Glyceryl Trinitrate versus Sham in the Treatment of Hyperacute Stroke: The Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) Feasibility Randomised Controlled Trial

INTRODUCTION: High blood pressure (BP) 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 h might improve functional outcome. METHODS: We randomly assigned hospitalised patients with an acute ischaemic or haemorrhagic stroke to 2 days of transdermal GTN (5 mg/day) or sham, started between 3 and 5 h after onset. The primary feasibility outcome was recruitment rate; proof-of-concept (PoC) was assessed at 90 days by central observers blinded to treatment assignment using the modified Rankin Scale (mRS). Data are number (%), median [interquartile range], or mean (standard deviation). Comparisons were assessed by multiple linear regression. RESULTS: Thirty-nine of an intended 120 participants were recruited. A total of 3,314 people were excluded, commonly related to presentation >5 h of onset or outside of researcher working hours, no eligible symptoms/signs or an unclear onset time. Mean age was 72 (SD 13) years, females were 41%, BP was 161.8 (18.4)/80.8 (14.9) mm Hg, and time from onset at baseline was 216 [186, 251] minutes. The fall in BP over 24 h did not differ between GTN versus sham. mRS at 3 months did not differ between the groups (difference in means, DIM -0.20, 95% confidence intervals -1.30, 0.90; p = 0.72). GTN was associated with improved cognition on the telephone interview of cognition scale (DIM 8.0, 95% CI 1.3, 14.8; p = 0.020). Although headache was more common, GTN was associated with fewer serious adverse events (p = 0.020). CONCLUSION: Recruitment limitations in this small single-centre trial prevented demonstration of feasibility for patients in the time window of 3-5 h post ictus. GTN demonstrated some evidence of PoC and was safe. A multicentre trial needs to further test this hypothesis.