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