This study aims to assess the comparative efficacy and safety of reteplase, alteplase, and tenecteplase in acute ischemic stroke (AIS).

The efficacy of tenecteplase in comparison to alteplase is well-researched. Reteplase, a more affordable alternative thrombolytic agent with a longer plasma half-life and reduced fibrin specificity, may have enhanced AIS-related outcomes.

We searched PubMed, ScienceDirect, Scopus, and Cochrane Central up to September 2024. We performed a frequentist network meta-analysis using the “netmeta” package in R v4.4.1. Risk ratios (RR) along with 95% CIs were pooled using a random effects model. Treatment ranking was performed using the p-scores. The quality of the included studies was assessed using the Cochrane RoB 2.0 tool and publication bias through funnel plots.

The results from 14 randomized trials were included. Higher mortality rates were reported by reteplase (RR= 3.14, 95% CI: [1.29, 7.61]) and tenecteplase (RR= 3.17, 95% CI: [2.27, 4.43]) when compared to alteplase. Reteplase (RR= 4.95, 95% CI: [3.92, 6.25]) and tenecteplase (RR=3.05, 95% CI: [2.77, 3.36]) significantly improved excellent functional outcomes however, the highest risk for poor functional outcomes was also demonstrated by reteplase (RR=3.14, 95%CI: [1.34,7.37]) and tenecteplase (RR=2.96, 95% CI: [2.23, 3.94]). Major neurological improvement at 72h showed increased association with tenecteplase (RR=3.68, 95%CI: [2.70, 5.02]) and reteplase (RR=3.64, 95% CI: [2.04,6.49]). A higher incidence of symptomatic intracranial hemorrhage (sICH) corresponded to tenecteplase (RR=4.16, 95% CI: [2.33,7.41]); reteplase did not show any significant association.

Despite enhanced functional recovery, reteplase demonstrated a higher risk of poor outcomes. Alteplase optimally reduced mortality, sICH, and poor functional outcomes whereas tenecteplase attained neurological improvement most effectively. The clinicians must tailor thrombolytic regimens after computing baseline characteristics to weigh the risks against the benefits.