Comparative efficacy and safety of tissue plasminogen activators (tPA) in acute ischemic stroke: A systematic review and network meta-analysis of randomized controlled trials

Background

Intravenous alteplase (ALT) is the standard treatment for acute ischemic stroke (AIS). However, recent trials comparing other tissue plasminogen activators (tPAs) like tenecteplase (TNK) and reteplase with ALT have yielded conflicting results. This necessitated a network meta-analysis to compare the efficacy and safety of various tPAs in AIS patients.

Methods

We searched MEDLINE, Embase, and CENTRAL (until September 15, 2024) for randomized controlled trials (RCTs) comparing TNK or reteplase (any dose) with ALT (0.9 mg/kg) in AIS patients. A frequentist network meta-analysis was performed using risk ratio (RR) and 95 % CI for each comparison, and P-scores ranked treatments. Analyses were done using R Software 4.4.1.

Results

Sixteen RCTs (9259 patients, 62.1 % males) were included. Reteplase 18+18 mg significantly improved excellent functional recovery (mRS 0-1) (RR: 1.13; p < 0.01) and independent ambulation (mRS 0-2) at 3 months (RR: 1.07; p < 0.01) compared to ALT. The 0.25 mg/kg TNK group also showed improved functional recovery (mRS 0-1) (RR: 1.06; p < 0.01). For safety, 0.1 mg/kg TNK was associated with a higher incidence of symptomatic intracranial hemorrhage (s-ICH) (RR: 7.27; p < 0.01). No significant differences in ICH or all-cause mortality were found between ALT and other treatments. Reteplase 18+18 mg ranked highest for functional recovery (P-score=0.9638) and ambulation (P-score=0.9749), while ALT ranked highest for s-ICH (P-score=0.8060). No significant differences were observed between reteplase and TNK.

Conclusion

Reteplase 18+18 mg and TNK 0.25 mg/kg demonstrated higher efficacy and comparable safety to ALT. Larger trials are needed to further explore these agents as alternatives to ALT.