Nerinetide Outcomes for Treatment of Acute Ischemic Stroke

Study Questions:

Does treatment with the neuroprotectant nerinetide improve outcomes for patients with acute ischemic stroke secondary to large vessel occlusion who undergo mechanical thrombectomy?


ESCAPE-NA1 is a multisite, randomized, placebo-controlled trial. Eligible patients had an acute ischemic stroke caused by occlusion of the intracranial internal carotid artery or proximal middle cerebral artery and were <12 hours from last known normal with mechanical thrombectomy planned. Patients could receive alteplase (intravenous tissue plasminogen activator [tPA]) if eligible. Patients were randomly assigned to receive either a dose of nerinetide or placebo, and this treatment was to be given before arterial access closure. The primary outcome was a favorable modified Rankin scale (mRS) score of 0-2 at 90 days. Safety outcomes included all serious adverse events and mortality. An intention-to-treat analysis was performed, and an analysis for treatment effect by alteplase use was prespecified.


A total of 549 patients received nerinetide and 556 received placebo. Approximately 60% of patients in both groups received alteplase. There was no difference in the primary outcome (mRS score 0-2) between the nerinetide and placebo groups (adjusted risk ratio [aRR], 1.04; 95% confidence interval [CI], 0.96-1.14). There were no differences in mortality or serious adverse events between the two groups. A treatment effect was observed in patients who were not treated with alteplase, such that patients treated with nerinetide were more likely to achieve an mRS score of 0-2 compared to those treated with placebo (59.3% compared to 49.6%; aRR, 1.18; 95% CI, 1.01-1.38) and had a lower risk of death compared to those treated with placebo (hazard ratio, 0.56; 95% CI, 0.35-0.95).


Nerinetide is a neuroprotective agent that inhibits neuronal excitotoxicity and showed promise in preclinical acute ischemic stroke trials. The results of this trial showed no benefit of nerinetide compared to placebo in preventing disability in all patients with acute ischemic stroke secondary to large vessel occlusion treated with thrombectomy. However, in a prespecified subgroup analysis of patients not treated with alteplase (IV tPA), nerinetide was associated with improved outcomes compared to placebo.


Historically, studies of neuroprotective agents in acute ischemic stroke have been disappointing, and this trial largely deserves that descriptor. While a treatment effect of nerinetide was observed in patients who were not treated with alteplase, this result will require confirmatory testing.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism

Keywords: Brain Ischemia, Carotid Artery, Internal, Middle Cerebral Artery, Neuroprotective Agents, Risk, Secondary Prevention, Stroke, Thrombectomy, Tissue Plasminogen Activator

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