Glyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial

Background High blood pressure is associated with a poor outcome after stroke. Trials of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, have suggested that treatment between 3 and 5 hours might improve functional outcome. Methods We randomly assigned hospitalised patients with an acute ischaemic or haemorrhagic stroke to 2 days of transdermal glyceryl trinitrate (GTN, 5 mg/day) or sham, started between 3 and 5 hours after onset. The primary feasibility outcome was recruitment rate; proof of concept was assessed by central observers blinded to treatment assignment at 90 days using the modified Rankin Scale (mRS). Data are number (%), median [interquartile range] or mean (standard deviation). Comparisons by adjusted multiple linear regression. Findings 39 of an intended 120 participants were recruited; common exclusions were presentation >5 hours of onset or out of researcher working hours, no eligible symptoms/signs or an unclear onset time. Mean age 72 (13) years, female 41%, blood pressure 161.8(18.4)/80.8(14.9) mmHg, time from onset at baseline 216 [186, 251] minutes. The fall in blood pressure over 24 hours did not differ between GTN versus sham. Headache was more common with GTN but there was no difference in serious adverse events. mRS at 3 months did not differ between the groups. Interpretation Recruitment limitations prevented demonstration of feasibility for patients in the time window of 3-5 hours post ictus. GTN appeared safe and showed some evidence of proof-of-concept. A multicentre trial needs to further test this hypothesis. Registration ISRCTN17654248 Date: 31/3/2021