Elsevier

The Lancet

Volume 393, Issue 10174, 2–8 March 2019, Pages 877-888
The Lancet

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

https://doi.org/10.1016/S0140-6736(19)30038-8Get rights and content

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

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.

Introduction

Timely administration of intravenous thrombolytic treatment is the mainstay of hyperacute reperfusion treatment in patients with acute ischaemic stroke, even with the advent of mechanical thrombectomy for those with proximal large vessel occlusion.1 The evidence strongly suggests that administration of intravenous alteplase (recombinant tissue plasminogen activator) within 4·5 h of acute ischaemic stroke onset results in a net benefit over harm from intracranial haemorrhage.2, 3 Ongoing research seeks to improve the efficacy and safety of mechanical and pharmacological reperfusion therapies in eligible patients with acute ischaemic stroke.

The alteplase dose-assessment arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) was unable to clearly show non-inferiority of low-dose intravenous alteplase compared with the standard dose with respect to death and dependency at 90 days, despite significant reductions in early (7-day) mortality and symptomatic intracerebral haemorrhage.4 However, controversy persists regarding control of peri-thrombolysis blood pressure, for which guidelines consistently contraindicate the use of alteplase in patients with systolic blood pressure of more than 185 mm Hg.5 Two large registries6, 7 have reported a positive association between increasing systolic blood pressure and increased risk of symptomatic intracerebral haemorrhage, even below this threshold: frequency of symptomatic intracerebral haemorrhage was four times higher in patients with systolic blood pressure of more than 170 mm Hg than it was in those with systolic blood pressure of 141–150 mm Hg.7 A U-shaped association for death and dependency is also evident, with the best outcomes associated with systolic blood pressure of 141–150 mm Hg. An ongoing concern, however, has been that rapid blood pressure reduction in the absence of reperfusion might worsen cerebral ischaemia due to hypoperfusion in failing collateral circulation into the ischaemic penumbra.8

The second, blood pressure control-assessment arm of the ENCHANTED trial was driven by uncertainty over whether any potential benefits related to a reduced risk of thrombolysis-related intracranial haemorrhage could be offset by worsened cerebral ischaemia associated with intensive blood pressure lowering. Herein, we report the results of the blood pressure control arm of the ENCHANTED trial, which tested the hypotheses that, following use of intravenous alteplase, a strategy of intensive blood pressure lowering (target systolic blood pressure 130–140 mm Hg) is superior to guideline-recommended blood pressure lowering (target systolic blood pressure <180 mm Hg) for improving functional recovery and reducing the risk of intracranial haemorrhage in patients with acute ischaemic stroke.

Section snippets

Study design and participants

ENCHANTED was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial with a 2 × 2 partial-factorial design, at 110 sites in 15 countries, to assess the effectiveness of low-dose versus standard-dose alteplase (previously published),5 and intensive versus guideline-recommended blood pressure control (described here). Details of the study design and rationale have been published elsewhere,9 and the protocol is available in the appendix. The statistical analysis

Results

From March 3, 2012, to April 30, 2018, 2227 patients with acute ischaemic stroke were randomly allocated (figure 1, appendix). 31 patients were excluded because of missing consent, or mistaken or duplicate randomisation, leaving 2196 included in the intention-to-treat analysis: 1081 (49·2%) in the intensive group and 1115 (50·8%) in the guideline group. 925 (42·1%) participants were also enrolled in the alteplase dose arm of the trial (456 [20·8%] receiving low-dose alteplase and 469 [21·4%]

Discussion

Our trial was driven by uncertainty over whether any benefit of intensive blood pressure lowering in terms of improving outcome in patients with acute ischaemic stroke, gained largely from a reduced risk of thrombolysis-related intracerebral haemorrhage, could be offset by the harm of promoting cerebral ischaemia. The main finding was that, in thrombolysis-treated patients with acute ischaemic stroke of predominantly mild-to-moderate severity, a strategy of intensive blood pressure lowering

Data sharing statement

Individual, de-identified participant data used in these analyses will be shared by request from any qualified investigator following approval of a protocol and signed data access agreement via the Research Office of The George Institute for Global Health, Australia.

References (24)

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    Rationale, design, and progress of the enhanced control of hypertension and thrombolysis stroke study (ENCHANTED) trial: an international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischemic stroke eligible for thrombolysis treatment

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    Statistical analysis plan for evaluating different intensities of blood pressure control in the enhanced control of hypertension and thrombolysis stroke study (ENCHANTED)

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