Elsevier

The Lancet

Volume 359, Issue 9315, 20 April 2002, Pages 1379-1387
The Lancet

Articles
Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up

https://doi.org/10.1016/S0140-6736(02)08351-4Get rights and content

Summary

Background

The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that pravastatin therapy over 6 years reduced mortality and cardiovascular events in patients with previous acute coronary syndromes and average cholesterol concentrations. We assessed the longer-term effects of initial treatment with pravastatin on further cardiovascular events and mortality over a total follow-up period of 8 years.

Methods

In the main trial, 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol concentration of 4·0–7·0 mmol/L were randomly assigned pravastatin 40 mg daily or placebo and followed up for 6 years. Subsequently, all patients were offered open-label pravastatin for 2 more years. Major cardiovascular events and adverse events were compared according to initial treatment assignment.

Findings

7680 (97% of those still alive) had 2 years of extended follow-up. 3766 (86%) of those assigned placebo and 3914 (88%) assigned pravastatin agreed to take open-label pravastatin. During this period, patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo, but a lower risk of death from all causes (219 [5·6%] vs 255 [6·8%], p=0·029), coronary heart disease (CHD) death (108 [2·8%] vs 137 [3·6%], p=0·026), and CHD death or non-fatal myocardial infarction (176 [4·5%] vs 196 [5·2%], p=0·08). Over the total 8-year period, all-cause mortality was 888 (19·7%) in the group originally assigned placebo and 717 (15·9%) in the group originally assigned pravastatin, CHD mortality was 510 (11·3%) versus 395 (8·8%), myocardial infarction was 570 (12·7%) versus 435 (9·6%; each p<0·0001), and stroke was 272 (6·0%) versus 224 (5·0%; p=0·015). Stronger evidence of separate treatment benefits than in the main trial was seen in important prespecified subgroups (women, patients aged ≥70 years, and those with total cholesterol <5·5 mmol/L). Pravastatin had no significant adverse effects.

Interpretation

The evidence of sustained treatment benefits and safety of long-term pravastatin treatment reinforces the importance of long-term cholesterol-lowering treatment for almost all patients with previous CHD events.

Introduction

Trials have shown that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase reduce the risk of death and major cardiovascular events after acute myocardial infarction1, 2, 3 and unstable angina pectoris.3 The three large-scale trials—the Scandinavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Events (CARE) study, and the Long-term Intervention with Pravastatin in Ischaemic Disease study (LIPID)—suggested a possible lag in the treatment effect of 1–2 years after treatment begins. The LIPID trial was terminated early, in 1997, owing to clear evidence of survival benefits with pravastatin treatment. At this time, there were few data on the long-term effectiveness or safety of HMG-CoA reductase inhibitors beyond 5–6 years of treatment. Therefore, after the termination of the LIPID study, all patients were offered pravastatin therapy, with the plan to assess outcomes and safety over at least a further 2 years. We also planned to assess the effects of pravastatin therapy in important subgroups of patients for which the initial study was not powerful enough to show independent significant effects. These subgroups included women, patients aged 70 years or older, and those with total plasma cholesterol concentrations of less than 5·5 mmol/L.

Section snippets

Double-blind period

The design and results of the original study have been published.3, 4 This randomised placebo-controlled trial was undertaken at 87 centres in Australia and New Zealand, and involved 9014 patients who had had an acute myocardial infarction or a hospital discharge diagnosis of unstable angina pectoris 3–36 months before study entry and whose total cholesterol concentration was 4·0–7·0 mmol/L. Patients were randomly assigned pravastatin 40 mg per day or placebo in addition to their usual

Results

Between June, 1990, and December, 1992, 9014 patients were randomised into the LIPID study (figure 1). Patients were followed up during the double-blind phase of the trial for a mean of 6·0 years; one patient was lost to follow-up. Of the 7882 patients alive at the end of this phase, 7680 (97%) consented to long-term follow-up; 3914 had been initially assigned pravastatin (pravastatin group) and 3766 placebo (placebo group). The randomised groups were well balanced for baseline characteristics,

Discussion

The main LIPID study showed that pravastatin reduced total mortality and all prespecified cardiovascular outcomes in patients with previous acute coronary syndromes and average baseline cholesterol concentrations. These effects were seen across a broad range of subgroups and lipid concentrations and were in addition to contemporary medical treatments as used at the time.3 With extended follow-up, the LIPID study has now shown that the benefits of the first 6 years of cholesterol-lowering

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