Elsevier

The Lancet

Volume 352, Issue 9137, 24 October 1998, Pages 1347-1351
The Lancet

Early Report
Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial

https://doi.org/10.1016/S0140-6736(98)03086-4Get rights and content

Summary

Background

Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial, investigated whether antihypertensive drug treatment could reduce the incidence of dementia.

Methods

Eligible patients had no dementia, were at least 60 years old, and had a blood pressure when seated of 160-219 mm hg systolic and below 95 mm hg diastolic. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5–20 mg/day), hydrochlorothiazide (12.5–25 mg/day), or both drugs, titrated or combined to reduce the systolic blood pressure by at least 20 mm hg to reach a value below 150 mm hg. Cognitive function was assessed by the mini mental state examination (MMSE). If the MMSE score was 23 or less, diagnostic tests for dementia were done (DSM-III-R criteria). The cause of dementia was established by the modified ischaemic score with brain imaging or the Hachinski score.

Findings

Median follow-up by intention to treat was 2·0 years. Compared with placebo (n=1180), active treatment (n=1238) reduced the incidence of dementia by 50% from 7·7 to 3·8 cases per 1000 patient-years (21 vs 11 patients, p=0·05). The median MMSE score at randomisation was 29 in both treatment groups. At the last available assessment, systolic and diastolic blood pressure were, respectively, 8·3 mm hg and 3·8 mm hg lower (plt;0·001) in the active-treatment group, but on average the MMSE scores did not change in either group. In the control patients, however, the MMSE decreased (p=0·04) with decreasing diastolic blood pressure, whereas in the active-treatment group MMSE scores improved slightly (p=0·01) with greater reduction in diastolic blood pressure (p=0·002 for between-group difference).

Interpretation

In elderly people with isolated systolic hypertension, antihypertensive treatment was associated with a lower incidence of dementia. If 1000 hypertensive patients were treated with antihypertensive drugs for 5 years 19 cases of dementia might be prevented.

Introduction

In 1997 the Rotterdam Study showed that indicators of atherosclerosis, such as hypertension, were associated not only with vascular dementia, but also with Alzheimer's disease.1 Although hypertension is the strongest risk factor for vascular dementia2 the placebo-controlled Systolic Hypertension in the Elderly Program (SHEP) study3 did not confirm the hypothesis that antihypertensive treatment, with chlortalidone, would reduce the incidence of dementia.

As part of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial,4, 5 the vascular dementia project aimed to investigate whether antihypertensive treatment starting with the calcium-channel blocker nitrendipine could prevent vascular dementia in older patients with isolated systolic hypertension. The Syst-Eur trial stopped on Feb 14, 1997, according to predefined stopping rules,5 because the second of four planned interim analyses had shown a significant benefit for stroke, the primary endpoint.4

Section snippets

General design

The protocol of the Syst-Eur trial, described elsewhere,4, 5 was approved by the ethics committee of all participating centres. Eligible patients had to have no dementia, be at least 60 years old, and have a systolic blood pressure when seated of 160–219 mm hg with diastolic blood pressure below 95 mm hg.

After stratification by centre, sex, and previous cardiovascular complications, the patients were randomly assigned double-blind treatment with active medication or placebo by means of a

Results

At 106 centres in 19 European countries 3162 patients were enrolled. However, owing to the early termination of the trial (figure 1), 692 patients did not accumulate 1 year of follow-up and their cognitive function was therefore not taken into account in this assessment (figure 2). In addition, 52 patients were excluded (figure 2). Thus, the number of patients for the present analysis totalled 2418. At randomisation, the patients allocated placebo (n=1180) and those allocated active treatment

Discussion

In elderly patients with isolated systolic hypertension, active treatment starting with the dihydropyridine calcium-channel blocker nitrendipine halved the rate of dementia from 7·7 to 3·8 cases per 1000 patient-years. Selective recruitment of relatively healthy patients who would accept long-term follow-up in a double-blind trial is likely to explain the high MMSE scores (median 29 points) at entry and the low incidence of dementia in the placebo group (7·7 per 1000 patient-years), compared

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