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Prehospital Nitroglycerin in Ultra-Acute Stroke
Study Questions:
What is the safety and efficacy of transdermal glyceryl trinitrate (GTN; also known as nitroglycerin) when given very early after presumed stroke onset by paramedics before participants were admitted to the hospital?
Methods:
The RIGHT-2 trial investigators performed a multicenter, paramedic-delivered, ambulance-based, prospective, randomized, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 hours of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure ≥120 mm Hg. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in the hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischemic attack (TIA) (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan.
Results:
Between October 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1,149 participants (n = 568 in the GTN group, n = 581 in the sham group). The median time to randomization was 71 minutes (interquartile range [IQR], 45-116). A total of 597 (52%) patients had ischemic stroke, 145 (13%) had intracerebral hemorrhage, 109 (9%) had TIA, and 297 (26%) had a nonstroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5.8 mm Hg compared with the sham group (p < 0.0001), and diastolic blood pressure was lowered by 2.6 mm Hg (p = 0.0026) at hospital admission. They found no difference in mRS between the groups in participants with a final diagnosis of stroke or TIA (cohort 1): 3 (IQR, 2-5; n = 420) in the GTN group versus 3 (2-5; n = 408) in the sham group; adjusted common odds ratio for poor outcome, 1.25 (95% confidence interval, 0.97-1.60; p = 0.083). They also found no difference in mRS between all patients (cohort 2: 3 [2-5]; n = 544, in the GTN group vs. 3 [2-5]; n = 558, in the sham group; 1.04 [0.84-1.29]; p = 0.69). They found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs. 23 in the sham group [p = 0.091]), or serious adverse events (188 in the GTN group vs. 170 in the sham group [p = 0.16]) between treatment groups.
Conclusions:
The authors concluded that prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke.
Perspective:
This study reports that ultra-acute administration of GTN within 4 hours of stroke onset did not affect functional outcome in patients with the target diagnosis of confirmed stroke or TIA or in the overall population. The study did demonstrate that it was feasible for UK paramedics to recruit, obtain consent, and treat patients with stroke in the prehospital environment. It should be noted that, although RIGHT-2 was overall a neutral trial, GTN was associated with a tendency for a worse functional outcome, particularly in patients with intracerebral hemorrhage, very early stroke (<1 hour), and severe stroke (Glasgow Coma Scale score <12, National Institutes of Health Stroke Scale score >12). While the signals of potential adverse effect of GTN in the intracerebral hemorrhage subgroup analysis are not definitive, it would be advisable to closely monitor safety in ongoing trials of prehospital GTN in ultra-acute stroke (ISRCTN99503308).
Keywords: Blood Pressure, Brain Ischemia, Cerebral Hemorrhage, Emergency Medical Technicians, Ischemic Attack, Transient, Nitroglycerin, Primary Prevention, Stroke, Systole, Treatment Outcome, Vascular Diseases
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