ArticlesEffects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis
Introduction
Epidemiological and clinical evidence suggests a significant inverse association between long-term intake of long-chain n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and mortality associated with coronary artery disease.1, 2, 3, 4, 5, 6, 7 Thus, the consumption of fish or fish-oil could protect against major events associated with coronary artery disease, especially fatal myocardial infarction and sudden cardiac death. Two large-scale secondary prevention trials, the Diet and Reinfarction Trial and the Gruppo Italiano per lo Studio della Sopravivenza nell' Infarto Miocardico-Prevenzione Trial, reported that increased consumption of fish or fish-oil supplements reduced coronary death in postinfarction patients.8, 9 No randomised trials have examined the effects of n-3 polyunsaturated fatty acids on major coronary events in a high-risk, primary prevention population.
EPA ethyl ester, which is purified from n-3 polyunsaturated fatty acids present in fish oil, is approved by Japan's Ministry of Health, Labour, and Welfare as a treatment for hyperlipidaemia and peripheral artery disease. The biological functions of EPA include reduction of platelet aggregation,10, 11 vasodilation,12, 13 antiproliferation,14 plaque-stabilisation,15 and reduction in lipid action.16, 17 Therefore the preventive effects of EPA on major cardiovascular events are of both clinical interest and therapeutic importance.
Primary and secondary prevention trials have proved that cholesterol-lowering treatment with inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase—statins—reduces the risk of all-cause mortality and major cardiovascular events in patients with a wide range of cholesterol concentrations, whether or not they have had coronary artery disease.18, 19, 20, 21 Thus, statins are now established as the first-line treatment for hyperlipidaemia.22 Preliminary data for treatment with a combination of n-3 polyunsaturated fatty acids and statins have shown beneficial effects on the lipid profiles of patients with a mixed type of hyperlipidaemia;23, 24, 25 however, no major long-term interventional trial has yet investigated whether the addition of EPA to conventional statin treatment would yield an incremental clinical benefit. The Japan EPA Lipid Intervention Study (JELIS) tests the hypothesis that long-term use of EPA is effective in reduction of major coronary events in Japanese hypercholesterolaemic patients given statins.
Section snippets
Study design and patients
We did a prospective, randomised open-label, blinded endpoint evaluation (PROBE).26 Our study design, and inclusion and exclusion criteria are described in detail elsewhere.27 We recruited 19 466 hypercholesterolaemic patients through local physicians from all regions of Japan between November, 1996, and November, 1999. Figure 1 shows the trial profile. The participants consisted of 5859 men (aged 40–75 years) and 12 786 postmenopausal women (aged up to 75 years), with or without coronary
Results
Patients were monitored for an average of 4·6 years (SD 1·1). Table 1 shows baseline characteristics of the treatment groups. The mean age of all patients was 61 years and 12 786 patients (69%) were women. Mean concentrations of total cholesterol and triglyceride were 7·1 mmol/L and 1·7 mmol/L; and mean LDL and HDL cholesterol concentrations were 4·7 mmol/L and 1·5 mmol/L, respectively. The webtable shows baseline characteristics for primary and secondary prevention subgroups. Of 3664 patients
Discussion
Our results show that EPA treatment reduced the frequency of major coronary events. The composite frequency of the primary endpoint in all patients for the EPA group was 19% lower than in controls. The risks of unstable angina and non-fatal coronary events were also substantially reduced, by 24% and 19%, respectively. The beneficial effects of EPA seemed much the same in both the secondary prevention and the primary prevention subgroups, although they were significant only in the EPA group
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