Elsevier

The Lancet

Volume 358, Issue 9287, 29 September 2001, Pages 1033-1041
The Lancet

Fast track — Articles
Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack

https://doi.org/10.1016/S0140-6736(01)06178-5Get rights and content

Summary

Background

Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack.

Methods

6105 individuals from 172 centres in Asia, Australasia, and Europe were randomly assigned active treatment (n=3051) or placebo (n=3054). Active treatment comprised a flexible regimen based on the angiotensin-converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat.

Findings

Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo (relative risk reduction 28% [95% Cl 17–38], p<0·0001). Active treatment also reduced the risk of total major vascular events (26% [16–34]). There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p<0·01). Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30–54). Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke.

Interpretation

This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.

Introduction

Strokes kill about 5 million people each year, making cerebrovascular disease the second leading cause of death worldwide.1 At least 15 million others have non-fatal strokes annually, and about a third are disabled as a consequence.2, 3 Among those who survive a stroke or a transient ischaemic attack, the risk of further stroke is very high: at least one in six suffer another stroke within 5 years.3 The identification of safe and effective treatments for the prevention of recurrent stroke is therefore a priority. Antiplatelet therapy reduces the risk of stroke and other major vascular events by between a sixth and a fifth among individuals with a history of ischaemic stroke or transient ischaemic attack,4, 5 and is now prescribed routinely to these patients. Carotid endarterectomy reduces the risk of recurrent ipsilateral stroke in those with carotid stenosis,6, 7 and anticoagulant therapy reduces recurrent stroke risk in those with atrial fibrillation,8 but each of these two treatments is suitable for only a small proportion of all patients with ischaemic stroke or transient ischaemic attack. No treatment has been proven to reduce recurrent stroke risk among patients with a history of cerebral haemorrhage.

Observational studies have shown that usual blood pressure levels are directly and continuously associated with the initial occurrence of ischaemic stroke and cerebral haemorrhage.9 As a consequence, blood pressure is recognised as an important determinant of the risk of initial stroke in non-hypertensive individuals as well as in those with hypertension.9, 10 Fewer data are available about the associations of blood pressure with recurrent stroke. Hypertension has been associated with an increased risk of stroke recurrence in some,11, 12 but not other,13 community studies of outcome after first stroke. In two small clinical studies,14, 15 blood pressure seemed to be directly associated with the risk of stroke recurrence among patients with a history of recent cerebral haemorrhage. In one of these studies,14 a J-shaped relation between blood pressure and recurrent stroke was seen among patients with a recent history of ischaemic stroke. However, such non-linearity might reflect “reverse causality”, whereby the most severe cerebrovascular disease lowers blood pressure and independently worsens prognosis.16 A much larger study17 of 2435 clinically stable individuals with a history of minor ischaemic stroke or transient ischaemic attack detected no evidence of non-linearity in the association of usual blood pressure with stroke recurrence: each 10 mm Hg lower level of systolic pressure was associated with a 28% (SE 8) lower risk of stroke.

Systematic reviews of randomised trials of blood-pressure-lowering drugs in hypertensive patients, mostly without cerebrovascular disease, have shown that sustained blood pressure reductions of about 5–6 mm Hg diastolic reduced the risk of initial stroke by about a third,18 with no large differences apparent between the main drug classes.19 Those studies provided little evidence about the separate effects of treatment on ischaemic stroke and cerebral haemorrhage. There are comparatively few randomised trials of blood-pressure-lowering drugs among patients with a history of cerebrovascular disease: a meta-analysis20 of the four trials with published final results (involving 2742 patients, most of whom had a history of ischaemic stroke) suggested that blood pressure reductions of about 6–8 mm Hg systolic and 3–4 mm Hg diastolic were associated with a fifth fewer recurrent strokes. However, the confidence interval for this estimate of treatment effect was wide and consistent with no worthwhile effect as well as with benefit. Analyses of subsets of patients with a history of cerebrovascular disease included in other trials of antihypertensive treatment regimens21 or of angiotensin-converting-enzyme (ACE) inhibitors22 yielded similar results. Clearer evidence of benefits of blood-pressure-lowering treatments for recurrent stroke risk was provided by a preliminary report from a trial of the diuretic indapamide among 5665 individuals with previous stroke or transient ischaemic attack.23 However, final results from that study remain unpublished.

The perindopril protection against recurrent stroke study (PROGRESS)24 was started by an independent collaborative research group in an effort to resolve clinical uncertainty about the efficacy and safety of routine blood-pressure-lowering therapy for individuals with a history of stroke or transient ischaemic attack. We report here the principal results from this randomised, placebo-controlled trial.

Section snippets

Patients and methods

The aim of PROGRESS was to determine the effects of a flexible blood-pressure-lowering regimen, involving an ACE inhibitor (perindopril) and a diuretic (indapamide), on the risk of stroke and other major vascular events among individuals with a history of stroke or transient ischaemic attack. The study was conducted in 172 collaborating centres from ten countries (see end of paper). The institutional ethics committee of each collaborating centre approved the trial and all participants provided

Patients' enrolment and baseline characteristics

7121 potential participants were registered and 1016 (14%) were subsequently found to be ineligible or withdrew during the 4-week active run-in period (figure 1). The main reasons for withdrawal during this period were dizziness or hypotension (3·4%), cough (2·7%), other suspected intolerance (2·3%), and participant's decision (2·0%). One case of non-fatal angio-oedema was documented during the run-in phase. 6105 individuals

Baseline characteristics of randomised participants

entered the randomised, double-blind phase: 3051 were assigned active treatment and 3054 were assigned placebo. Of those assigned active treatment, the regimen comprised combination therapy with perindopril plus indapamide for 1770 individuals (58%) and single-drug therapy with perindopril alone for 1281 (42%). Of those assigned placebo, the regimen comprised double placebo for 1774 individuals (58%) and single placebo for 1280 (42%).

The characteristics of randomised participants are described

Discussion

This randomised controlled trial among individuals with previous stroke or transient ischaemic attack shows that a flexible blood-pressure-lowering regimen, which included perindopril for all patients and indapamide for 58%, reduced blood pressure by an average of 9/4 mm Hg and the risk of stroke by more than a quarter. Over 4 years, annual stroke incidence was reduced from 3·8% to 2·7%. There was a reduction in the risk of fatal or disabling stroke as well as that of less severe stroke, and a

References (34)

  • R Hart et al.

    Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis

    Ann Intern Med

    (1999)
  • Blood pressure, cholesterol and stroke in eastern Asia

    Lancet

    (1998)
  • Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts

    Lancet

    (1995)
  • M Alter et al.

    Stroke in the Lehigh Valley: risk factors for recurrent stroke

    Neurology

    (1987)
  • M Alter et al.

    Hypertension and risk of stroke recurrence

    Stroke

    (1994)
  • J Burn et al.

    Long-term risk of recurrent stroke after a first-ever stroke: the Oxfordshire Community Stroke Project

    Stroke

    (1994)
  • K Irie et al.

    The J-curve phenomenon in stroke recurrence

    Stroke

    (1993)
  • Cited by (0)

    Members listed at end of paper

    View full text