Elsevier

The Lancet

Volume 363, Issue 9426, 19 June 2004, Pages 2022-2031
The Lancet

Articles
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

https://doi.org/10.1016/S0140-6736(04)16451-9Get rights and content

Summary

Background

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk.

Methods

15 245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4–2 years.

Findings

Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4·0/2·1 mm Hg lower in amlodipine than valsartan group after 1 month; 1·5/1·3 mm Hg after 1 year; p<0·001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10·6%, 25·5 per 1000 patient-years) and 789 in the amlodipine group (10·4%, 24·7 per 1000 patient-years; hazard ratio 1·04, 95% CI 0·94–1·15, p=0·49).

Interpretation

The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Published online June 14, 2004 http://image.thelancet.com/extras/04art4187web.pdf

Introduction

Substantial benefits in prevention of major cardiovascular morbidity and mortality in high-risk populations have been reported with calcium antagonists1, 2, 3 and angiotensin-converting enzyme (ACE) inhibitors.4 However, large hypertension trials have failed to show significant differences between treatment regimens based on diuretics, β blockers, calcium antagonists, ACE inhibitors, or α blockers.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 The LIFE study16 showed advantages for the angiotensin-receptor blocker losartan over the β blocker atenolol in hypertensive patients with left ventricular hypertrophy, primarily a 25% reduction in strokes. Subsequently, the second National Australian Blood Pressure study17 reported fewer cardiovascular events in patients treated with ACE inhibitor compared with diuretics. Therefore, the issue of whether the mechanism of action of antihypertensive drugs might influence their clinical effect remains unresolved.

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial offered a further opportunity to test this hypothesis by comparing the effects of two contemporary agents. VALUE18, 19, 20 was designed to compare the effects of treatment regimens based on the angiotensin-receptor blocker valsartan or on the calcium antagonist amlodipine on cardiac morbidity and mortality in patients with essential hypertension and at high risk for cardiac disease. The study hypothesis was that for the same level of blood-pressure (BP) control, valsartan-based treatment would be superior to amlodipine-based treatment in reduction of cardiac morbidity and mortality. There is strong evidence that raised concentrations of angiotensin II are an independent risk factor for cardiac disease.21 Valsartan was expected to reduce cardiac morbidity beyond its BP-lowering effect. Amlodipine was chosen as comparator because it effectively lowers BP but has not been proven to have specific cardioprotective properties.10, 15

The trial used a specific predefined algorithm dependent on age, risk, and disease factor to recruit a population of patients with hypertension at high risk of cardiac disease. In this article we report the main outcome results.

Section snippets

Study design

VALUE was an investigator-designed, prospective, multinational, double-blind, randomised, active-controlled, parallel-group trial. The primary objective was, at the same level of achieved BP, to compare the long-term effects on the incidence of cardiac morbidity and mortality, of antihypertensive therapy started with once-daily valsartan or amlodipine, in hypertensive patients with high cardiovascular risk. The complete study design has been published.18

A computer-generated randomisation list

Results

15313 eligible patients in 31 countries were randomised between September, 1997 and November, 1999. The two treatment groups were similar in terms of demographic characteristics, severity of hypertension, antihypertensive drug use before enrolment, and prevalence of coexisting cardiovascular conditions (table 1). 68 patients in nine centres were excluded because of good clinical practice deficiencies, and therefore 15 245 randomised patients were included in the analysis. 11 centres prematurely

Discussion

The VALUE trial was designed to test the hypothesis that, for the same level of BP control, a valsartan-based regimen would be better than an amlodipine-based regimen for cardioprotection in patients with hypertension. For the primary composite endpoint of cardiac morbidity and mortality and for all-cause mortality, no significant differences were noted between the treatment groups. The amlodipine group had a significantly lower incidence of myocardial infarction and higher rate of new-onset

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