Title : Antithrombotic strategies for the secondary prevention of ischemic stroke : A systematic review and network meta-analysis
Abstract:
Background: The ideal antithrombotic strategy for preventing recurrent stroke remains uncertain, given the need to balance ischemic risk reduction with bleeding complications. We performed a network meta-analysis comparing antiplatelets, vitamin K antagonists, and direct oral anticoagulants (DOACs) in patients with a history of ischemic stroke or TIA.
Methods: We performed a systematic review and network meta-analysis in accordance with PRISMA guidelines. Comprehensive searches of PubMed and Cochrane databases identified 25 randomized controlled trials—9 evaluating antiplatelet agents and 16 evaluating anticoagulants for secondary stroke prevention. Study quality was evaluated using the Cochrane Risk of Bias tool. Pooled hazard ratios (HRs) were calculated using a random-effects model. Publication bias was examined through funnel plots and Egger’s test. A frequentist network meta-analysis was conducted to estimate HRs, and treatment efficacy and safety were ranked using Surface Under the Cumulative Ranking Curve (SUCRA) values. A matrix plot was generated to display the relationship between stroke recurrence and major bleeding risk.
Results: Across multiple trials, apixaban (SUCRA: 91%) and dabigatran (110/150 mg; SUCRA: 87%) were among the most effective in reducing stroke recurrence. Clopidogrel and aspirin-dipyridamole outperformed aspirin monotherapy but were less effective than DOACs. Asundexian, a Factor XIa inhibitor, was less effective than apixaban (HR 3.79; 95% CI, 2.46–5.83). Short-term dual antiplatelet therapy (DAPT) administered for 21 days or less reduced the risk of recurrence by 26% compared to aspirin (HR 0.74; 95% CI, 0.61–0.88), whereas extended DAPT showed no additional benefit (HR 1.20; 95% CI, 0.92–1.57). Apixaban demonstrated the most favorable safety profile, with lower rates of major bleeding (HR ~1.13) and intracranial hemorrhage (HR ~0.85). In contrast, rivaroxaban and edoxaban were associated with increased ICH risk, as seen in NAVIGATE-ESUS (ICH HR 4.02). Short-term DAPT posed moderate bleeding risk (HR 1.86; 95% CI, 0.87–2.85), while extended use raised bleeding further (HR 1.20; 95% CI, 0.91–1.58). No treatment showed a significant mortality benefit. However, warfarin was linked to higher mortality (WASID HR 2.33; 95% CI, 1.19–4.59), while DOACs—especially edoxaban—showed favorable trends (HR 0.86; 95% CI, 0.77–0.97).
Conclusions: Apixaban and dabigatran offer the most favorable balance between effectiveness and safety. Short-term DAPT appears beneficial during the early high-risk phase but is not recommended for extended use. Emerging agents such as asundexian need additional evidence before routine use. Prolonged DAPT and warfarin in the context of intracranial atherosclerosis (ICAD) may pose increased risks and should be approached with caution.
