Sabet, Haneen

Abstract Background and aims Intravenous thrombolysis (IVT) is the most common acute ischemic stroke (AIS) treatment. This study compared the efficacy and safety of different IVT agents to determine the optimal option for AIS management. Methods A comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane CENTRAL until 23 March 2025. Randomized controlled trials (RCTs) on alteplase (tPA), tenecteplase (TNK), reteplase, and recombinant human pro-urokinase (rhPro-UK) of any dose in AIS were included. A frequentist network meta-analysis was conducted using R software to pool risk ratios (RRs) with 95% confidence intervals (CIs). Results Twenty-one RCTs (10,852 patients) were included. Compared with tPA 0.9 mg/kg, tPA 0.6 mg/kg showed a lower risk of symptomatic intracranial hemorrhage (RR, 95% CI: 0.48 [0.27–0.86]), whereas TNK 0.4 mg/kg showed a higher risk (RR, 95% CI: 1.88 [1.06–3.35]). Reteplase 18 + 18 mg (RR, 95% CI: 1.13 [1.05–1.21]) and TNK 0.25 mg/kg (RR, 95% CI: 1.05 [1.01–1.10]) were associated with higher rates of excellent functional outcome at 90 days (mRS 0–1) compared with tPA 0.9 mg/kg. No significant differences were observed among interventions in 90-day mortality and favorable function outcomes (mRS 0–2), or serious adverse events. Conclusions Thrombolytic efficacy and safety in AIS appear to be dose dependent. A lower tPA dose (0.6 mg/kg) improved safety; reteplase 18 + 18 mg and TNK 0.25 mg/kg favored functional recovery, whereas a higher TNK dose increased sICH risk, underscoring the importance of dose optimization in IVT selection. Conflict of interest Haneen Sabet: nothing to disclose, Moaz Elsayed Abouelmagd: nothing to disclose, Abdelrahman Shata: nothing to disclose, Mohamed El-Moslemani: nothing to disclose, Diana Kadi: nothing to disclose, Dina Essam Abo-elnour: nothing to disclose, Abdallah Abbas: nothing to disclose, Ramanathan Kadirvel: nothing to disclose, Sherief Ghozy: nothing to disclose Figure 1 - belongs to Results

Objective: To evaluate the safety and efficacy of recombinant human prourokinase (rhPro-UK) administered via intravenous (IV) and intra-arterial (IA) routes in acute ischemic stroke (AIS) patients compared with standard treatments. Methods: A comprehensive search was conducted in accordance with PRISMA guidelines across Scopus, Web of Science, and PubMed until 11 December 2024. Randomized controlled trials (RCTs) assessing rhPro-UK’s efficacy and safety were included. Outcomes included the modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), mortality, and adverse events (AEs). Data analysis used risk difference (RD) with 95% confidence intervals (CIs). Results: Six RCTs (n = 3993) met the inclusion criteria. IV rhPro-UK showed comparable efficacy to the comparator for the mRS 0–1 at 90 days (RD: 0.00, 95% CI: [−0.04, 0.04]) and the mRS 0–2 (RD: −0.01, 95% CI: [−0.03, 0.01], P = 0.23). IA rhPro-UK significantly improved the mRS 0–1 (RD: 0.13, 95% CI: [0.01, 0.26], P = 0.04). The NIHSS reduction was significant for IV rhPro-UK (MD: −0.83, 95% [CI: −1.36, −0.29]). IV rhPro-UK did not significantly reduce the risk of systemic bleeding (RD: −0.10, 95% CI: [−0.24, 0.03], P = 0.12), serious AEs (RD: −0.01, 95% CI: [−0.04, 0.02], P = 0.53), or mortality (RD: 0.01, 95% CI: −0.01, 0.02). IA rhPro-UK significantly increased hemorrhage with neurological deterioration (RD: 0.08, 95% CI: [0.01, 0.14], P = 0.02). Conclusions: IV rhPro-UK provides non-inferior efficacy to both alteplase and standard care with a better safety profile at 35 mg, while IA rhPro-UK enhances functional outcomes in middle cerebral artery occlusions, albeit with safety concerns. Further trials are needed to confirm long-term outcomes, optimal dosing, and broader applicability.