Elsevier

The Lancet

Volume 350, Issue 9080, 13 September 1997, Pages 757-764
The Lancet

Articles
Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension*

https://doi.org/10.1016/S0140-6736(97)05381-6Get rights and content

Summary

Background

Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint.

Methods

All patients (≥60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160–219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10–40 mg daily, with the possible addition of enalapril 5–20 mg daily and hydrochlorothiazide 12·5–25·0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat.

Findings

At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n=2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n=2398). The between-group differences were systolic 10·1 mm Hg (95% CI 8·8–11·4) and diastolic, 4·5 mm Hg (3·9–5·1). Active treatment reduced the total rate of stroke from 13·7 to 7·9 endpoints per 1000 patient-years (42% reduction; p=0·003). Non-fatal stroke decreased by 44% (p=0·007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p=0·03). Non-fatal cardiac endpoints decreased by 33% (p=0·03) and all fatal and non-fatal cardiovascular endpoints by 31% (p<0·001). Cardiovascular mortality was slightly lower on active treatment (27%, p=0·07), but all-cause mortality was not influenced (−14%; p=0·22).

Interpretation

Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Introduction

The prevalence of isolated systolic hypertension increases with age. Among people aged 70 and older the prevalence is 8%, and it rises to to more than 25% among those aged 80 years or older.1 In 1989, the European Working Party on High Blood Pressure in the Elderly started a placebocontrolled double-blind trial–Systolic Hypertension in Europe (Syst-Eur).2 Active treatment was started with the calcium-channel blocker nitrendipine,3 with the possible addition of enalapril, hydrochlorothiazide, or both. In 1991, the Systolic Hypertension in the Elderly (SHEP) trial showed that diuretic-based treatment prevented stroke, myocardial infarction, and congestive heart failure.4 Because of the remaining uncertainties about the treatment of isolated systolic hypertension in the elderly,5, 6, 7, 8, 9 the Syst-Eur trial continued after the SHEP results were published.4 Furthermore, controversy about calcium-channel blockers as first-line antihypertensive agents10, 11, 12, 13 highlighted the lack of evidence that these drugs reduce cardiovascular risk.

We report the morbidity and mortality results of the Syst-Eur trial. We stopped the trial on Feb 14, 1997, after the second interim analysis because we had reached the primary endpoint of a significant benefit for stroke.2

Section snippets

Methods

The protocol of this trial2 was approved by the ethics committees of the University of Leuven and the participating centres. We used the principles outlined in the Helsinki declaration.14

Patients were recruited from 198 centres in 23 countries across western and eastern Europe. Each centre kept a register of screened patients. Eligible patients were at least 60 years old. On masked placebo during the run-in phase, their sitting systolic blood pressure ranged from 160 mm Hg to 219 mm Hg, their

Results

Of 8926 screened patients 6403 (71·7%) were eligible for enrolment in the run-in period (figure 2). 1708 patients were not included because of blood pressure values outside the recruitment range (n=910 [53·4%]), withdrawal of consent (n=439 [25·7%]), the presence or occurrence of cardiovascular or non-cardiovascular illnesses, prohibiting randomisation (n=202 [11·8%]), symptoms or treatment with masked placebo (n=55 [3·2%]), on for undocumented reasons (n=333 [19·5%]). 1262 (26·9%) of

Discussion

The antihypertensive drugs used in our trial were the dihydropyridine calcium-channel blocker nitrendipine, the converting-enzyme inhibitor enalapril, and the thiazide diuretic hydrochlorothiazide. Among elderly patients with isolated systolic hypertension, these drugs reduced the risk of stroke and the occurrence of various other cardiovascular complications. We saw the benefit of active treatment soon after randomisation, when most patients were still on monotherapy with nitrendipine.

References (34)

  • NM Kaplan

    Systolic Hypertension in the Elderly Program (SHEP) and Swedish Trial in Old Patients with Hypertension (STOP): the promises and the potential problems

    Am J Hypertens

    (1992)
  • J Ménard et al.

    Some lessons from Systolic Hypertension in the Elderly Program (SHEP)

    Am J Hypertens

    (1992)
  • J Staessen et al.

    Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials

    J Hum Hypertens

    (1991)
  • JA Staessen et al.

    Inverse association between baseline pressure and benefit from treatment in isolated systolic hypertension

    Hypertension

    (1994)
  • CD Furberg et al.

    Nifedipine: dose-related increase in mortality in patients with coronary heart disease

    Circulation

    (1995)
  • BM Psaty et al.

    The risk of myocardial infarction associated with antihypertensive drug therapies

    JAMA

    (1995)
  • Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects

    Bull Pan Am Health Organ

    (1990)
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