This systematic review and meta-analysis aimed to evaluate the safety and efficacy of nerinetide in acute ischemic stroke (AIS) patients undergoing endovascular thrombectomy (EVT) without prior or concurrent intravenous thrombolysis (IVT).

Acute ischaemic stroke (AIS) due to large vessel occlusion is highly disabling and requires rapid reperfusion for optimal outcomes. Endovascular thrombectomy (EVT) has transformed care; however, many patients still experience poor functional recovery despite successful recanalisation. This has fuelled interest in adjunctive neuroprotective strategies to mitigate ischaemic injury before reperfusion.

Nerinetide has shown in preclinical models to reduce infarct volume and improve neurological recovery. However, its efficacy is diminished when co-administered with intravenous thrombolysis (IVT), as alteplase-generated plasmin inactivates nerinetide.

Three RCTs comprising 726 patients in the nerinetide group and 668 in the placebo group were included. Nerinetide did not significantly improve functional outcomes: 90-day modified Rankin Scale (mRS) 0–1 (RR 1.02, 95% CI: [0.70, 1.48], P = 0.92) and mRS 0–2 (RR 1.07, 95% CI: [0.93, 1.22], P = 0.35). No significant differences were observed in 90-day mortality (RR 0.89, 95% CI: [0.60, 1.34], P = 0.59) or adverse events including symptomatic intracranial hemorrhage (RR 0.80, 95% CI: [0.44, 1.45], P = 0.46).

Nerinetide administration during EVT in AIS patients without IVT did not significantly improve functional independence, survival, or safety outcomes compared to placebo. Although preclinical data supported neuroprotection, clinical benefits were not observed, highlighting the challenges in translating neuroprotective strategies into effective stroke therapies.