Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. 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 UKbased ambulances by paramedics, with treatment continued in 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 ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.

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Word count 4490 AbbreviationsAim To test the safety and efficacy of 4 days of transdermal GTN (5 mg/day) versus sham in patients with ultra-acute presumed stroke who are recruited by paramedics prior to hospital presentation.Sample size estimates The sample size of 850 patients will allow a shift in the modified Rankin Scale (mRS) with odds ratio 0.70 (GTN versus sham, ordinal logistic regression) to be detected with 90% power at 5% significance (2-sided). Design The Rapid Intervention with Glyceryl trinitrate in Hypertensive strokeTrial-2 (RIGHT-2) is a multicentre UK prospective randomised sham-controlled outcome-blinded parallel-group trial in 850 patients with ultra-acute (<4 hours of onset) FAST-positive presumed stroke and systolic BP >120 mmHg who present to the ambulance service following a 999 emergency call. Data collection is performed via a secure internet site with real-time data validation. Study outcomesThe primary outcome is the mRS measured centrally by telephone at 90 days and masked to treatment. Secondary outcomes include:BP, impairment, recurrence, dysphagia, neuroimaging markers of the acute lesion including vessel patency, discharge disposition, length of stay, death, cognition, quality of life and mood. Neuroimaging and serious adverse events are adjudicated blinded to treatment.Discussion RIGHT-2 has recruited more than 500 participants from 7 UK ambulance services.RIGHT-2 protocol 21/7/17

Introduction: The ongoing Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2) is testing the safety and efficacy of paramedic-delivered transdermal glyceryl trinitrate (GTN) in patients with ultra-acute stroke. We sought to assess whether stroke mimics have a benign outcome in comparison to stroke patients. Methods: RIGHT-2 is an ongoing prospective randomised single-blind blinded-endpoint parallel group trial enrolling 1050 previously independently patients with suspected stroke (Face Arm Speech Test score ≥2/3) within 4 hours of onset. Consenting patients are randomised to receive GTN or sham patch in the pre-hospital setting. The primary outcome is the modified Rankin scale (mRS) assessed at day 90. Data are number (%) or mean (standard deviation). Results: As of July 2017, 600 patients had been recruited of which 146 (24.3%) were stroke mimics. Mimics were younger, age 65.1 (18.1) years; had a lower NIHSS 5.6 (6.3) vs 11.4 (7.4); and higher Glasgow coma scale, 14.3 (1.8) vs 13.6 (2.3) than stroke participants. The most common diagnoses were: seizure (16%), migraine/headache (16%) and functional (10%). Of those who have completed day 90 follow-up compared with stroke, mimics had significantly better functional outcome, mRS 2.6 (2.0) vs 3.9 (1.8), p<0.0001, and quality of life, and lower disability and depression scores, and a lower death rate, 11 (12.1%) vs 73 (26.4%), p=0.0047. Conclusion: Although their outcome is better than stroke participants, mimics do not necessarily have benign outcomes. Pragmatic pre-hospital trials with safety data on mimics may ultimately ease implementation of interventions into clinical practice.