The demand for more effective and safer thrombolytic agents for acute ischemic stroke (AIS) has been increasingly recognized. Reteplase is a mutant form of alteplase with practical advantages. Nevertheless, the role of reteplase in patients with AIS is uncertain.

We searched electronic databases to identify randomised clinical trials (RCTs) comparing reteplase to alteplase in AIS patients presenting within 4.5 h. The primary outcomes were the 90-day excellent functional outcome (modified Rankin scale [mRS] of 0–1) and symptomatic intracerebral hemorrhage (sICH). Secondary outcomes included 90-day good functional outcome (mRS 0–2), early neurological improvement (ENI), and 90-day mortality. Odds ratios (ORs) with 95 % confidence intervals (CIs) were pooled using the fixed-effects model.

Of the 544 identified records, we included two high-quality RCTs (1588 patients). A total of 833 patients received reteplase (60 with 12 + 12 mg and 773 with 18 + 18 mg), while 755 patients received alteplase 0.9 mg/kg. Reteplase was associated with higher rates of excellent functional outcomes (OR, 1.55 [95 % CI, 1.23–1.95]), good functional outcomes (OR, 1.36 [95 % CI, 1.04–1.77]), and ENI (OR, 1.42 [95 %CI, 1.16–1.73]) compared to alteplase. Similar rates of sICH (OR, 1.25 [95 %CI, 0.64–2.47]) and mortality (OR, 1.18 [95 %CI, 0.72–1.92]) were noted. Optimal benefits were reported in patients treated with 18 + 18 mg of reteplase.

In this meta-analysis, reteplase, particularly at the 18 + 18 mg dose, was more effective than alteplase with comparable safety profiles. These findings suggest that reteplase could be a viable alternative to alteplase for stroke thrombolysis. Multinational trials are needed to validate the generalizability of these results to a broader population.