Elsevier

The Lancet

Volume 366, Issue 9489, 10–16 September 2005, Pages 895-906
The Lancet

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Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial

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Summary

Background

The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and β blockers used. For a given reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and β blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril.

Methods

We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50–100 mg adding bendroflumethiazide 1·25–2·5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infaction) and fatal CHD. Analysis was by intention to treat.

Findings

The study was stopped prematurely after 5·5 years' median follow-up and accumulated in total 106 153 patient-years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0·90, 95% CI 0·79–1·02, p=0·1052), fatal and non-fatal stroke (327 vs 422; 0·77, 0·66–0·89, p=0·0003), total cardiovascular events and procedures (1362 vs 1602; 0·84, 0·78–0·90, p<0·0001), and all-cause mortality (738 vs 820; 0·89, 0·81–0·99, p=0·025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0·70, 0·63–0·78, p<0·0001).

Interpretation

The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.

Introduction

Hypertension is the most important preventable cause of premature death in developed countries,1 and the benefits of antihypertensive drugs for prevention of cardiovascular mortality and morbidity are well established.2 Although the findings of an early meta-analysis3 of the results of 17 hypertension trials—all of which used standard diuretic or β blocker therapy, or both—indicated that lowering of blood pressure was associated with a significant fall in coronary heart disease (CHD) events, the benefit noted was less than that expected from prospective observational data. Furthermore, no individual trial had shown a significant reduction in CHD events. The possibility was raised3 that newer antihypertensive agents, such as calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors, might be more effective than therapy based on diuretics or β blockers. However, there were limited data on the relative effects of newer blood-pressure lowering agents compared with standard treatment options, especially in specific combination treatment regimens.3

The issue of which antihypertensive agent should be used in first-line treatment has been controversial for almost two decades. However, to reach the target blood pressures recommended in national and international guidelines,4, 5, 6, 7 two or more antihypertensive agents need to be used in most patients.8 Furthermore, European4 and American5 guidelines include the recommendation to initiate therapy with a combination, although to date limited morbidity or mortality trial evidence for optimum combinations of antihypertensive agents are available. This absence of trial evidence results in guidelines4, 5, 6, 7 that offer different recommendations with respect to combinations of antihypertensive agents.

The most frequent combination of antihypertensive medications used worldwide when this trial was initiated was a β blocker plus a diuretic,9, 10 and the most commonly used drugs within these classes were atenolol and thiazides, respectively. Hence, we selected atenolol and bendroflumethiazide with potassium as the reference comparator drugs for ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm). The shortfall of beneficial effects on coronary events of treatment with β blockers or diuretics (often ascribed to their adverse metabolic effects) made comparison of atenolol and thiazide with a totally new combination without such metabolic side-effects a rational choice.3 During the 1990s, some observational data11 raised questions about the safety of dihydropyridine calcium-channel blockers. These agents were in common use and were effective blood-pressure lowering agents,12 but no trials were available to establish their safety and efficacy until 1997,13 and then only in the context of isolated systolic hypertension. Similarly, despite the widespread use of ACE inhibitors in the 1990s, no placebo-controlled trials were done to establish their safety and efficacy. Consequently, along with their favourable metabolic profiles, we chose to compare the effect on non-fatal myocardial infarction and fatal CHD of a combination of a dihydropyridine calcium-channel blocker (amlodipine) and an ACE inhibitor (perindopril) with that of a β blocker and a thiazide diuretic.

Section snippets

Participants

The detailed ASCOT protocol, including study design, organisation, clinical measurements, endpoint definitions, power calculations, recruitment rates, and some preliminary baseline characteristics, has been published,14 and further detailed information is available on the ASCOT website.

Briefly, between February, 1998, and May, 2000, we recruited patients to an independent, investigator-inititated, investigator-led, multicentre, prospective, randomised controlled trial.14, 15, 16 Patients were

Results

Figure 1 shows the trial profile and table 2 the baseline characteristics of the 19 257 patients randomised. In the Nordic countries, 686 family practices randomised patients, and in the UK and Ireland 32 regional centres to which patients were referred by their family doctors recruited patients. Two centres, including a total of 85 patients were excluded before the end of study because of irregularities with respect to blood-pressure measurements.18 Participants were well matched between

Discussion

The findings of ASCOT-BPLA show that in hypertensive patients at moderate risk of developing cardiovascular events, an antihypertensive drug regimen starting with amlodipine adding perindopril as required is better than one starting with atenolol adding thiazide as required in terms of reducing the incidence of all types of cardiovascular events and all-cause mortality, and in terms of risk of subsequent new-onset diabetes. Compared with the atenolol-based regimen, the amlodipine-based regimen

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