (2 RCTs) hours after symptom onset. The panel comprised general internists, stroke neurologists, patients and a patient caregiver, geriatricians, methodologists, a critical care physician, a vascular surgeon, a nurse, and a physiotherapist. No panel member reported a financial conflict of interest. The panel used the Grading of Recommendations, Assessment, Development and Evaluation approach to appraise evidence and develop recommendations, and considered the balance of therapy benefits, harms, and burdens; quality of evidence for each outcome; patient values and preferences; and practical intervention issues. Results and Recommendations The panel made 2 strong recommendations (benefits outweigh harms for almost everyone; all or nearly all informed patients would likely want this option) for patients with high-risk TIA or minor ischemic stroke: 1. Start DAPT with aspirin and clopidogrel rather than single-agent therapy 24 hours after the index TIA or stroke. The evidence for this recommendation is in the Table based on the results of the systematic review*. 2. Administer DAPT for 10 to 21 days rather than >21 days after the index TIA or stroke. {This recommendation is based on indirect evidence using individual patient data back-calculated from Kaplan-Meier curves of the trials comparing aspirin plus clopidogrel with aspirin alone}*. An online version of the recommendations and evidence summary is available at https://app.magicapp.org/app#/guideline/2602. Conclusion An expert panel made strong recommendations in favor of starting clopidogrel plus aspirin vs aspirin alone 24 hours after a high-risk transient ischemic attack or minor ischemic stroke and continuing dual therapy for 10 to 21 days. DAPT (aspirin plus clopidogrel) vs aspirin alone in high-risk transient ischemic attack or minor ischemic stroke Outcomes Number of trials (n) Weighted event rates At 90 d DAPT Aspirin alone RRR (95% CI) NNT (CI) Recurrent nonfatal stroke 3 (10301) 4.4% 6.3% 30% (20 to 39) 53 (40 to 77) Nonfatal functional disability 2 (9690) 13% 14% 10% (1 to 19) NS Poor quality of life 1 (5131) 5.5% 6.8% 19% (1 to 34) NS RRI (CI) All-cause mortality 2 (9690) 0.6% 0.5% 27% (27 to 123) NS Moderate or major extracranial bleeding 3 (10075) 0.5% 0.3% 71% (8 to 220) NS DAPT = dual antiplatelet therapy; NS = not significant; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from relative risks, absolute effect estimates, and CIs in the systematic review. Findings are based on high-quality evidence (recurrent nonfatal stroke) or moderate-quality evidence (all other outcomes) assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Aspirin-alone event rates from the included multinational POINT trial for all outcomes other than poor quality of life (event rate from the CHANCE trial). Modified Rankin Scale score 2 to 5. EuroQol-5 Dimension index score 0.5. Commentary From individual trials and the systematic review and meta-analysis associated with the guideline by Prasad and colleagues, it has become clear that early administration of DAPT after stroke or TIA reduces early risk for ischemic stroke recurrence. Prasad and colleagues used the pooled relative risk from the 3 RCTs comparing DAPT with aspirin alone and applied it to the baseline absolute risk from the multiethnic POINT trial to estimate a 1.9% absolute risk reduction in stroke with DAPT. Much of the benefit of DAPT occurs during the high-risk period 10 days after minor stroke or TIA, and the guideline authors asked how long DAPT should be continued. To answer this question, they used a method of extracting individual patient time-to-event data from published Kaplan-Meier figures and pooled them for meta-analysis. Similar to an analysis of the CHANCE trial, which concluded that DAPT had no benefit beyond 14 days (1), pooled analysis showed that benefit did not outweigh risk beyond 21 days of DAPT. As the pooled analysis showed a low absolute risk (about 1%) for stroke beyond the first 3 weeks with single antiplatelet therapy, the possibility of relevant benefit with DAPT seems low. One still might hope to find a higher-risk subgroup for which the benefit is greater with DAPT beyond the first 10 days. An atherosclerotic mechanism of stroke has higher early risk for recurrence (2) and higher potential benefit of DAPT than other stroke types, but the subgroup analysis of 1 trial that focused on patients with intracranial atherosclerosis found no greater relative benefit with DAPT in this subgroup (3). In translating the data to clinical practice, a key point to remember is that DAPT was administered early, within 24 hours after minor stroke or high-risk TIA of noncardioembolic mechanism. Patients for whom surgical interventions were planned, who presented days or weeks after stroke, or who had large and severe strokes (with potentially higher risk for intracranial hemorrhage or systemic complications) were not studied.