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 PRISMA-guided systematic review of randomized controlled trials (RCTs) comparing eAPT initiated within 24 hours 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 GRADE certainty ratings were performed. RESULTS: Twelve RCTs with 4,595 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; I² 10.4%; GRADE moderate), and mortality (OR 1.15, 0.83-1.58; I² 14.8%; GRADE moderate) but not intracranial hemorrhage (OR 1.01, 0.64-1.60; I² 52.6%; GRADE low). Functional outcomes were not improved: mRS 0-1 (OR 1.10, 0.83-1.46; I² 60.5%; GRADE low) and mRS 0-2 (OR 1.27, 0.89-1.80; I² 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, 1.02-4.45) and possible benefit for mRS 0-2 with tirofiban (OR 2.07, 1.25-3.43). CONCLUSIONS: Routine early antiplatelet therapy within 24 hours 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.