Efficacy and Safety of Nerinetide in Acute Ischemic Stroke Patients: A Systematic Review, Meta-Analysis and Meta Regression

Abstract

Purpose: Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. Nerinetide, a neuroprotective peptide, may limit ischemic brain injury. This systematic review and meta-analysis evaluated the efficacy and safety of nerinetide versus placebo in patients with AIS. Method: Following the PRISMA and AMSTAR 2 guidelines, PubMed, MEDLINE, Cochrane Library, ScienceDirect, and ClinicalTrials.gov were searched until July 2025 for randomized controlled trials (RCTs) involving adult patients with AIS. The primary outcome was mortality, and secondary outcomes included functional recovery (modified Rankin Scale [mRS] scores of 0–1 and 0–2 and Barthel index scores of ≥95), infarct volume, and adverse events. Pooled risk ratios (RR) or mean differences (MD) were calculated using a random-effects model, and meta-regression was used to explore baseline moderators. Findings: Three RCTs (n = 2462) were included in the analysis. Nerinetide showed a borderline significant mortality reduction versus placebo (RR = 0.86; 95% CI 0.75–1.00; p = 0.05) with low heterogeneity (I2 = 11%). No significant differences were found in functional recovery or overall infarct volume, although subgroup analyses without reperfusion therapy suggested a possible benefit. The rates of adverse events, including serious events, thromboembolism, seizures, and hypotension, were similar between the groups. Meta-regression indicated that atrial fibrillation (p = 0.0489) and prior stroke (p = 0.0519) were associated with a higher mortality risk. Conclusion: Nerinetide may modestly reduce mortality in AIS without increasing adverse events but does not significantly improve the functional outcomes. The benefits may be greater in patients who do not receive thrombolysis. Further large-scale trials are warranted to clarify the optimal use and interactions with reperfusion therapies.