Considering prehospital stroke trials: did RIGHT-2 get it right?
Authors: Karen C Johnston, Valerie L Durkalski-Mauldin
Journal: The Lancet (2019)

Hypertension at the time of first assessment in stroke is common and associated with poor outcome.1Leonardi-Bee J Bath PM Phillips SJ Sandercock PA Blood pressure and clinical outcomes in the International Stroke Trial.Stroke. 2002; 33: 1315-1320Crossref PubMed Scopus (787) Google Scholar, 2Ohwaki K Yano E Nagashima H Hirata M Nakagomi T Tamura A Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement.Stroke. 2004; 35: 1364-1367Crossref PubMed Scopus (320) Google Scholar Previous clinical trials have shown that lowering of blood pressure in the first 24 h of ischaemic stroke3Nasi LA Martins SCO Gus M et al.Early manipulation of arterial blood pressure in acute ischemic stroke (MAPAS): results of a randomized controlled trial.Neurocrit Care. 2018; (published online Nov 20.)DOI:0.1007/s12028-018-0642-5Crossref PubMed Scopus (21) Google Scholar and in the first 6 h in intracerebral haemorrhage4Qureshi AI Palesch YY Barsan WG et al.Intensive blood–pressure lowering in patients with acute cerebral hemorrhage.N Engl J Med. 2016; 375: 1033-1043Crossref PubMed Scopus (573) Google Scholar, 5Anderson CS Heeley E Huang Y et al.Rapid blood–pressure lowering in patients with acute intracerebral hemorrhage.N Engl J Med. 2013; 368: 2355-2365Crossref PubMed Scopus (1042) Google Scholar does not improve outcomes in these populations. The RIGHT-2 study6The RIGHT-2 InvestigatorsPrehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial.Lancet. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S0140-6736(19)30194-1Google Scholar in The Lancet was a multicentre, ambulance-based, randomised, sham-controlled, phase 3 trial with masked outcome assessment designed to assess the safety and efficacy of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, in a hyperacute stroke population. 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. The investigators enrolled a total of 1149 patients (mean age 72·5 years; 48% women) and found no improved outcome in the GTN group compared with the sham group in cohort 1 (patients with stroke or transient ischaemic attack; adjusted common odds ratio [acOR] 1·25 [95% CI 0·97–1·60]; p=0·083) or in cohort 2 (all patients—ie, intention to treat [ITT]; 1·04 [0·84–1·29]; p=0·69). No difference was found between the two groups in deaths at day 4 in either cohort (cohort 1: acOR 1·17 [0·57–2·39]; p=0·68; cohort 1: 1·19 [0·60–2·35]; p=0·63). Additional analyses suggested potential harm, with worse outcomes in patients with intracerebral haemorrhage (p=0·057), the earliest enrolled (<1 h) patients (p=0·014), and the most severe strokes (National Institutes of Health Stroke Scale >12; 0·044). We believe the clinical community now has data from numerous populations suggesting that blood pressure lowering in the acute and hyperacute setting is not beneficial to patients with stroke. Although the intervention did not improve clinical outcome, prehospital treatment with GTN used 184 ambulance stations in eight ambulances services in England and Wales as the trial sites, and 516 paramedics as the front-line recruiting investigators. This trial6The RIGHT-2 InvestigatorsPrehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial.Lancet. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S0140-6736(19)30194-1Google Scholar is the first in the UK to our knowledge to show the ability of the emergency medical service teams to successfully enrol in a hyperacute stroke clinical trial in the field. The FAST-MAG trial7Saver JL Starkman S Eckstein M et al.Prehospital use of magnesium sulfate as neuroprotection in acute stroke.N Engl J Med. 2015; 372: 528-536Crossref PubMed Scopus (270) Google Scholar in the USA has previously shown such a model, with the enrolment of 1700 patients in a phase 3 trial assessing magnesium (4 g intravenous magnesium sulphate) in acute stroke in the Los Angeles area. Such trials are changing the paradigm of acute stroke research by showing the feasibility of very early treatment initiation within a median of 45 min for FAST-MAG7Saver JL Starkman S Eckstein M et al.Prehospital use of magnesium sulfate as neuroprotection in acute stroke.N Engl J Med. 2015; 372: 528-536Crossref PubMed Scopus (270) Google Scholar and 73 min for RIGHT-2.6The RIGHT-2 InvestigatorsPrehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial.Lancet. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S0140-6736(19)30194-1Google Scholar The limitations of a prehospital enrolment model are also shown in RIGHT-2. This trial had an original sample size of 850 patients (425 per group), which provided 90% power to detect an ordinal shift in the mRS. This sample size took into account a 3% loss to follow-up and a 20% stroke mimic rate. During the trial, the non-stroke diagnosis rate exceeded 30% in patients who were randomly assigned, therefore reducing the power to assess the efficacy of the intervention in the target population. Thus, the sample size was increased to 1050 to maintain statistical power at the predefined clinically relevant difference. Additionally, a decision was made by the trial steering committee to specify a hierarchical analysis with the first analysis of patients with stroke or transient ischaemic attack (cohort 1) and the second analysis of all patients (the ITT population; cohort 2), which presumably was the primary analysis population initially. The final study population (n=1149; cohort 1, n=852) included 52% with ischaemic stroke, 13% intracerebral haemorrhage, 9% transient ischaemic attack, and 26% stroke mimics. The RIGHT-2 investigators stated that they did not expect the treatment to benefit non-stroke patients but acknowledged that this population would be enrolled and treated under the current design. Although cohort 1 primary analysis addresses this high mimic rate, future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis. Incorporation of additional features, similar to what was done in FAST-MAG,7Saver JL Starkman S Eckstein M et al.Prehospital use of magnesium sulfate as neuroprotection in acute stroke.N Engl J Med. 2015; 372: 528-536Crossref PubMed Scopus (270) Google Scholar might help avoid a high stroke mimic rate. FAST-MAG had 73% of patients with ischaemic stroke and 23% of patients with haemorrhagic stroke with only a 4% stroke mimic rate. The trial design used a physician on the telephone with the emergency medical teams at the time of enrolment.7Saver JL Starkman S Eckstein M et al.Prehospital use of magnesium sulfate as neuroprotection in acute stroke.N Engl J Med. 2015; 372: 528-536Crossref PubMed Scopus (270) Google Scholar The use of telemedicine techniques in the ambulance to bring the stroke provider into direct contact with the patient and emergency medical services provider might be another approach in clinical trials to reduce enrolment of mimics.8Magdon-Ismail Z Benesch C Cushman JT et al.Establishing recommendations for stroke systems in the thrombectomy era: the upstate New York stakeholder proceedings.Stroke. 2017; 48: 2003-2006Crossref PubMed Scopus (9) Google Scholar Early data suggest reliability of technology9Chapman SSN Govindarajan P Padrick MM et al.A low-cost, tablet-based option for prehospital neurologic assessment: the iTREAT study.Neurology. 2016; 87: 19-26Crossref PubMed Scopus (40) Google Scholar and accurate stroke diagnosis,10Espinoza AV Van Hooff RJ De Smedt A et al.for the PreSSUM-ConsortiumDevelopment and pilot testing of 24/7 in-ambulance telemedicine for acute stroke: prehospital stroke study at the Universitari Ziekenhuis Brussel-Project.Cerebrovasc Dis. 2016; 42: 15-22Crossref PubMed Scopus (20) Google Scholar although further research is needed. Improved tools to exclude stroke mimics in the field have been difficult to develop and validate.11Glober N Sporer K Guluma K et al.Acute stroke: current evidence-based recommendations for prehospital care.West J Emerg Med. 2016; 17: 104-128Crossref PubMed Scopus (31) Google Scholar The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischaemic stroke from intracerebral haemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations. In addition to design aspects, a key element in the interpretation of the results of RIGHT-26The RIGHT-2 InvestigatorsPrehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial.Lancet. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S0140-6736(19)30194-1Google Scholar is the effect of the intervention on blood pressure, as measured by the separation between the two treatment groups. Systolic blood pressure was lower in the GTN group than the sham group by 5·8 mm Hg after initial treatment, and diastolic blood pressure was lower by 2·6 mm Hg; at day 2, systolic blood pressure was lower by 5·3 mm Hg and diastolic by 2·6 mm Hg in the GTN group compared with the sham group. However, these differences between groups in blood pressure might not be considered clinically relevant in this setting. The ATACH-24Qureshi AI Palesch YY Barsan WG et al.Intensive blood–pressure lowering in patients with acute cerebral hemorrhage.N Engl J Med. 2016; 375: 1033-1043Crossref PubMed Scopus (573) Google Scholar and Interact-25Anderson CS Heeley E Huang Y et al.Rapid blood–pressure lowering in patients with acute intracerebral hemorrhage.N Engl J Med. 2013; 368: 2355-2365Crossref PubMed Scopus (1042) Google Scholar studies showed a 12–14 mm Hg systolic blood pressure difference between treatment groups, although they also did not show benefit in the patients with intracerebral haemorrhage. Additionally, the RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4 (45% in cohort 1; 36% in cohort 2). Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 h of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke. Additionally, the trial has added to the existing data that show that future hyperacute treatment trials can successfully offer study treatment in the prehospital setting. We declare no competing interests. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trialPrehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting. Full-Text PDF Open Access