Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials

Abstract

Background. Nitric oxide (NO) donors are a candidate treatment for acute stroke and two trials have suggested that they might improve outcome if administered within 4–6 hours of stroke onset. We assessed the safety and efficacy of NO donors using individual patient data (IPD) from completed trials. Methods. Randomised controlled trials of NO donors in patients with acute or subacute stroke were identified and IPD sought from the trialists. The effect of NO donor versus control on functional outcome was assessed using the modified Rankin scale (mRS) and death, by time to randomisation. Secondary outcomes included measures of disability, mood, and quality of life. Results. Five trials (4,197 participants) were identified, all involving glyceryl trinitrate (GTN). Compared with control, GTN lowered blood pressure by 7.4/3.3 mmHg. At day 90, GTN did not alter any clinical measures. However, in 312 patients randomised within 6 hours of stroke onset, GTN was associated with beneficial shifts in the mRS (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.34–0.78) and reduced death (OR 0.32, 95% CI 0.14–0.78). Conclusions. NO donors do not alter outcome in patients with recent stroke. However, when administered within 6 hours, NO donors might improve outcomes in both ischaemic and haemorrhagic stroke.

Statistical analysis plan for the ‘Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2)’

“…Four small clinical studies of glyceryl trinitrate (GTN), a NO donor that can be administered transdermally, in patients with recent stroke found that it reduced blood pressure (an independent risk factor for a poor outcome (22)(23)(24)) and pulse pressure; had no effects on middle cerebral artery blood flow velocity, cerebral blood flow, or intracranial pressure; did not alter platelet activity (so GTN can be given in ICH); (14,(25)(26)(27) (28); however, functional outcome was improved in those patients recruited within 6 hours (a prespecified subgroup) (28,29), this result mirroring that seen in RIGHT (30).…”

Therapeutic Potential of Transdermal Glyceryl Trinitrate in the Management of Acute Stroke

“…An individual patient data meta-analysis using data from the five completed GTN trials (GTN-1/2/3, ENOS, RIGHT, n  = 4197) supported the findings that treatment with GTN within 6 h of onset ( n  = 312), but not later, improved functional outcome and secondary outcomes across a range of domains: cognition; death; disability; mood; and quality of life (Table 2) [50]. The time-dependent effect on functional outcome was seen in both IS and ICH; a finding supported by a subgroup analysis of participants with ICH from the ENOS trial [51].…”

“…As previously alluded to, GTN positively influenced several clinical outcomes when given early in both IS and ICH [50]. Whether GTN has the same effects in patients with lacunar syndromes, lacunar strokes or small vessel disease is unclear and further analysis is required.…”

“…In the aforementioned meta-analysis, those with IS who received thrombolysis, given either before or after randomisation, had a significant shift to less death or dependency in the presence of GTN. A tendency to improved outcome was also seen in those with IS who did not receive intravenous alteplase [50]. …”

“…A tendency to improved outcome was also seen in those with IS who did not receive intravenous alteplase [50]. …”