Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial.

BACKGROUND: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. METHODS: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. FINDINGS: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]). INTERPRETATION: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study.

BACKGROUND: Due to the time-sensitive effect of endovascular treatment, rapid prehospital identification of large-vessel occlusion in individuals with suspected stroke is essential to optimise outcome. Interhospital transfers are an important cause of delay of endovascular treatment. Prehospital stroke scales have been proposed to select patients with large-vessel occlusion for direct transport to an endovascular-capable intervention centre. We aimed to prospectively validate eight prehospital stroke scales in the field. METHODS: We did a multicentre, prospective, observational cohort study of adults with suspected stroke (aged ≥18 years) who were transported by ambulance to one of eight hospitals in southwest Netherlands. Suspected stroke was defined by a positive Face-Arm-Speech-Time (FAST) test. We included individuals with blood glucose of at least 2·5 mmol/L. People who presented more than 6 h after symptom onset were excluded from the analysis. After structured training, paramedics used a mobile app to assess items from eight prehospital stroke scales: Rapid Arterial oCclusion Evaluation (RACE), Los Angeles Motor Scale (LAMS), Cincinnati Stroke Triage Assessment Tool (C-STAT), Gaze-Face-Arm-Speech-Time (G-FAST), Prehospital Acute Stroke Severity (PASS), Cincinnati Prehospital Stroke Scale (CPSS), Conveniently-Grasped Field Assessment Stroke Triage (CG-FAST), and the FAST-PLUS (Face-Arm-Speech-Time plus severe arm or leg motor deficit) test. The primary outcome was the clinical diagnosis of ischaemic stroke with a proximal intracranial large-vessel occlusion in the anterior circulation (aLVO) on CT angiography. Baseline neuroimaging was centrally assessed by neuroradiologists to validate the true occlusion status. Prehospital stroke scale performance was expressed as the area under the receiver operating characteristic curve (AUC) and was compared with National Institutes of Health Stroke Scale (NIHSS) scores assessed by clinicians at the emergency department. This study was registered at the Netherlands Trial Register, NL7387. FINDINGS: Between Aug 13, 2018, and Sept 2, 2019, 1039 people (median age 72 years [IQR 61-81]) with suspected stroke were identified by paramedics, of whom 120 (12%) were diagnosed with aLVO. Of all prehospital stroke scales, the AUC for RACE was highest (0·83, 95% CI 0·79-0·86), followed by the AUC for G-FAST (0·80, 0·76-0·84), CG-FAST (0·80, 0·76-0·84), LAMS (0·79, 0·75-0·83), CPSS (0·79, 0·75-0·83), PASS (0·76, 0·72-0·80), C-STAT (0·75, 0·71-0·80), and FAST-PLUS (0·72, 0·67-0·76). The NIHSS as assessed by a clinician in the emergency department did somewhat better than the prehospital stroke scales with an AUC of 0·86 (95% CI 0·83-0·89). INTERPRETATION: Prehospital stroke scales detect aLVO with acceptable-to-good accuracy. RACE, G-FAST, and CG-FAST are the best performing prehospital stroke scales out of the eight scales tested and approach the performance of the clinician-assessed NIHSS. Further studies are needed to investigate whether use of these scales in regional transportation strategies can optimise outcomes of patients with ischaemic stroke. FUNDING: BeterKeten Collaboration and Theia Foundation (Zilveren Kruis).