JELIS published: Fish oil added to statin therapy reduces risk of major coronary events

March 30, 2007

Kobe, Japan - Results of the Japan EPA Lipid Intervention Study (JELIS), first presented at the American Heart Association 2005 Scientific Sessions, have now been published in the March 31, 2007 issue of the Lancet[1]. As previously reported by heartwire , the addition of eicosapentaenoic acid (EPA) to low-dose statin therapy significantly reduced the incidence of major coronary events, largely driven by a reduction in unstable angina, when compared with patients taking statins alone.

A subgroup analysis of the study, which involved a large number of primary-prevention patients, revealed that statin-treated secondary-prevention patients gained the most benefit from fish-oil supplementation.

Investigators led by Dr Mitsuhiro Yokoyama (Kobe University Graduate School of Medicine, Japan) believe the benefit provided by the addition of EPA, a long-chain, n-3 polyunsaturated fatty acid, to statin therapy does not appear to be mediated by the effects of cholesterol lowering. In both treatment groups, there was a 26% reduction in LDL-cholesterol levels.

"The beneficial effects of EPA could have stemmed from many biological effects that lead to the attenuation of thrombosis, inflammation, and arrhythmia, in addition to a reduction of triglycerides," write the authors. "Overall, this study shows that EPA, at a dose of 1800 mg per day, is a very promising regimen for prevention of major coronary events, especially since EPA seems to act through several biological mechanisms."

Dr Dariush Mozaffarian (Harvard Medical School, Boston, MA), who wrote an editorial accompanying the published JELIS results[2], commends the efforts of the JELIS investigators, adding that this study should inspire other clinical trials of the effects of fish oil and other dietary factors and habits on cardiovascular health.

"Compared with drugs, invasive procedures, and devices, modest dietary changes are low risk, inexpensive, and widely available," writes Mozaffarian. "We must curb our infatuation with downstream risk factors and treatments and focus on the fundamental risk factors for cardiovascular disease: dietary habits, smoking, and physical activity. If the millions of heart attacks occurring each year were not a clarion call, the obesity epidemic certainly should be."

19% reduction in major coronary events

The JELIS study enrolled more than 18 000 patients, of whom 9326 were given 1800 mg/day of highly purified EPA capsules and 9319 served as controls. In Japan, this high-dose EPA has been available since 1990 for treating lipid abnormalities and peripheral artery disease and is considerably higher than the dose available over the counter in North America.

Patients in the trial were all taking low-dose statins, with more than 90% treated with pravastatin 10 mg and simvastatin 5 mg. At baseline, LDL-cholesterol levels in the control arm (statin alone) and the study arm (statin plus EPA) were approximately 183 mg/dL.

After a mean follow-up of 4.6 years, the addition of EPA to low-dose statin therapy resulted in a statistically significant 19% reduction in the risk of major coronary events, defined as sudden cardiac death, fatal or nonfatal MI, unstable angina, or the need for revascularization.

JELIS: Hazard ratios of clinical end points

Outcome Statin alone (%) Statin plus EPA (%) HR (95% CI)
All patients      
Major coronary events 3.5 2.8 0.81 (0.69-0.95)
Sudden cardiac death 0.2 0.2 1.06 (0.55-2.07)
Fatal MI 0.2 0.1 0.79 (0.36-1.74)
Nonfatal MI 0.9 0.7 0.75 (0.54-1.04)
Unstable angina 2.1 1.6 0.76 (0.62-0.95)
CABG or PTCA 2.4 2.1 0.86 (0.71-1.05)
Primary prevention of CAD      
Major coronary events 1.7 1.4 0.82 (0.63-1.06)
Sudden cardiac death 0.1 0.1 1.25 (0.34-4.67)
Fatal MI 0.1 0.1 1.00 (0.32-3.11)
Nonfatal MI 0.6 0.5 0.80 (0.52-1.24)
Unstable angina 0.9 0.8 0.85 (0.60-1.19)
CABG or PTCA 1.0 0.9 0.87 (0.62-1.21)
Secondary prevention of CAD      
Major coronary events 10.7 8.7 0.81 (0.66-1.00)
Sudden cardiac death 0.7 0.7 1.02 (0.47-2.19)
Fatal MI 0.4 0.3 0.64 (0.21-1.94)
Nonfatal MI 2.1 1.4 0.70 (0.42-1.14)
Unstable angina 6.7 4.8 0.72 (0.55-0.95)
CABG or PTCA 8.0 7.0 0.87 (0.69-1.10)

Commenting on the findings, Mozaffarian writes that the absence of effect on cardiac death is to be expected, because the benefit of fish or fish-oil consumption for this end point is nonlinear. Most risk reduction, he writes, occurs with modest intake, typically around 250 mg of EPA per day, which corresponds to one to two servings of fish per week. In Japan, average fish consumption is one serving per day, and 90% of individuals eat fish once a week. As a result, most of the population is already above the threshold for preventing cardiac death, writes Mozaffarian.

What is surprising, he continues, is the significant reduction in nonfatal coronary events, with subjects taking EPA having 19% fewer events than controls, a finding not observed in most US and European studies. Although the trial was open label and such soft end points as unstable angina and coronary revascularization could have been the result of patients' behavior, physicians' treatment, or event ascertainment, these findings should not be discounted, writes Mozaffarian.

"In view of the diverse physiological effects of fish oil and their differing dose-response curve, the main benefit at lower levels of consumption might be prevention of ventricular arrhythmia, whereas at high levels of consumption (eg, more than 1 g per day of EPA or DHA [docosahexaenoic acid]), modest benefits for nonfatal coronary events could also begin to occur because of, for example, triglyceride lowering or antihypertensive or anti-inflammatory effects."

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