Review: After stroke or TIA, adding clopidogrel to aspirin for 1 month reduces recurrence and MACE

Abstract

Question After ischemic stroke (IS) or transient ischemic attack (TIA), do the efficacy and safety of aspirin plus clopidogrel (dual antiplatelet therapy) (DAPT) vs aspirin alone vary by DAPT duration? Review scope Included studies compared DAPT with aspirin alone in patients 18 years of age who had noncardioembolic IS or TIA and were not appropriate for thrombolysis. Primary outcomes were recurrent IS (efficacy) and major bleeding (safety). Other outcomes included all-cause mortality and major adverse cardiovascular (CV) events, including CV mortality, myocardial infarction, and recurrent stroke. Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Central Register of Controlled Trials to Jun 2018; and reference lists were searched for randomized controlled trials (RCTs). 10 RCTs (n =15434, mean age 64 y, 61% men) met inclusion criteria. Duration of DAPT was 1 month (6 RCTs), 3 months (1 RCT), and >3 months (2 RCTs); 1 RCT reported outcomes after 1 month and 3 months of DAPT. Median time from IS or TIA onset to treatment was 48 hours (range 12 h to <180 d), and median DAPT duration was 1 mo (range 7 d to 41 mo). 10 trials had adequate allocation concealment, and 7 were double-blind. Definition of major bleeding varied across trials. Main results The main results are in the Table. Conclusion After ischemic stroke or transient ischemic attack, adding clopidogrel to aspirin for 1 month reduces recurrent ischemic stroke and major adverse cardiovascular events and does not increase major bleeding. Aspirin plus clopidogrel vs aspirin alone after ischemic stroke (IS) or transient ischemic attack* Outcomes Aspirin + clopidogrel duration Number of trials (n) Unweighted event rates At 7 d to 41 mo follow-up Aspirin + clopidogrel Aspirin alone RRR (95% CI) NNT (CI) Recurrent IS 1 mo 6 (6941) 6.4% 10.0% 47% (22 to 63) 29 (22 to 44) 3 mo 2 (5273) 4.8% 6.7% 28% (10 to 42) 56 (33 to 167) >3 mo 2 (3236) 6.3% 7.7% 19% (4 to 37) NS Major adverse cardiovascular events 1 mo 5 (11061) 5.9% 8.7% 32% (22 to 40) 39 (28 to 67) 3 mo 2 (5273) 5.2% 6.9% 24% (6 to 39) 63 (35 to 250) >3 mo 1 (3020) 10% 12% 13% (7 to 29) NS RRI (CI) NNH (CI) Major bleeding 1 mo 4 (11825) 0.4% 0.2% 82% (9 to 262) NS 3 mo 2 (5273) 1.1% 0.4% 158% (19 to 460) NS >3mo 2 (3236) 6.6% 3.4% 87% (36 to 156) 42 (23 to 334) All-cause mortality 1 mo 3 (6089) 0.5% 0.4% 15% (47 to 148) NS 3 mo 2 (5273) 0.7% 0.5% 56% (23 to 218) NS >3 mo 1 (3020) 7.4% 5.1% 45% (10 to 93) 44 (25 to 167) *NS = not significant; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from aspirin-alone event rates, risk ratios, and CIs in article using a random-effects model; NNT, NNH, and CI calculated from risk differences and CIs in article supplement. Total number of patients included in the trials. 7 d to 3 mo with DAPT duration 1 mo, 3 mo with DAPT duration 3 mo, and 28 to 41 mo with DAPT duration >3 mo. Information provided by author. Risk difference 0.012, 95% CI 0.006 to 0.03. Commentary The rate of recurrent stroke is highest in the first weeks after IS or TIA. Aspirin reduces early recurrent stroke by about 13% (odds ratio 0.87, 95% CI 0.79 to 0.97) (1), ticagrelor has not been shown to be superior to aspirin (2), and clopidogrel alone has not been studied in acute IS or TIA. A meta-analysis of 18 RCTs of DAPT vs monotherapy in 15515 patients with acute IS or TIA found that DAPT reduced early recurrent stroke (5.4% vs 7.8%) (risk ratio [RR] 0.69, CI 0.61 to 0.78) but increased major bleeding (0.6% vs 0.3%) (RR 1.77, CI 1.09 to 2.87) (3). Triple therapy with aspirin, clopidogrel, and dipyridamole further increased bleeding without reducing recurrent stroke (4). A meta-analysis of 3 RCTs of clopidogrel plus aspirin vs aspirin alone in 10447 patients with acute (<24 h after symptom onset) minor IS or TIA found that most stroke events and most of the benefit with DAPT occurred in the first 10 to 21 days (5). The review by Rahman and colleagues extends the evidence for DAPT and supports limiting its use to 1 month to maximize benefit and minimize bleeding risk. For now, patients with acute TIA or mild IS should receive loading doses of aspirin, 160 to 300 mg, plus clopidogrel, 300 to 600 mg, as soon as possible; they should continue on a maintenance dose of DAPT for 1 month before changing to aspirin, clopidogrel, or aspirin and dipyridamole. Trials are examining the safety and efficacy of adding ticagrelor, cilostazol, or a direct oral anticoagulant to aspirin, and adding a factor XI inhibitor to aspirin plus clopidogrel. The latter suggests that clopidogrel plus aspirin may now be the gold standard for patients with acute minor IS or TIA.