Elsevier

The Lancet

Volume 361, Issue 9364, 5 April 2003, Pages 1149-1158
The Lancet

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Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

https://doi.org/10.1016/S0140-6736(03)12948-0Get rights and content

Summary

Background

The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic.

Methods

Of 19 342 hypertensive patients (aged 40–79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10 305 with non-fasting total cholesterol concentrations 6·5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat.

Findings

Treatment was stopped after a median follow-up of 3·3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0·64 [95% CI 0·50–0·83], p=0·0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0·73 [0·56–0·96], p=0·024), total cardiovascular events (389 vs 486, 0·79 [0·69–0·90], p=0·0005), and total coronary events (178 vs 247, 0·71 [0·59–0·86], p=0·0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0·87 [0·71–1·06], p=0·16). Atorvastatin lowered total serum cholesterol by about 1·3 mmol/L compared with placebo at 12 months, and by 1·1 mmol/L after 3 years of follow-up.

Interpretation

The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

Published online April 2,2003 http://image.thelancet.com/extras/03art3046web.pdf

Introduction

A series of large randomised endpoint trials1, 2, 3, 4, 5, 6, 7, 8, 9, 10 has established the benefits of statins for the prevention of major fatal and non-fatal cardiovascular events. These data are consistent with experimental,11 observational12 and other trial data13, 14 in establishing dyslipidaemia as a major independent risk factor for coronary heart disease (CHD). On the basis of observational data, the causal association between dyslipidaemia and increased rates of cerebrovascular disease is unclear,15 but trial evidence has shown notable reductions in stroke rates associated with statin use.16

Intervention studies have confirmed the cardiovascular benefits of statins in primary prevention,6, 7 secondary prevention,1, 2, 3, 4, 5 and acute coronary syndromes,17 across a wide age range2, 8, 9 and among patients with total cholesterol concentrations much lower than average.8

The relation between CHD risk plotted on a doubling scale and serum cholesterol in observational studies is roughly linear, such that a long-term cholesterol concentration lowered by about 1·0 mmol/L corresponds to about 50% less CHD, irrespective of cholesterol concentration.18 In intervention studies, however, the lowering of cholesterol by 1·0 mmol/L maintained over a period of 5 years corresponds to only about 25–35% fewer CHD events.19

Observational data indicate that coexistent risk factors, such as raised blood pressure and dyslipidaemia, generally exert a multiplicative effect on the risk of experiencing cardiovascular events,20 and subgroup analyses of intervention studies2, 3, 4, 7, 8 suggest that the relative cardiovascular benefits of lipid lowering are similar among hypertensive and normotensive participants.

However in ALLHAT,10 the use of pravastatin versus usual care in patients with mild to moderate hypertension produced only non-significant reductions in cardiovascular events.

Most cardiovascular events and deaths attributable to raised blood pressure21 and dyslipidaemia18 occur among patients with blood pressure and lipid concentrations deemed normal. Assessment of the effects of lipid lowering is, therefore, important in patients with reasonably controlled blood pressures and normal or only mildly or moderately raised serum cholesterol concentrations.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is an independent, investigator-initiated and investigator-led, multicentre, randomised trial22 designed to compare two antihypertensive treatment strategies for the prevention of CHD events in more than 18 000 hypertensive patients who have no history of CHD. The study uses the Prospective Randomised Open Blinded Endpoints (PROBE) design.23 In addition, by way of a two-by-two factorial design, ASCOT has included a double-blind randomised comparison of the cardiovascular effects of atorvastatin, a statin, with placebo among patients who have total cholesterol concentrations of 6·5 mmol/L or less. This lipid-lowering arm of ASCOT forms the subject of this report.

The detailed ASCOT protocol, including study design, organisation, clinical measurements, endpoint definitions, rationale for choice of treatment strategies, power calculations, recruitment rates, and some baseline characteristics has previously been published,22 and further detailed information is available on the ASCOT website.24 In summary, the primary objective of the lipid-lowering arm was to assess and compare the long-term effects on the combined endpoint of non-fatal myocardial infarction, including so-called silent myocardial infarction, and fatal CHD of a statin (plus antihypertensive treatment) compared with placebo (plus matched antihypertensive treatment) among patients with total cholesterol concentrations of 6·5 mmol/L or less. The secondary endpoints of the lipid-lowering arm were the primary outcome without silent events, all-cause mortality, total cardiovascular mortality, fatal and non-fatal stroke, fatal and non-fatal heart failure, total coronary endpoints, and total cardiovascular events. Tertiary objectives were also prespecified, including the assessment of the effects of statin on the primary endpoint among several subgroups.

Section snippets

Patients

Patients eligible for inclusion in the lipid-lowering arm of ASCOT were men and women aged between 40 and 79 years at randomisation, with either untreated hypertension, defined as systolic blood pressure of 160 mm Hg or more, diastolic blood pressure of 100 mm Hg or more, or both, or treated hypertension with systolic blood pressure of 140 mm Hg or more, diastolic blood pressure 90 mm Hg or more, or both. Patients had to be eligible for the blood-pressure-lowering arm, have total cholesterol

Results

Of the 19 342 patients randomised to one of the two antihypertensive regimens 10 305 were further randomly assigned atorvastatin 10 mg daily or placebo (figure 1). Baseline characteristics of participants in these two randomised groups were well matched (table 1).

Participants were mainly white (95%) and male (81%), with a mean age of 63 years. The average number of the additional cardiovascular risk factors required for inclusion in the trial was 3·7. Baseline blood pressure and lipid

Discussion

Our findings in the lipid-lowering arm of ASCOT show that in hypertensive patients, who on average were at moderate risk of developing cardiovascular events, cholesterol lowering with atorvastatin 10 mg conferred a 36% reduction in fatal CHD and non-fatal myocardial infarction compared with placebo. This effect seemed to emerge early, such that the data safety monitoring board recommended early termination of the trial. This decision was also affected by the significant reductions in other

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