Treatment with clopidogrel with aspirin or ticagrelor with aspirin produces similar risk reduction of stroke recurrence or death

1. Treatment after a minor stroke or transient ischemic attack with dual anti-platelet therapy (DAPT), either clopidogrel with aspirin or ticagrelor with aspirin, similarly reduces the risk of stroke or death, which is more than treatment with aspirin alone.

2. Both DAPTs had a similar risk of major hemorrhage, 90-day mortality, and adverse event rates, but clopidogrel and aspirin had a superior decrease in risk of disability due to stroke.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Having a minor ischemic stroke or transient ischemic attack (TIA) is a risk factor for having a subsequent stroke. Short-term dual anti-platelet therapy (DAPT) using clopidogrel and acetylsalicylic acid (ASA; aspirin) or using ticagrelor and aspirin is known to be better than monotherapy for secondary stroke prevention after TIA. This study aimed to compare the efficacy and safety of the two DAPT protocols. This metanalysis compared recurrent stroke or death rates, functional disability via the modified Rankin Scale (mRS), and safety between ticagrelor and aspirin, clopidogrel and aspirin, and aspirin after TIA or minor stroke. Pooling the data between the 5 eligible randomized controlled trials (RCTs) and 4 subgroup analyses identified that using a DAPT was superior to aspirin alone at stroke or death prevention and the two DAPT protocols were similar at stroke or death prevention. Specifically, both DAPTs decreased the incidence of ischemic stroke, with clopidogrel having a superior effect.  Neither DAPT regimen increased the risk of hemorrhagic stroke.. Both DAPTs increased the risk of major hemorrhage. While both DAPTs and aspirin had similar 90-day mortality and adverse event rates, clopidogrel and aspirin were associated with a decreased risk of functional disability versus aspirin alone. One strength of this metanalysis is the a priori publication of the search strategy to reduce bias. Additionally, it featured net metanalysis, which could rank treatments, unlike other metanalysis. One consideration is that this metanalysis may have overlooked a significant portion of data by only including RCTs, though it can then claim causative relations. A limitation of this study is that treatment durations and follow-up time differed in the different included RCTs as did the inclusion and exclusion criteria, though minimally. Finally, there was no assessment of publication bias because of the net metanalysis method used.

Click to read the study in JAMA Neurology

Relevant Reading: Ticagrelor Is Superior to Clopidogrel in Inhibiting Platelet Reactivity in Patients With Minor Stroke or TIA

In-Depth [systematic review and meta-analysis]: This metanalysis averaged the recurrent stroke or death rates at 90 days in RCTs that compared ticagrelor and aspirin, clopidogrel and aspirin, and aspirin use in adults within 72 hours of TIA or minor stroke. Additionally, it assessed functional disability via the mRS and adverse events. RCTs were found in English or French on MEDLINE, Embase, Cochrane Registry of Clinical Trials, the World Stroke Congress and International Stroke Conference and selected by two independent reviewers. Bias was assessed using the Cochrane Risk of Bias tool for randomized trials version 2 (RoB2). 5 RCTs and 4 subgroup analyses (N = 22,098; 10,722 received aspirin, 5,517 received clopidogrel and aspirin, and 5,859 received ticagrelor and aspirin) met the inclusion criteria out of the 4014 unique titles screened. The studies were all at low risk of bias by RoB2. 3 RCTs compared clopidogrel and aspirin to aspirin, 1 RCT compared ticagrelor and aspirin to aspirin, and 1 RCT compared clopidogrel and aspirin to ticagrelor and aspirin, all of similar doses for 21-90 days. The included RCTs included similarly aged participants and definitions of stroke. Consistent with previous studies, clopidogrel and aspirin were superior at preventing stroke or death than aspirin alone (HR = 0.74, 95% Credible Intervals (CrI) = 0.65-0.84), as was ticagrelor and aspirin (HR = 0.79, 95% CrI = 0.68-0.91). Clopidogrel and aspirin were similar to ticagrelor and aspirin at stroke and death prevention (HR = 0.94, 95% CrI = 0.78-1.13). Compared to aspirin alone, clopidogrel and aspirin (HR = 0.71; 95% CrI = 0.62-0.82) and ticagrelor and aspirin (OR = 0.74, 95% CrI = 0.64-0.86) both reduced recurrent ischemic stroke. Clopidogrel performed best on surface under the cumulative rank curve (SUCRA) while aspirin alone had the highest risk for ischemic stroke and death prevention. Neither DAPT protocol increased the risk of hemorrhagic stroke compared to aspirin, nor compared to each other (HR = 0.67, 95% CrI = 0.26-1.70). Ticagrelor and aspirin had the highest risk of hemorrhagic stroke by SUCRA. Both DAPT protocols increased the risk of major hemorrhage compared to aspirin alone (clopidogrel: HR = 1.78, 95% CrI = 1.09-2.92; ticagrelor: HR = 2.63, 95%CrI = 1.51-4.82). Clopidogrel and aspirin had lower disability risk compared to aspirin alone (HR = 0.82; 95% CrI = 0.74-0.91) and compared to ticagrelor and aspirin (HR = 0.85, 95% CrI = 0.75-0.97). All of the treatments had comparable 90-day mortality, though ticagrelor and aspirin had the highest SUCRA, as well as highest rate of adverse events. There was no statistically significant difference in reduction of stroke or death on sensitivity analysis between treatment after a minor stroke or TIA with clopidogrel and aspirin compared with ticagrelor and aspirin (HR = 0.83, 95% CrI, 0.68-1.02); clopidogrel and aspirin had the lowest risk of stroke recurrence by SUCRA (0.96) compared to ticagrelor and aspirin (0.4) and aspiring (0).

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