Fish Oil Sinks Coronary Event Rates When Added to Statins

KOBE, Japan, March 30 -- Fish-oil supplements added to statin therapy can further reduce the risk of major coronary events, even among patients who already eat a diet heavy in fish, investigators here reported.

Among more than 18,000 patients with hypercholesterolemia and a history of coronary artery disease, the addition to statins of eicosapentaenoic acid, a long-chain-n-3 fatty acid in fish oil, reduced the occurrence of major coronary events by 19% over statins alone, reported Mitsuhiro Yokoyama, M.D., from Kobe University here, and colleagues.

Eicosapentaenoic acid, (EPA) was associated with significant reductions in unstable angina and non-fatal coronary events, but there were no differences in either sudden cardiac death or coronary death, the investigators in the Japan EPA Lipid Intervention Study (JELIS).wrote in the March 31 issue of The Lancet.

In an accompanying editorial, Dariush Mozaffarian, M.D., Dr.P.H., of the Harvard School of Public Health commented that the findings lack the flash of clinical trial results on blockbuster drugs, but they show that a low-risk and inexpensive intervention could have a major effect on health

"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," he wrote. "If the millions of heart attacks occurring each year were not a clarion call, the obesity epidemic certainly should be. The JELIS investigators should be commended, and their efforts should inspire additional clinical trials of the effects of fish oil and other dietary factors and habits on cardiovascular health."

The JELIS investigators recruited 18,645 patients from 1996 to 1999, with a total cholesterol of 6.5 mmol/L (253 mg/dL) or greater. The patients were randomly assigned to 1,800 mg of EPA daily with a statin (9,326 patients) or statin therapy alone (9,319).

EPA was given at a dose of 600 mg, three times a day after meals (to a total of 1,800 mg per day). Statin therapy was initiated with either 10 mg of pravastatin (Pravachol) or 5 mg of simvastatin (Zocor) once daily as first-line treatment. For patients with uncontrolled hypercholesterolemia, the daily dose could be increased to 20 mg of pravastatin or 10 mg of simvastatin.

The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal MI, and other nonfatal events, including unstable angina, angioplasty, stenting, or coronary artery bypass graft. Follow-up was for five years, with analysis by intention-to-treat.

The authors found that at the mean follow-up of 4.6 years, 2.8% of patients in the EPA group (262 patients) and 3.5% of controls (324 patients) had a major coronary event. This difference translated into a 19% relative reduction in the primary endpoint for the EPA group (P=0.011).

In both groups, LDL concentrations decreased by 25%, from a mean of 4.7 mmol/L (183 mg/dL) at baseline, and total cholesterol declined by 19%.

The omega-3 fatty acid was also associated with a significant reduction of 24% in the frequency of unstable angina, although there were no significant differences in the rate of either coronary death or myocardial infarction between the groups.

"The frequency of fatal or non-fatal myocardial infarction was not significantly reduced (23%) in the EPA group," the authors wrote. "However, that of non-fatal coronary events (including non-fatal myocardial infarction, unstable angina, and events of angioplasty, stenting, or coronary artery bypass grafting) was significantly lower (19%) in the EPA group than in controls."

Yet in a subgroup of patients with coronary artery disease who had already suffered a major coronary event (secondary prevention group), EPA treatment was associated with a significant 19% reduction in total major coronary events, and a 28% reduction in the incidence of unstable angina.

That the authors did not see an effect of EPA on mortality is not surprising, Dr. Mozaffarian commented.

"In Japan, average fish consumption is one serving of 85 g (3 oz; 900 mg EPA and DHA) per day, and 90% of individuals eat fish at least once a week," he wrote. "Thus, most of the population is already above the threshold for preventing cardiac death. In any such population, one would expect low baseline rates of cardiac death, and little further reduction in cardiac death with additional fish-oil consumption."

He also noted that the reduction in non-fatal events was consistent with findings of observational studies of Japanese populations and some U.S populations with high levels of fish consumption.

The investigators wrote that their study was limited by an open, unblinded design, and by the use of pravastatin or simvastatin as first-line agents (because they were the only statins available in Japan at study outset). In addition, the trial was underpowered for analysis of subgroups, because of the low incidence of coronary artery disease in the Japanese population.