Benefits and safety of transdermal glyceryl trinitrate in acute stroke: A systematic review and meta‐analysis of randomized trials

• Published in: Academic emergency medicine 2022-06, Vol.29 (6), p.772-788
• Main Authors: Lim, Beng Leong, Lee, Wei Feng, Ng, Wei Ming, Situ, Wangmin, Loo, Kee Vooi, Man Goh, Carmen Jia, Chan, Wui Ling
• Format: Article
• Language: English
• Subjects: Clinical outcomes; Clinical trials; Emergency medical care; glyceryl trinitrate; GTN; Meta-analysis; Mortality; Nitrates; Patient safety; Stroke; transdermal; Transdermal medication
• ISSN: 1069-6563; 1553-2712
• DOI: 10.1111/acem.14408

Background Transdermal glyceryl trinitrate (GTN) has potential beneficial properties in acute stroke including intracerebral hemorrhage (ICH) and possible clinical benefits suggested in ultra‐early stroke (≤6 h). Our meta‐analysis updated the evidence on its safety and benefits in acute stroke. Methods We searched major electronic databases for randomized trials comparing transdermal GTN versus placebo/control in acute stroke. Primary outcomes were mortality, 90‐day modified Rankin Scale (mRS), and blood pressure (BP) effects. Secondary outcomes included early, late, resource utilization, and surrogate outcomes. Safety outcomes were adverse events. Reviewers identified studies, extracted data, and assessed risk of bias (RoB) using a modified Cochrane RoB instrument and quality of evidence (QoE) using GRADE. We also performed a priori subgroup and trial sequential analyses (TSA) on primary outcomes. These subgroup analyses were ICH versus ischemic stroke, minor (NIHSS ≤5) versus major (NIHSS >5) ischemic stroke, ischemic stroke with versus without thrombolysis, prehospital versus non prehospital settings, time from stroke to randomization ≤6 h versus >6 h, and high versus low overall RoB studies. Results Seven eligible primary trials enrolled 5363 patients. GTN reduced BP (mean difference [MD] = –4.74 mm Hg, 95% confidence interval [CI] = –6.03 to –3.45 mm Hg] and diastolic BP (MD = –2.94 mm Hg, 95% CI = –3.74 to −2.13 mm Hg) 24 h posttreatment but did not affect 4‐ to 10‐day mortality (relative risk [RR] = 1.11, 95% CI = 0.82 to 1.49), 90‐day mortality (RR = 0.96, 95% CI = 0.77 to 1.19), and 90‐day mRS >2 (RR = 0.98, 95% CI = 0.93 to 1.03) compared to control/placebo. The QoE was high for primary outcomes with no subgroup effects detected. GTN did not affect secondary outcomes and increased risk of headache and hypotension. TSA generally supported our conclusions regarding primary outcomes. Conclusions Transdermal GTN reduces BP in acute stroke but does not alter clinical outcomes even in ultra‐early stroke (≤6 h).