Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack

Meta-Analysis of Randomized Controlled Trials

Kirtipal Bhatia, MD; Vardhmaan Jain, MD; Devika Aggarwal, MD; Muthiah Vaduganathan, MD, MPH; Sameer Arora, MD, MPH; Zeeshan Hussain, MD; Guneesh Uberoi, MD; Alfonso Tafur, MD, MSc; Cen Zhang, MD; Mark Ricciardi, MD; Arman Qamar, MD, MPH

Disclosures

Stroke. 2021;52(6):e217-e223. 

In This Article

Discussion

Our meta-analysis supports the use of DAPT with aspirin and a P2Y12 inhibitor as compared with aspirin monotherapy in patients presenting with minor ischemic stroke or TIA, with the recognition of increased risk of major bleeding. Pooled analysis of trial-level data revealed a statistically significant reduction in recurrent stroke, driven mainly by a reduction in ischemic stroke. In addition, treatment with DAPT resulted in a significantly lower risk of MACE. Although there was no significant increase in the risk of hemorrhagic stroke, DAPT was associated with an increased risk of major bleeding.

The FASTER trial was the first study to examine the efficacy of early DAPT (aspirin and clopidogrel) compared with aspirin monotherapy in patients with minor stroke or TIA. In this trial, the patients in the DAPT arm had a numerically lower but statistically nonsignificant reduction in recurrent strokes at the expense of increase in symptomatic bleeding at 90 days follow-up. After the preliminary insights from the FASTER trial, the efficacy and safety of the combination of aspirin and clopidogrel in preventing recurrent stroke in minor stroke (National Institutes of Health Stroke Scale score ≤3) or high-risk TIA (ABCD2 score ≥4) was established by 2 large scale multicenter studies: the CHANCE and POINT trials. The CHANCE trial was a multicenter trial that was conducted in China. Patients randomized to the DAPT arm received a combination of aspirin and clopidogrel for 21 days. Patients with DAPT had a significant reduction in recurrent stroke and MACE events with no significant difference in the risk of severe or moderate bleeding. In contrast to CHANCE, the POINT trial was a multinational trial that randomized patients within 12 hours of symptom onset and continued aspirin and clopidogrel in the DAPT arm for 90 days. Although DAPT proved superior to aspirin monotherapy in preventing recurrent ischemic strokes, the risk of major and minor hemorrhage was significantly increased. A secondary analysis of the treatment effect stratified by different time points demonstrated that the combination of aspirin and clopidogrel significantly reduced the rate of ischemic events largely during the initial 7 to 30 days whereas the risk of hemorrhage increased significantly between 8 and 90 days after starting treatment. Possible causes for the low bleeding events in CHANCE included a shorter duration DAPT (21 days in CHANCE versus 90 days in POINT) and increased prevalence of genetic polymorphism of CYP2C19 in the Asian population resulting in decreased antiplatelet effect.

Ticagrelor is a direct antagonist of the P2Y12 inhibitor and has a more consistent and potent antiplatelet effect compared with clopidogrel. The THALES trial tested the efficacy of adding ticagrelor to aspirin monotherapy in preventing recurrent strokes. 11 016 patients with mild to moderate stroke (National Institutes of Health Stroke Scale score ≤5) or high-risk TIA (ABCD2 score ≥6) were included and DAPT was given for 30 days. Patients receiving DAPT had a lower rate of recurrent stroke or all-cause death. Incidence of overall disability (modified Rankin Scale score >1) was similar between the treatment arms. Although bleeding events occurred infrequently, patients on DAPT had an increased risk of moderate to severe bleeding driven by an increase in intracranial or fatal bleeding when compared with aspirin monotherapy. This was in contrast to the POINT trial, where the increased risk of major hemorrhage was driven by nonfatal extracranial bleeding events in the DAPT arm. However, the POINT and CHANCE trials utilized lower loading dosing of aspirin (75 and 162 mg, respectively) compared with the THALES trial. Taken together, in patients with minor stroke or high-risk TIA, short-term DAPT for at least 21 days resulted in significant reduction in recurrent stroke, albeit at a small but significantly increased risk of major bleeding. Current data are insufficient to suggest one P2Y12 agent over the other. The ongoing CHANCE-2 trial comparing different DAPT strategies may provide further insight.

Our meta-analysis has certain limitations. Differences in the definition of major bleeding and doses used, along with variation in the duration of follow-up likely contributed to the moderate heterogeneity associated with the primary safety outcome of major bleeding. There was residual heterogeneity even after adjusting for the follow-up period and duration of DAPT. Due to the lack of patient-level data, we were also unable to investigate the effect of background therapies on the primary efficacy and safety end points. All trials enrolled patients with minor strokes or high-risk TIAs, so these meta-analytic findings do not generalize to patients with moderate to severe strokes, low-risk TIA, presumed cardioembolic strokes, and patients receiving anticoagulation or intravenous fibrinolytics.

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