Elsevier

The Lancet

Volume 377, Issue 9767, 26 February–4 March 2011, Pages 741-750
The Lancet

Fast track — Articles
The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial

https://doi.org/10.1016/S0140-6736(11)60104-9Get rights and content

Summary

Background

Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure.

Methods

Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354.

Findings

2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p<0·0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1·09, 95% CI 0·84–1·41; p=0·52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1·17, 95% CI 1·00–1·38; p=0·048 [not significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (<1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo.

Interpretation

There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect.

Funding

South-Eastern Norway Regional Health Authority; Oslo University Hospital Ullevål; AstraZeneca; Takeda.

Introduction

Raised blood pressure is common in patients with acute stroke, and is associated with poor short-term and long-term outcomes.1, 2, 3 The hypertensive response can have several causes, including inadequately treated or undiagnosed hypertension, stress response with activation of neuroendocrine systems, damage to autonomic centres in the brain, and increased intracranial pressure.4

The optimum management of blood pressure in acute stroke is not known,5 and current practice is to accept high blood pressure in this situation.6, 7, 8 Under normal circumstances, cerebral autoregulation sustains constant cerebral blood flow across an extensive range of systemic blood pressures.9 In acute stroke, the autoregulatory mechanism can be impaired or damaged, and cerebral tissue perfusion relies on systemic blood pressure. In this situation, blood-pressure reduction can compromise perfusion of the penumbra and cause further infarction, as suggested by a small trial of intravenous nimodipine.10 Conversely, high blood pressure can cause brain oedema or haemorrhage, and data from the International Stroke Trial2 showed a clear association between systolic blood pressure in the acute phase and early death and poor long-term outcome.

The angiotensin-receptor blocker candesartan has shown promising effects on infarct size and neurological status in several experimental studies.11, 12 The ACCESS study13 of 342 patients with acute stroke and high blood pressure suggested that treatment with candesartan during the first week of stroke reduces the incidence of vascular events and deaths during the first 12 months (odds ratio [OR] 0·48, 95% CI 0·25–0·90). The mechanisms by which angiotensin-receptor blockers can affect the risk of death and vascular events are unknown. Studies of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers in cardiovascular disease suggest specific neuroprotective effects beyond the effects of blood-pressure lowering,14, 15, 16 but whether similar effects can be seen in acute stroke remains to be shown. We aimed to assess whether careful blood-pressure lowering treatment with candesartan is beneficial in a wide range of patients with acute stroke and raised blood pressure.

Section snippets

Study design and participants

The Scandinavian Candesartan Acute Stroke Trial (SCAST) was a north European, multicentre, randomised, placebo-controlled, double-blind trial of candesartan in patients with acute stroke and raised blood pressure. Details of the design have been reported elsewhere.17 Patients aged 18 years or older with a clinical diagnosis of stroke (ischaemic or haemorrhagic), presenting within 30 h of symptom onset and with systolic blood pressure higher than 140 mm Hg were potential candidates for

Results

2029 patients were recruited from 146 centres in Belgium, Denmark, Estonia, Finland, Germany, Lithuania, Norway, Poland, and Sweden between June 5, 2005, and Feb 25, 2010 (figure 1). Patient recruitment was stopped before the intended sample size was reached because recruitment was slower than had been expected and the research grant expired. The decision to stop patient recruitment was made in May, 2009, by the trial steering committee. It was based purely on administrative grounds, without

Discussion

In this trial, we noted no beneficial effect of blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan in patients with acute stroke and raised blood pressure. For functional outcome, one of the two co-primary effect variables, the distribution of mRS scores at 6 months was less favourable for patients treated with candesartan than for those on placebo, but the difference was not significant because the p value (0·048) was greater than the threshold of 0·025

References (31)

  • J Broderick et al.

    Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group

    Circulation

    (2007)
  • S Strandgaard

    Autoregulation of cerebral circulation in hypertension

    Acta Neurol Scand

    (1978)
  • NG Wahlgren et al.

    Intravenous Nimodipine West European Stroke Trial (INWEST) of Nimodipine in the Treatment of Acute Ischaemic Stroke

    Cerebrovasc Dis

    (1994)
  • SC Fagan et al.

    Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection

    J Hypertens

    (2006)
  • W Kozak et al.

    Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study

    J Pharmacol Exp Ther

    (2008)
  • Cited by (439)

    View all citing articles on Scopus
    View full text