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Discussion
JELIS - Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study
Faculty and Disclosures
Presenter: Mitsuhiro Yokoyama, MD, PhD (Kobe University Graduate School of Medicine, Japan)
The first large-scale, prospective, randomized trial of combined treatment with a statin and an omega-3 fatty acid originally derived from fish, eicosapentaenoic acid (EPA), has shown that the addition of EPA to statin therapy provides additional benefit in preventing major coronary events, apparently through lipid-independent mechanisms.[1] The Japan eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) tested the effects of long-term use of EPA 1800 mg/day in addition to a statin in Japanese patients with hypercholesterolemia. The results add support to previous evidence of the beneficial effect of omega-3 fatty acids in patients with known coronary heart disease, and show that that effect can extend the benefit of statins, the JELIS investigators believe.
Rationale and Study Design
Both epidemiologic and randomized clinical trials have shown that intake of long-chain polyunsaturated omega-3 fatty acids (PUFAs), which are abundant in fish, might have a significant role in preventing the development of coronary heart disease. However, more clinical studies are needed to confirm and further define the health benefits of omega-3 fatty acid supplements for both primary and secondary prevention. The main purpose of JELIS was to examine the clinical effectiveness of EPA oil given as an additional treatment to patients taking statins for hypercholesterolemia. JELIS was designed as a prospective, randomized, open-label, blinded endpoint trial, with a maximum follow-up of 5 years.[2] Subgroup analysis was undertaken to determine whether the effect of EPA differed in primary and secondary prevention.
Patients and Treatment
Men aged 40-75 years and postmenopausal women aged =75 years with serum total cholesterol =250 mg/dL were eligible for the study. A total of 18,645 subjects (mean age, 61 years; 31% male) were recruited. About 36% of the subjects were hypertensive, 15% had diabetes, and 20% had coronary artery disease (CAD). All were randomized to pravastatin 10 mg/day or simvastatin 5 mg/day (control group) or the same statin doses with EPA 1800 mg/day. The EPA formulation used in the trial was Epadel (Mochida; Tokyo, Japan), an ethical drug containing highly purified (>98%) fish-derived ethyl EPA, which is currently indicated in Japan for the treatment of arteriosclerosis and hyperlipidemia.
Lipids
Mean total and low-density lipoprotein (LDL)-cholesterol levels in the JELIS participants at baseline were 275 mg/dL (7.1 mmol/L) and 180 mg/dL (4.6 mmol/L), respectively. At the end of the study, total cholesterol and LDL-cholesterol levels were reduced equivalently in both treatment groups, by 19% and 26%, respectively. Triglycerides were reduced by 10% in the EPA group vs 5% in the control group. These reductions in lipids were seen at 6 months, and levels remained stable throughout the remaining duration of follow-up. High-density lipoprotein (HDL)-cholesterol remained stable throughout the study.
Primary and Secondary Endpoints
After mean follow-up of 4.6 years, the primary endpoint of major coronary events, defined as sudden cardiac death, fatal or nonfatal myocardial infarction (MI), unstable angina pectoris, and coronary artery bypass graft/percutaneous coronary intervention (CABG/PCI), was significantly reduced by 19% in the EPA group compared with the statin-only group (Table 1). Among the primary endpoint components, a 24% reduction in unstable angina in the EPA group was the only significant difference compared with the control group.
Table 1. Primary Endpoint
Control (%) EPA (%) HR 95% CI P Value
Major coronary events 3.5 2.8 0.81 0.69-0.95 .011
Sudden cardiac death 0.2 0.2 1.06 0.55-2.07 .954
Fatal MI 0.2 0.1 0.79 0.36-1.74 .557
Nonfatal MI 0.9 0.7 0.75 0.54-1.04 .086
Unstable angina 2.1 1.6 0.76 0.62-0.95 .014
CABG/PCI 2.4 2.1 0.86 0.71-1.05 .135
CABG = coronary artery bypass graft; CI = confidence interval; EPA = eicosapentaenoic acid; HR = hazard ratio; MI = myocardial infarction; PCI = percutaneous coronary intervention
Analysis of combined endpoints showed a significant 19% reduction in nonfatal coronary events, defined as nonfatal MI, unstable angina, or CABG/PCI, in the EPA group vs controls (P = .015). There was no significant difference in all-cause mortality between the 2 treatment groups.
Primary and Secondary Prevention Subgroup Analyses
In the 14,981 subjects with no history of coronary artery disease (CAD), major coronary events were reduced by 18% in the EPA group vs the controls, although this difference was not significant (Table 2). Nonsignificant reductions were also seen in nonfatal MI, unstable angina, and CABG/PCI, and in combined endpoints of coronary death or MI, fatal or nonfatal MI, and nonfatal coronary events.
Table 2. Primary Endpoint (Primary Prevention)
Control (%) EPA (%) HR 95% CI P Value
Major coronary event 1.7 1.4 0.82 0.63-1.06 .132
Sudden cardiac death 0.1 0.1 1.25 0.34-4.67 .736
Fatal MI 0.1 0.1 1.00 0.32-3.11 .995
Nonfatal MI 0.6 0.5 0.80 0.52-1.24 .321
Unstable angina 2.9 0.8 0.85 0.60-1.19 .338
CABG/PCI 1.0 0.9 0.87 0.62-1.21 .400
CABG = coronary artery bypass graft; CI = confidence interval; EPA = eicosapentaenoic acid; HR = hazard ratio; MI = myocardial infarction; PCI = percutaneous coronary intervention
Compared with the primary prevention subgroups, the 3664 subjects with a history of CAD tended to be on antiplatelet drugs, antihypertensive agents, and nitrates, and in these secondary prevention patients, EPA was associated with a significant 19% reduction in major coronary events compared with the control group (Table 3). Unstable angina was also significantly reduced in the EPA group, by 28%. Nonsignificant reductions were seen in fatal MI, nonfatal MI, and CABG/PCI and in combined endpoints.
Table 3. Primary Endpoint (Secondary Prevention)
Control (%) EPA (%) HR 95% CI P Value
Major coronary event 10.7 8.7 0.81 0.66-1.00 .048
Sudden cardiac death 0.7 0.7 1.02 0.47-2.19 .967
Fatal MI 0.4 0.3 0.64 0.21-1.94 .421
Nonfatal MI 2.1 1.4 0.70 0.42-1.14 .150
Unstable angina 6.7 4.9 0.72 0.55-0.95 .019
CABG/PCI 8.0 7.0 0.87 0.69-1.10 .243
CABG = coronary artery bypass graft; CI = confidence interval; EPA = eicosapentaenoic acid; HR = hazard ratio; MI = myocardial infarction; PCI = percutaneous coronary intervention
Safety
A higher incidence of adverse events, especially gastrointestinal disorders, skin disorders, and abnormal liver function tests, was recorded in the EPA group than in the control group (25.3% vs 21.7%, P < .0001) (Table 4). Most of these adverse events were mild. In the EPA group, the 11.7% who experienced an adverse event stopped treatment, compared with 7.2% in the controls.
Table 4. Serious Adverse Events (SAEs)
SAE Control (%) EPA (%) P Value
Hemorrhage 3.4 3.8 .172
Abnormal liver function test 3.5 4.1 .032
Cancer 2.4 2.6 .263
Joint, lumbar, muscle pain 2.0 1.6 .043
Gastrointestinal disorder 1.7 3.8 < .0001
Skin rash/itching 0.7 1.7 < .0001
EPA = eicosapentaenoic acid
Implications
Both treatments lowered LDL-cholesterol by the same amount, yet the combination of EPA plus statin produced a greater reduction in major coronary events, suggesting a mechanism independent of lipid lowering, Prof. Yokoyama pointed out. This was further indicated by stratification of major coronary events by on-treatment LDL-cholesterol levels (< 120, 120-140, and > 140 mg/dL), which showed no differences in relative risk reduction. After adjustment for age, gender, and prevention strategy, an inverse association was found between the risk of major coronary events and EPA/arachidonic acid ratio, suggesting that the effect of EPA may be antithrombotic or anti-inflammatory, or the effect may be such that it increases the stability of the atherosclerotic plaque, Prof. Yokoyama suggested.
AHA-designated discussant Beatriz L Rodriguez, MD, PhD (University of Hawaii, Honolulu), observed that although the overall reduction in major coronary events in JELIS was an "interesting" result, "there was no strong evidence that EPA affects mortality one way or another." It would be of great value, she suggested, for the study to continue the follow-up in order to reach an assessment of total mortality. Stroke outcomes and cerebral hemorrhage should also be explored, because of the potential coagulant effects of fish oils. Prof. Rodriguez also noted that EPA levels were 5 times higher in the JELIS subjects than in Western populations. In Japan, average fish consumption is very high compared with that of Western populations, and it is unclear whether the EPA doses proposed in this study would have the same effect in populations that have a substantially lower fish consumption. In addition, because the JELIS subjects had high levels of LDL-cholesterol, care should be taken in extrapolating these results to the general population, she cautioned.
Other commentators outside the session, including AHA President Robert Eckel, MD (University of Colorado Health Sciences Center, Denver), also noted that application of the JELIS results might be difficult in Western populations. "An important consideration is that the dose of omega-3 fatty acids, 1800 mg a day of highly purified EPA, is more than the standard over-the-counter supplement [in the United States]," Dr. Eckel pointed out. The most common fish oil supplements used in the United States contain 180 mg of EPA (as well as another omega-3 fatty acid, docosahexaenoic acid). In its official statement about fish consumption and fish oil,[3] the AHA says that a dietary approach to increasing omega-3 fatty acid intake is preferable to supplements, but this may not be possible for patients with CAD, who need to increase their intake to about 1 g/day for CHD risk reduction. The statement stresses the need for "high-quality omega-3 fatty acid supplements, free of contaminants," as an important prerequisite to their extensive use.
The JELIS study was funded by Mochida Pharmaceutical Co, Ltd, Tokyo, Japan.
References
Yokoyama M. Effects of eicosapentaenoic acid (EPA) on major cardiovascular events in hypercholesterolemic patients: the Japan EPA Lipid Intervention Study (JELIS). American Heart Association Scientific Sessions 2005; November 13-16, 2005; Dallas, Texas. Late Breaking Clinical Trials II.
Yokoyama M, Origasa H; JELIS Investigators. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J. 2003;146:613-620.
Kris-Etherton PM, Harris WS, Appel LJ; the Nutrition Committee. AHA Scientific Statement. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.
