Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

The RIGHT-2 Investigators

Lancet Published:February 06, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)30194-1

Summary

Background 背景

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.

急性卒中患者高血压极为常见，是不良预后的预测指标；然后降压治疗的大规模临床试验得到了不同的结果，超级性卒中患者高血压治疗尚不确定。我们评价在卒中起病后极早期经皮给与一氧化氮供体硝酸甘油(GTN)能否改善预后。

Methods 方法

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 UK-based 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.

我们进行了一项多中心、医疗辅助人员在救护车上实施、前瞻随机、假对照、终点设盲的3期临床试验，入选起病4小时内的疑诊卒中成年患者，面、臂、言语、时间评分量表2或3分，且收缩压不低于120 mmHg。患者被随机分组(1:1)，由医疗辅助人员在救护车上给予经皮GTN（GTN组；5 mg qd，疗效4天）或外表相似的假药（假药组），并在医院继续治疗。医疗辅助人员对治疗分组未设盲，患者设盲。主要预后指标为90天时改良Rankin评分（mRS；反映功能预后的指标），通过对治疗分组设盲的中心电话随访进行。根据统计分析计划进行分层分析，首先对确诊卒中或TIA的患者（队列1），然后对所有接受随机分组的患者（意向治疗，队列2）。试验在 ISRCTN注册，注册号ISRCTN26986053。

Findings 结果

Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs170 in the sham group [p=0·16]) between treatment groups.

2015年10月22日至2018年5月23日间，英国8个急救服务中心的516名医疗辅助人员共入选1149名患者（GTN组568名，假药组581名）。至随机分组的中位时间为71 分钟(IQR 45–116)。对事件的最后分析表明，597名 (52%)患者为缺血性卒中，145名 (13%)为脑出血，109名 (9%)为TIA，297名 (26%)为非卒中。与假药组相比，入院时GTN组患者收缩压下降5·8 mm Hg (p<0·0001)，舒张压降低2·6 mm Hg (p=0·0026)。我们发现，最终诊断为卒中或TIA的患者（队列1）两组间mRS评分并无差异：GTN组3 (IQR 2–5; n=420)，假药组3 (2–5; n=408)，校正后不良预后的比数比1·25 (95% CI 0·97–1·60; p=0·083)；对所有患者的分析也未发现mRS存在差异（队列2：GTN组3 [2–5]; n=544 vs 假药组3 [2–5]; n=558；1·04 [0·84–1·29]; p=0·69）。治疗组间次要预后指标也没有差异，包括死亡（治疗相关死亡：GTN组36例 vs 假药组23例[p=0·091]）或严重不良事件（GTN组188例 vs 假治疗组170例[p=0·16]）。

Interpretation 结论

Prehospital 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.

院前采用经皮GTN治疗不能改善疑诊卒中患者的功能预后。在超急性院前情况下，英国的医疗辅助人员能够取得知情同意并对卒中患者进行治疗。

Funding 资助

British Heart Foundation.