Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial

Craig S Anderson, Yining Huang, Richard I Lindley, et al

Lancet Published:February 07, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)30038-8

Summary

Background 背景

Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke.

收缩压超过185 mmHg是急性缺血性卒中患者静脉rTPA溶栓的禁忌症，但目标收缩压并不清楚。我们对急性缺血性卒中患者接受rTPA治疗后强化降压与指南推荐降压的效果进行了评价。

Methods 方法

We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130–140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616.

我们进行了一项国际、部分析因设计、开放标签、终点设盲临床试验，15个国家的110个中心入选符合溶栓标准且收缩压不低于150 mmHg的急性缺血性卒中患者（年龄 ≥18岁）。符合入选标准的患者接受随机分组（采用基于网络的中心系统进行1:1分组），在卒中发病6小时内接受强化（1小时内达到目标收缩压130-140 mmHg）或指南（目标收缩压< 180 mmHg）降压治疗，持续72小时。主要预后指标为90天时功能状态，根据改良Rankin评分改变进行评价，并采用非校正有序logistic回归分析。关键的安全性预后指标为任何脑出血。主要预后与安全性预后评估采用设盲法进行。采用意向治疗分析。试验在ClinicalTrials.gov注册，注册号 NCT01422616。

Findings 结果

Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6–4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87–1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60–0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70–1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome.

2012年3月3日至2018年4月3日间，共有2227名患者接受随机分组。因知情同意丢失及错误或重复随机等原因排除31名患者后，共纳入2196名符合rTPA溶栓的急性缺血性卒中患者：强化组1081名，指南组1115名。2175名患者实际接受了静脉rTPA，其中1466名(67·4%)使用标准剂量。从发生卒中到随机分组的中位事件为3·3 h (IQR 2·6–4·1)。强化组24小时平均收缩压为 144·3 mm Hg (SD 10·2)，指南组为 149·8 mm Hg (12·0) (p<0·0001)。强化组1072名患者及指南组1108名患者有主要预后指标数据。两组间90天功能状态（mRS评分分布）并无差异（未校正比数比 [OR] 1·01, 95% CI 0·87–1·17, p=0·8702）。强化组更少患者(160/1081 [14·8%] of 1081 vs. 209/1115 [18·7%])发生脑出血(OR 0·75, 0·60–0·94, p=0·0137)。强化组(210/1081 [19·4%]) 与指南组(245/1115 [22·0%]; OR 0·86, 0·70–1·05, p=0·1412)严重不良事件患者数没有显著差异。没有证据表明强化降压与rTPA溶栓剂量（低 vs 标准）对主要预后指标存在交互作用。

Interpretation 结论

Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group.

尽管强化降压是安全的，但是与指南治疗相比，脑出血减少并未导致临床预后改善。这些结果可能不支持将强化降压治疗用于接受rTPA溶栓的轻中度急性缺血性卒中患者。需要进一步研究确定这一人群早期强化降压治疗获益或危害的机制。

Funding 资助

National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.