To compare the functional outcomes of intravenous alteplase and tenecteplase against placebo before thrombectomy in acute ischemic stroke.

Alteplase and tenecteplase differ as thrombolytics for acute ischemic stroke, yet comparative effectiveness on functional outcomes before mechanical thrombectomy remains uncertain.

We conducted a systematic review and meta-analysis following PRISMA guidelines. Suitable studies were identified through a comprehensive search performed across major databases up to July 2025. Data were analyzed using R (version 4.5.1) in RStudio, with the packages netmeta, gemtc, BUGSnet and bnma. Frequentist analysis was employed to indirectly measure the efficacy using random models.

Across 7 included RCTs, Modified Rankin Scale (mRS) outcomes provided differential insights: mRS at 90 days showed a significant difference favouring alteplase over tenecteplase and placebo as per Frequentist analysis (MD 1 [0.30, 1.70]); SUCRA ranked alteplase highest(84.3%) over placebo(63%) and tenecteplase(2.7%). While mRS 0-1 and 0-2 at 90 days were more likely with tenecteplase (frequentist OR 1.47 [1.1,2.1] and 1.50[1.1,2.0], respectively), SUCRA consistently ranked tenecteplase highest (95.5% and 97.2%) over alteplase(38.2% and 21.5%) and placebo(16.3% and 31.3%). For mRS 0-3, trends favoured tenecteplase (SUCRA 90.0%) over alteplase(46.3%) and placebo(13.6%), though confidence intervals crossed unity[0.99,1.99]. Frequentist analysis supports the above results, favouring tenecteplase, except mean mRS at 90 days. Inconsistencies across models were minimal.

This NMA highlights the significant differences between the two lytics. Tenecteplase persistently ranked highest for long-term functional independence, suggesting a potential advantage in sustained recovery after stroke. Further large scale RCTs are necessary to achieve clinical translation. Variations in functional outcomes likely result from mechanisms involving thrombolytic potency, reperfusion quality, and neural tissue repair.