Dallas, TX - 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.

Dr Mitsuhiro Yokoyama

Presenting the results of the Japan EPA Lipid Intervention Study (JELIS) during the late-breaking clinical-trials session at the American Heart Association Scientific Sessions 2005, Dr Mitsuhiro Yokoyama (Kobe University Graduate School of Medicine, Japan) said that the mechanism of benefit with EPA, a seafood-based, long-chain, n-3 polyunsaturated fatty acid, appears to be unrelated to the effects of cholesterol lowering.

Commenting on the results of the study for heartwire, Dr Lawrence Appel (Johns Hopkins University School of Medicine, Baltimore, MD) said the findings are impressive given that the benefit of fish oil was observed on top of a regimen of statin therapy. He added that there are still some unknowns about which patient population would benefit most from fish oil.

"My own sense is that the verdict is still out in terms of primary prevention," said Appel. "A lot of sudden death occurs in individuals who have not had a previous heart attack. This is the group we're really concerned about as clinicians. The first manifestation of disease is something that patients typically can't recover from."

Large population of patients

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

Patients in the trial were all taking low-dose statins; more than 90% were 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 182 mg/dL and 181 mg/dL, respectively. Total cholesterol levels were also very high; 275 mg/dL was the average baseline level in both groups.

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.

Incidence of major coronary events

Outcome (%)	Statin alone (n=9319)	Statin plus EPA (n=9326)	Hazard ratio (95% CI)
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)

Investigators also conducted a prespecified subgroup analysis that looked at the effect of adding EPA to statin therapy in primary- and secondary-prevention CAD patients. In the primary-prevention cohort, there was an 18% reduction in the risk of major coronary events with EPA-plus-statin therapy when compared with the control group, although the results did not achieve statistical significance. In the secondary-prevention cohort, there was a statistically significant 19% reduction in the risk of coronary events. Like the primary analyses, the reduction in risk was driven primarily by a reduction in the risk of unstable angina.

In terms of adverse events, there were slightly more events related to gastrointestinal distress and skin abnormalities. Abnormal liver-enzyme elevations were also observed, but investigators say these side effects were mild.

Speaking with heartwire, Yokoyama said the benefit provided by the addition of EPA 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. An analysis of patients who achieved different on-treatment LDL-cholesterol levels, including those who achieved an LDL-cholesterol level of <120 mg/dL and those with an LDL-cholesterol level >140 mg/dL, revealed equivalent reductions in the risk of coronary events.

Asked about the discrepancies between the findings of the GISSI trial, where dietary supplementation with fish oil reduced the risk of sudden death, and this trial, where no benefit on sudden death was observed, Yokoyama said the two patient populations were different. Different lifestyles and diet—Japanese people eat nearly five times more fish than people in Western countries—and different risk-factor profiles explain part of this difference, he said. Moreover, patients in GISSI were given smaller doses of omega-3 fatty acids, which might have contributed to the reduction in sudden death, whereas JELIS investigators treated patients with higher doses of EPA. A higher dose of EPA might exert its benefit by stabilizing unstable plaque, said Yokoyama.

Appel agreed, noting that the EPA likely affects the progression of underlying atherosclerosis.

"The sudden-death benefit that was seen in the GISSI trial was seen almost immediately, within about six months," said Appel. "When you look at these curves [in JELIS], the benefit is occurring one or two years out, when you're presumably dealing with some type of mechanism related to atherosclerosis."

What about other patients?

In terms of generalizing the results to other populations, Appel said it would be difficult. Plasma EPA levels in the Japanese cohort were high, because of the high (1800-mg) dose of EPA and the fact that the Japanese diet is rich in fish. Moreover, the doses of statin used in this trial were very low, despite the high baseline LDL-cholesterol levels of subjects in the control and study arms.

"There is an unresolved question about whether or not you would have attained the same benefit by increasing the dose of statin," said Appel. "But I don't think that many people think that simvastatin and fish oil are the same. They are likely complementary in their mechanisms."

Speaking during the late-breaking clinical-trials session, Dr Beatriz Rodriguez (University of Hawaii, Honolulu), the discussant for the JELIS study, pointed out that there were no significant differences between the two study arms in total mortality. "There is no strong evidence that EPA affects mortality one way or the other," she said, adding that value would be gained if the trial were extended and the patients studied further. Rodriguez said that stroke outcomes, in particular cerebral hemorrhage, should be explored further because of the potential anticoagulation effects of fish oils.

Rodriguez also pointed out that there are many possible mechanisms that might explain the benefits of fish oil, specifically in secondary prevention. Antithrombotic effects, lowering of triglyceride levels, retardation of atherosclerotic plaque, anti-inflammatory effects, and the possible effects on platelet-derived growth factors could contribute to the observed benefits.