P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack

Zi-Xiao Li, MD, PhD; Yunyun Xiong, MD, PhD; Hong-Qiu Gu, PhD; Marc Fisher, MD; Ying Xian, MD, PhD; S. Claiborne Johnston, MD, PhD; Yong-Jun Wang, MD


Stroke. 2021;52(7):2250-2257. 

In This Article

Abstract and Introduction


Background and Purpose: We performed a systemic review and meta-analysis to elucidate the effectiveness and safety of dual antiplatelet (DAPT) therapy with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack.

Methods: Following Preferred Reported Items for Systematic Review and Meta-Analysis standards for meta-analyses, Medline, Embase, Cochrane Central Register of Controlled Trials, and the Cochrane Library were searched for randomized controlled trials that included patients with a diagnosis of an acute mild ischemic stroke or high-risk transient ischemic attack, intervention of DAPT therapy with clopidogrel/ticagrelor and aspirin versus aspirin alone from January 2012 to July 2020. The outcomes included subsequent stroke, all-cause mortality, cardiovascular death, hemorrhage (mild, moderate, or severe), and myocardial infarction. A DerSimonian-Laird random-effects model was used to estimate pooled risk ratio (RR) and corresponding 95% CI in R package meta. We assessed the heterogeneity of data across studies with use of the Cochran Q statistic and I 2 test.

Results: Four eligible trials involving 21 493 participants were included in the meta-analysis. DAPT therapy started within 24 hours of symptom onset reduced the risk of stroke recurrence by 24% (RR, 0.76 [95% CI, 0.68–0.83], I 2=0%) but was not associated with a change in all-cause mortality (RR, 1.30 [95% CI, 0.90–1.89], I 2=0%), cardiovascular death (RR, 1.34 [95% CI, 0.56–3.17], I 2=0%), mild bleeding (RR, 1.25 [95% CI, 0.37–4.29], I 2=94%), or myocardial infarction (RR, 1.45 [95% CI, 0.62–3.39], I 2=0%). However, DAPT was associated with an increased risk of severe or moderate bleeding (RR, 2.17 [95% CI, 1.16–4.08], I 2=41%); further sensitivity tests found that the association was limited to trials with DAPT treatment duration over 21 days (RR, 2.86 [95% CI, 1.75–4.67], I 2=0%) or ticagrelor (RR, 2.17 [95% CI, 1.16–4.08], I 2=37%) but not within 21 days or clopidogrel.

Conclusions: In patients with noncardioembolic mild stroke or high-risk transient ischemic attack, DAPT with aspirin and clopidogrel/ticagrelor is more effective than aspirin alone for recurrent stroke prevention with a small absolute increase in the risk of severe or moderate bleeding.


Acute mild ischemic stroke or transient ischemic attack (TIA) accounts for 65% of all ischemic cerebrovascular events.[1] A recent large prospective study revealed that the risk of subsequent ischemic stroke in mild stroke and high-risk TIA within 1 week was 8%,[2] with a risk of 10.5% within 3 months after the index event.[3]

Based on the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events)[4] and the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke),[5] recent acute stroke management guidelines recommended initiating dual antiplatelet (DAPT) with aspirin and clopidogrel within 24 hours after symptom onset and continuing it for 21 days in patients with noncardioembolic high-risk TIA and minor stroke (National Institutes of Health Stroke Scale score ≤3).[6] However, clopidogrel requires hepatic conversion to its active form and a substantial percentage of patients have clopidogrel resistance because of a genetic predisposition to reduced conversion.[7] Ticagrelor rapidly and reversibly binds and inhibits the P2Y12 receptor on platelets without the need for conversion to an active form.[8,9] Recently, the THALES trial (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) demonstrated that patients with acute mild ischemic stroke or high-risk TIA randomized to receive ticagrelor and aspirin had a lower risk of a subsequent stroke or death as compared to aspirin alone during 30 days follow-up.[10]

We performed an updated systematic review and meta-analysis of randomized, placebo-controlled trials that enrolled patients with mild ischemic stroke or high-risk TIA within 3 days of presentation and elucidated the effectiveness and safety of DAPT therapy with clopidogrel or ticagrelor and aspirin versus aspirin alone.