Safety and efficacy of early antiplatelet therapy after intravenous thrombolysis for acute ischemic stroke: A comprehensive meta-analysis with trial sequential analysis

Background: Early antiplatelet therapy after intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients may prevent re-occlusion and early neurological deterioration, but it could increase hemorrhagic transformation. Evidence remains conflicting, particularly with emerging contemporary trials. Methods: We conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided systematic review of randomized controlled trials (RCTs) comparing early antiplatelet therapy (eAPT) initiated within 24 h after IVT (with or without thrombectomy) versus standard timing (>24 h), placebo, or no antiplatelet therapy (CRD420251276445). Random-effects models were used to estimate odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs). Trial sequential analysis, subgroup analyses, meta-regression, and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) certainty ratings were performed. Results: Twelve RCTs with 4595 patients were included. Early antiplatelet therapy led to higher non-significant odds of symptomatic intracranial hemorrhage (sICH; OR = 1.68, 95% CI = 0.94–3.01; I 2 = 10.4%; GRADE moderate), and mortality (OR = 1.15, 95% CI = 0.83–1.58; I 2 = 14.8%; GRADE moderate) but not intracranial hemorrhage (OR = 1.01, 95% CI = 0.64–1.60; I 2 = 52.6%; GRADE low). Functional outcomes were not improved: Modified Rankin Scale (mRS) 0–1 (OR = 1.10, 95% CI = 0.83–1.46; I 2 = 60.5%; GRADE low) and mRS 0–2 (OR = 1.27, 95% CI = 0.89–1.80; I 2 = 73.4%; GRADE very low). Trial sequential analysis indicated evidence remains inconclusive. Agent-specific subgroup analyses suggested higher sICH with early aspirin (OR = 2.13, 95% CI = 1.02–4.45) and possible benefit for mRS 0–2 with tirofiban (OR = 2.07, 95% CI = 1.25–3.43). Conclusion: Routine early antiplatelet therapy within 24 h after IVT does not provide conclusive functional benefit, and our analysis cannot exclude clinically meaningful hemorrhagic harm. Further adequately powered RCTs are needed to define whether any selected regimen—especially tirofiban—has a favorable risk–benefit profile.