Elsevier

The Lancet

Volume 368, Issue 9542, 30 September–6 October 2006, Pages 1155-1163
The Lancet

Articles
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial

https://doi.org/10.1016/S0140-6736(06)69472-5Get rights and content

Summary

Background

Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population.

Methods

In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5·69–6·98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10–20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705.

Findings

3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5·3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2·1% (from 6·27 mmol/L to 6·13 mmol/L) and 11·5% (from 6·27 mmol/L to 5·55 mmol/L) and mean LDL cholesterol by 3·2% (from 4·05 mmol/L to 3·90 mmol/L) and 18·0% (from 4·05 mmol/L to 3·31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0·67, 95% CI 0·49–0·91; p=0·01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups.

Interpretation

Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

Introduction

Several large-scale primary and secondary prevention trials1, 2, 3, 4, 5, 6, 7, 8, 9, 10 have reported that cholesterol-lowering therapy can reduce the rates of the first occurrence and recurrence of coronary heart disease by about 20–40%. However, little is known of the relation between decreasing cholesterol concentrations and risk reduction for coronary heart disease in Japan, since many of the trials were done in countries with higher incidences of coronary heart disease than those seen in Japan.11, 12 Whether the results of clinical studies done outside Asia can be extrapolated to Japanese patients with hypercholesterolaemia is not known because of the differences in lifestyle and the incidence of coronary heart disease and stroke between Japan and western countries (about a third lower and two times higher, respectively).

This prospective randomised controlled trial was designed to assess the primary preventive effect of a statin against coronary heart disease in daily clinical practice in Japan. The dose of pravastatin used in this study is consistent with the approved dose in Japan and lower than the doses used in previous large-scale clinical trials done in western populations. Thus, the results from this trial will provide valuable guidance about the future treatment of hypercholesterolaemia in Japan.

Section snippets

Patients

The details of this prospective randomised, open-labelled, blinded-endpoint13 study have been reported previously.14 Briefly, men and postmenopausal women aged 40–70 years with a bodyweight of 40 kg or more and hypercholesterolaemia (total cholesterol concentration 5·69–6·98 mmol/L) were eligible for study enrolment between February, 1994, and March, 1999. Major exclusion criteria were familial hypercholesterolaemia and a history of coronary heart disease or stroke. Other exclusion criteria

Results

Figure 1 shows the trial profile. Of 7832 patients who were analysed, 2223 consented and 1013 refused to extend follow-up. The remaining 4596 patients completed the study at 5 years. The baseline characteristics of the analysed patients are presented in table 1.

7730 (98·7%) study patients completed follow-up after 5 years or more, and no difference was seen in the number of patients followed in both groups. The follow-up period was 41 195 person-years (mean follow-up period 5·3 years). In the

Discussion

This study shows that low doses of pravastatin can reduce the risk of coronary heart disease in Japanese patients, despite only small to moderate reductions in total cholesterol and LDL-cholesterol concentrations. Thus, in low-risk populations—eg, hypercholesterolaemic Japanese patients with high HDL cholesterol—less aggressive cholesterol-lowering therapy might be sufficient to produce a substantial and beneficial risk reduction for the primary prevention of coronary heart disease.

This trial,

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