TY - JOUR
T1 - Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP)
T2 - an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial
AU - van den Berg, Sophie A.
AU - Uniken Venema, Simone M.
AU - Reinink, Hendrik
AU - Hofmeijer, Jeannette
AU - Schonewille, Wouter J.
AU - Miedema, Irene
AU - Fransen, Puck S. S.
AU - O Pruissen, D. Martijn
AU - Raaijmakers, Theodora W. M.
AU - van Dijk, Gert W.
AU - de Leeuw, Frank-Erik
AU - van Vliet, Jorine A.
AU - Kwa, Vincent I. H.
AU - Kerkhoff, Henk
AU - van 't Net, Alex
AU - Boomars, Rene
AU - Siegers, Arjen
AU - Lok, Tycho
AU - Caminada, Klaartje
AU - Esteve Cuevas, Laura M.
AU - Visser, Marieke C.
AU - Zwetsloot, Casper P.
AU - Boomsma, Jooske M. F.
AU - Schipper, Mirjam H.
AU - van Eijkelenburg, Roeland P. J.
AU - Berkhemer, Olvert A.
AU - Nieboer, Daan
AU - Lingsma, Hester F.
AU - Emmer, Bart J.
AU - van Oostenbrugge, Robert J.
AU - van der Lugt, Aad
AU - Roos, Yvo B. W. E. M.
AU - Majoie, Charles B. L. M.
AU - Dippel, Diederik W. J.
AU - Nederkoorn, Paul J.
AU - van der Worp, H. Bart
AU - MR ASAP Investigators
AU - van Ahee, Ayla
AU - Visseren, Frank
AU - Halkes, Patricia
AU - van Eijk, Ruben
AU - Zock, Elles
AU - van den Berg, Rene
AU - Beenen, Ludo
AU - Roosendaal, Stefan
AU - Coutinho, Jonathan
AU - van Voorst, Henk
AU - LeCouffe, Natalie
AU - Kappelhof, Manon
AU - Tolhuisen, Manon
AU - Brouwer, Josje
AU - Simons, Michelle
AU - Steenwinkel, Frans
AU - Jansen, Ben
N1 - Funding Information: We thank the patients who participated in this trial, the relatives who contributed to this trial, the study teams at the participating ambulance services and hospitals (including all paramedics who treated patients), and the members of the trial DSMB. We thank Berber Zweedijk and Wouter Sluis for adjudicating outcomes. This study was funded by the CONTRAST consortium, which acknowledges financial support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015–01: CONTRAST), and from the Brain Foundation Netherlands (HA2015.01.06). The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the public–private partnership allowance made available by Health Holland Top Sector Life Sciences & Health to stimulate public–private partnerships (LSHM17016). This work was also funded, in part, through unrestricted funding from Stryker, Medtronic, and Cerenovus. Funding Information: HR reports financial support from the European Union's Horizon 2020 research and innovation program, paid to his institution. BJE reports financial support from Health Holland Top Sector Life Sciences & Health (via the Top Consortia for Knowledge and Innovation's public–private partnership), paid to his institution; and unpaid board membership of UEMS Neuroradiology and the Dutch Society of Radiology, Division of Neuroradiology. CBLMM, DWJD, PJN and HBvdW report funding from the Dutch Heart Foundation and Stryker, all paid to their institutions or the CONTRAST consortium. CBLMM reports financial support from the TWIN Foundation and Health Evaluation Netherlands, all paid to his institution. CBLMM and HBvdW report financial support from the European Commission, all paid to their institutions. CBLMM and YBWEMR are minor shareholders of Nicolab. DWJD reports grants from Medtronic, Cerenovus, Penumbra, Brain Foundation Netherlands, ZON MW–The Netherlands Organisation for Health Research and Development, and Health Holland Top Sector Life Sciences & Health, all paid to his institution. HBvdW reports honoraria for consultancy from Bayer and LivaNova, all paid to his institution. All other authors declare no competing interests. Publisher Copyright: © 2022 Elsevier Ltd
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85140052288&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1474-4422(22)00333-7
DO - https://doi.org/10.1016/S1474-4422(22)00333-7
M3 - Article
C2 - 36058230
SN - 1474-4422
VL - 21
SP - 971
EP - 981
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 11
ER -