Elsevier

The Lancet

Volume 353, Issue 9153, 20 February 1999, Pages 611-616
The Lancet

Articles
Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial

https://doi.org/10.1016/S0140-6736(98)05012-0Get rights and content

Summary

Background

Angiotensin-converting-enzyme (ACE) inhibitors have been used for more than a decade to treat high blood pressure, despite the lack of data from randomised intervention trials to show that such treatment affects cardiovascular morbidity and mortality. The Captopril Prevention Project (CAPPP) is a randomised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension.

Methods

CAPPP was a prospective, randomised, open trial with blinded endpoint evaluation. 10 985 patients were enrolled at 536 health centres in Sweden and Finland. Patients aged 25–66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were randomly assigned captopril or conventional antihypertensive treatment (diuretics, β-blockers). Analysis was by intention-to-treat. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke, and other cardiovascular deaths.

Findings

Of 5492 patients assigned captopril and 5493 assigned conventional therapy, 14 and 13, respectively, were lost to follow-up. Primary endpoint events occurred in 363 patients in the captopril group (11·1 per 1000 patient-years) and 335 in the conventional-treatment group (10·2 per 1000 patient-years; relative risk 1·05 [95% Cl 0·90–1·22], p=0·52). Cardiovascular mortality was lower with captopril than with conventional treatment (76 vs 95 events; relative risk 0·77 [0·57–1·04], p=0·092), the rate of fatal and non-fatal myocardial infarction was similar (162 vs 161), but fatal and non-fatal stroke was more common with captopril (189 vs 148; 1·25 [1·01–1·55]. p=0·044).

Interpretation

Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality. The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients randomised to conventional therapy.

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors are used widely in the treatment of high blood pressure. Guidelines for the management of hypertension issued by WHO and the International Society of Hypertension, class ACE inhibitors as suitable for first-line treatment, along with diuretics and β-blockers. Guidelines issued by the Joint National Committee in the USA used to state the same thing, but more recent versions of these guidelines have not recommended ACE inhibitors as first-line treatment. This change reflects the fact that no data from prospective and randomised trials in hypertensive patients have shown that ACE inhibitor treatment protects against cardiovascular morbidity and mortality.

There has been concern about the safety of newer antihypertensive agents and whether they give the same benefits as diuretics and β-blockers; such concern has focused on calcium antagonists but not ACE inhibitors. The Captopril Prevention Project (CAPPP) was designed as a prospective intervention trial to compare the potential benefits to cardiovascular morbidity and mortality of a regimen based on the ACE inhibitor captopril with a conventional antihypertensive regimen of diuretics or β-blockers. For ethical reasons, a long-term comparison with placebo was not done.

The scientific background and rationale of the CAPPP study have been reported elsewhere.5 Observations on intermediary endpoints, which were available when the study was planned in the late 1980s, suggested that an antihypertensive regimen based on an ACE inhibitor might offer benefits equal to or greater than those of conventional antihypertensive treatment with diuretics, β-blockers, or both.6 ACE inhibitors help to reverse left-ventricular hypertrophy,7, 8 itself a powerful indicator of cardiovascular risk,9, 10 improve cardiac function in patients with left-ventricular dysfunction,11, 12 have favourable metabolic effects,13 and help to maintain quality of life.14 More recently, benefits of ACE inhibition have been shown in patients with diabetic nephropathy15 and in diabetic patients in general.16 ACE inhibitors also maintain renal function in patients with primary hypertension,17, 18 which strengthens the hypothesis that a therapeutic regimen based on ACE inhibitors in the treatment of primary hypertension could reduce the risk of cardiovascular morbidity and mortality.

Section snippets

Study population

The CAPPP trial, at 536 health centres in Sweden and Finland, used the design of the PROBE study19 (Prospective Randomised Open Blinded Endpoint), which is similar to routine clinical practice. Men and women aged 25–66 years who had treated or untreated primary hypertension were included in the trial if their diastolic blood pressure was 100 mm Hg or higher on two separate occasions. Exclusion criteria were secondary hypertension, serum creatinine concentration of more than 150 μmol/L, and

Results

11 018 patients were enrolled in the study, but 33 were excluded because of their age. Of the remaining 10 985 patients, 5492 were randomly assigned captopril treatment and 5493 were randomly assigned conventional treatment (figure 1). Follow-up lasted for a mean of 6·1 years: a total of 67 239 patient-years were recorded. Only 27 (0·25%) patients were lost to follow-up.

Baseline characteristics (table 1) and effects on blood pressure have been described elsewhere.20 Blood pressure at baseline

Discussion

Our conventional randomisation procedure, using sealed envelopes, resulted in an imbalance between groups at baseline in terms of the blood pressure measurements. We corrected our data for imbalance in blood pressure at baseline, sex, and the prevalence of diabetes in the analyses. Centralised randomisation by fax21 would have been preferable, but this procedure was not standard 10 years ago, when this study was planned.

The proportion of patients lost to follow-up (0·25%) is not as low as that

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