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Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial
The Lancet Neurology ( IF 46.5 ) Pub Date : 2022-09-01 , DOI: 10.1016/s1474-4422(22)00333-7
Sophie A van den Berg 1 , Simone M Uniken Venema 2 , Hendrik Reinink 2 , Jeannette Hofmeijer 3 , Wouter J Schonewille 4 , Irene Miedema 5 , Puck S S Fransen 6 , D Martijn O Pruissen 7 , Theodora W M Raaijmakers 8 , Gert W van Dijk 9 , Frank-Erik de Leeuw 10 , Jorine A van Vliet 11 , Vincent I H Kwa 12 , Henk Kerkhoff 13 , Alex van 't Net 14 , Rene Boomars 15 , Arjen Siegers 16 , Tycho Lok 17 , Klaartje Caminada 18 , Laura M Esteve Cuevas 19 , Marieke C Visser 20 , Casper P Zwetsloot 21 , Jooske M F Boomsma 22 , Mirjam H Schipper 23 , Roeland P J van Eijkelenburg 24 , Olvert A Berkhemer 25 , Daan Nieboer 26 , Hester F Lingsma 26 , Bart J Emmer 27 , Robert J van Oostenbrugge 28 , Aad van der Lugt 29 , Yvo B W E M Roos 1 , Charles B L M Majoie 27 , Diederik W J Dippel 30 , Paul J Nederkoorn 1 , H Bart van der Worp 2 ,
Affiliation  

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.



中文翻译:

院前经皮三硝酸甘油酯治疗疑似急性中风患者 (MR ASAP):一项基于救护车、多中心、随机、开放标签、终点盲法的 3 期试验

背景

对先前随机研究的汇总分析表明,极早使用三硝酸甘油酯(也称为硝酸甘油)治疗可改善急性缺血性中风或脑出血患者的功能结果,但这一发现未在最近的一项试验中得到证实 (RIGHT-2) . 我们的目的是评估疑似急性中风的患者是否从症状发作后 3 小时内开始的硝酸甘油中获益。

方法

MR ASAP 是一项 3 期、随机、开放标签、盲法终点试验,在为荷兰 18 家医院提供服务的六辆救护车服务中进行。符合条件的参与者(年龄≥18 岁)可能被诊断为急性中风(由护理人员评估),面部-手臂-语言时间测试得分为 2 或 3,收缩压至少为 140 毫米汞柱,并且可能症状出现后 3 小时内开始治疗。参与者由救护人员随机分配 (1:1),使用基于网络的安全电子应用程序,随机块大小由救护车服务分层,接受透皮三硝酸甘油 5 mg/天 24 小时加标准护理(三硝酸甘油组) 或在院前环境中单独进行标准护理(对照组)。知情同意被推迟到到达医院后。主要结果是 90 天时使用改良 Rankin 量表 (mRS) 评估的功能结果。安全结果包括 7 天内死亡、90 天内死亡和严重不良事件。分析基于修改后的治疗意向,治疗效果表示为比值比 (OR) 或常见 OR,并根据基线预后因素进行了调整。我们分别分析了总人群和目标人群(即脑出血、缺血性卒中或短暂性脑缺血发作患者)。目标样本量为 1400 名患者。该试验注册为 ISRCTN99503308。和治疗效果表示为比值比 (OR) 或常见 OR,并根据基线预后因素进行调整。我们分别分析了总人群和目标人群(即脑出血、缺血性卒中或短暂性脑缺血发作患者)。目标样本量为 1400 名患者。该试验注册为 ISRCTN99503308。和治疗效果表示为比值比 (OR) 或常见 OR,并根据基线预后因素进行调整。我们分别分析了总人群和目标人群(即脑出血、缺血性卒中或短暂性脑缺血发作患者)。目标样本量为 1400 名患者。该试验注册为 ISRCTN99503308。

发现

2021 年 6 月 24 日,根据数据和安全监测委员会的建议,MR ASAP 试验提前终止,由于脑出血患者的安全问题,招募停止。2018 年 4 月 4 日至 2021 年 2 月 12 日期间,380 名患者被随机分配到一个研究组。325 人提供知情同意或在获得同意前死亡,其中 170 人被分配到三硝酸甘油酯组,155 人被分配到对照组。这些患者被包括在总人口中。201 名患者 (62%) 患有缺血性中风,34 名 (10%) 患者患有短暂性脑缺血发作,56 名 (17%) 患者患有脑出血,34 名 (10%) 患者患有中风样症状。在总人群 (n=325) 中,三硝酸甘油酯组和对照组在 90 天时的中位 mRS 评分均为 2 (IQR 1–4)(调整后的共同 OR 0·97 [95% CI 0·65–1· 47])。在目标人群 (n=291) 中,三硝酸甘油酯组的 90 天 mRS 评分为 2 (2–4),对照组为 3 (1–4) (0·92 [0·59–1· 43]). 在总人群中,两个研究组之间在 90 天内死亡(调整后的 OR 1·07 [0·53–2·14])或严重不良事件(未调整的 OR 1·23 [0· 76–1·99])。在脑出血患者中,分配至三硝酸甘油组的 35 名患者中有 12 名 (34%) 与分配至对照组的 21 名患者中的两名 (10%) 在 7 天内死亡(调整后的 OR 5·91 [0·78–44·81] ); 三硝酸甘油酯组 35 人中有 16 人 (46%) 和对照组 20 人中有 11 人 (55%) 在 90 天内死亡(调整后的 OR 为 0·87 [0·18–4·17])。三硝酸甘油酯组的 90 天 mRS 评分为 2 (2–4),而对照组为 3 (1–4) (0·92 [0·59–1·43])。在总人群中,两个研究组之间在 90 天内死亡(调整后的 OR 1·07 [0·53–2·14])或严重不良事件(未调整的 OR 1·23 [0· 76–1·99])。在脑出血患者中,分配至三硝酸甘油组的 35 名患者中有 12 名 (34%) 与分配至对照组的 21 名患者中的两名 (10%) 在 7 天内死亡(调整后的 OR 5·91 [0·78–44·81] ); 三硝酸甘油酯组 35 人中有 16 人 (46%) 和对照组 20 人中有 11 人 (55%) 在 90 天内死亡(调整后的 OR 为 0·87 [0·18–4·17])。三硝酸甘油酯组的 90 天 mRS 评分为 2 (2–4),而对照组为 3 (1–4) (0·92 [0·59–1·43])。在总人群中,两个研究组之间在 90 天内死亡(调整后的 OR 1·07 [0·53–2·14])或严重不良事件(未调整的 OR 1·23 [0· 76–1·99])。在脑出血患者中,分配至三硝酸甘油组的 35 名患者中有 12 名 (34%) 与分配至对照组的 21 名患者中的两名 (10%) 在 7 天内死亡(调整后的 OR 5·91 [0·78–44·81] ); 三硝酸甘油酯组 35 人中有 16 人 (46%) 和对照组 20 人中有 11 人 (55%) 在 90 天内死亡(调整后的 OR 为 0·87 [0·18–4·17])。两个研究组之间在 90 天内死亡(调整后的 OR 1·07 [0·53–2·14])或严重不良事件(未调整的 OR 1·23 [0·76–1·99])方面没有差异]). 在脑出血患者中,分配至三硝酸甘油组的 35 名患者中有 12 名 (34%) 与分配至对照组的 21 名患者中的两名 (10%) 在 7 天内死亡(调整后的 OR 5·91 [0·78–44·81] ); 三硝酸甘油酯组 35 人中有 16 人 (46%) 和对照组 20 人中有 11 人 (55%) 在 90 天内死亡(调整后的 OR 为 0·87 [0·18–4·17])。两个研究组之间在 90 天内死亡(调整后的 OR 1·07 [0·53–2·14])或严重不良事件(未调整的 OR 1·23 [0·76–1·99])方面没有差异]). 在脑出血患者中,分配至三硝酸甘油组的 35 名患者中有 12 名 (34%) 与分配至对照组的 21 名患者中的两名 (10%) 在 7 天内死亡(调整后的 OR 5·91 [0·78–44·81] ); 三硝酸甘油酯组 35 人中有 16 人 (46%) 和对照组 20 人中有 11 人 (55%) 在 90 天内死亡(调整后的 OR 为 0·87 [0·18–4·17])。

解释

我们发现在疑似急性中风患者的院前环境中,在症状发作后 3 小时内开始透皮三硝酸甘油酯没有任何益处的迹象。三硝酸甘油酯对脑出血患者的潜在早期危害信号表明,在这种情况下应避免使用三硝酸甘油酯。

资金

急性中风新疗法合作联盟、荷兰大脑基金会、经济事务部、Stryker、Medtronic、Cerenovus 和荷兰心脏基金会。

更新日期:2022-09-01
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