Comparative efficacy of different acute reperfusion therapies for acute ischemic stroke: a comprehensive benefit-risk analysis of clinical trials

Background: Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit-risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset-to-treatment time (OTT). Methods: A comprehensive literature search was conducted to identify all available published, peer-reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit-to-risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0-1) or functional independence (BRR2, mRS score: 0-2) at 3 months divided by the percentage of patients who died during the same period. Results: A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria. IV therapy with tenecteplase (TNK) was found to have the highest BRRs (BRR1 = 5.76 and BRR2 = 6.82 for low-dose TNK; BRR1 = 5.80 and BRR2 = 6.87 for high-dose TNK), followed by sonothrombolysis (BRR1 = 2.75 and BRR2 = 3.38), while endovascular thrombectomy with MERCI retriever was found to have the lowest BRRs (BRR1 range, 0.31-0.65; BRR2 range, 0.52-1.18). A second degree negative polynomial correlation was detected between favorable functional outcome and OTT (R 2 value: 0.6419; P < 0.00001) indicating the time dependency of clinical efficacy of all reperfusion therapies. Conclusion: Intravenous thrombolysis (IVT) with TNK and sonothrombolysis have the higher BRR among investigational reperfusion therapies. The combination of sonothrombolysis with IV administration of TNK appears a potentially promising therapeutic option deserving further investigation.