Fish Oil Plus Statins
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Yokoyama M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
Synopsis: EPA treatment added to statins reduces nonfatal CHD events in hypercholesterolaemic Japanese patients.
Secondary prevention trials have demonstrated reduced coronary heart disease (CHD) deaths in post myocardial infarction (MI) patients who consume fish or fish oil, but no prospective randomized primary prevention trials have been done. Thus, the Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) was conducted to test the hypothesis that adding EPA to statin therapy would reduce major coronary events in hypercholesterolaemic Japanese patients. They recruited 18,645 patients with a total cholesterol of > 250 mg/dl with or without a history of CHD, who consume a large amount of fish. The patients were divided into those with CHD (3,664) and those without (14,981). They were randomized to receive EPA with statin or stain alone. All received dietary advice. The statins were either pravastatin up to 20 mg/day or simvastatin up to 10 mg/day. EPA 600 mg was administered 3 times a day after meals. The patients were followed for an average of 4.6 years. The primary endpoint was any major CHD event. Secondary endpoints included total mortality, stroke and peripheral artery disease.
Results. The primary endpoint occurred in 2.8% of the EPA group and 3.5% of the statin alone group, a relative risk reduction of 19% (p = 0.011). Unstable angina decreased 24% (p = 0.014) and all other nonfatal CHD endpoints, including MI, were significantly reduced (p = 0.015). The results were the same across LDL levels above or below 180 mg/dl. The primary prevention subgroup exhibited an 18% decrease in the primary endpoint in the EPA group which was not statistically significant. The secondary prevention group showed a 19% decrease which was significant (p = 0.048). All-cause mortality and stroke did not differ between groups. Total cholesterol, LDL and triglycerides decreased on therapy, but only the decrease in triglycerides was significantly greater on EPA. Neither treatment had much affect on HDL. Adverse events were more common on EPA, especially gastrointestinal (3.8 vs 1.7%), skin (1.7 vs 0.7%) and hemorrhage (1.1 vs 0.6%). The authors concluded that EPA treatment added to statins reduces nonfatal CHD events in hypercholesterolaemic Japanese patients.
Commentary
This is an interesting study because despite a fish consumption that is 5 times most Western diets, supplemental EPA significantly reduced nonfatal CHD events in hypercholesterolaemic Japanese patients. Previous secondary prevention observational studies have shown that increased fish or fish oil consumption rescues fatal CHD and sudden death, but not nonfatal events. These results prompted speculation that fish oils are antiarrhythmic. Why the difference in these results? There are several potential explanations. It could be simply that the study was underpowered for fatal events. There is a low rate of death from CHD in Japan, especially in women, who comprised 69% of the study population. Most of the patients in the trial were in the primary prevention arm where the reduction in the primary endpoint did not achieve statistical significance. It could be that prospective trials avoid some of the biases of observational studies and reveal the true effect of a therapy. Fish oils contain many fatty acids and have many effects including reductions in triglycerides, thrombosis and inflammation. Perhaps EPA is less effective than fish oil. Given the high fish consumption of the Japanese, perhaps some beneficial threshold had already been crossed and further benefits from EPA therapy were more difficult to achieve. However, you can't say they didn't try. EPA levels were increased from 97 to 169 mol% after 5 years of therapy, a whopping 70% increase. Also, it had a cost in adverse effects with 25% experiencing one or more on EPA, but only 12% discontinued EPA due to adverse effects in this population. It is not known whether a lower dose would have produced similar benefits. Of interest EPA levels in most Western industrialized countries is 0.3 mol%.
Another issue with this study is that low doses of 2 statins were used. Although cholesterol levels were reduced, we don't know if any particular targets were achieved. Perhaps larger doses of statins would have accomplished the same results as adding EPA. However, the beneficial effects of EPA did not seem to be related to LDL levels, and except for triglycerides, EPA did not further change lipid levels in the study. This would argue against a statin-like effect, but doesn't mean that high dose statins couldn't achieve similar results.
So what do we tell our patients now about the use of fish oils? Clearly their potential benefit outweighs any potential harm in both primary and secondary prevention populations with high cholesterol values. They are one of the few therapies that lower triglycerides. In patients with high LDL, we don't know if they have benefits beyond aggressive LDL lowering with statins. In this study the average LDL on therapy was > 130 mg/dl. Recent studies with statins clearly show the benefits of LDL levels < 130, especially in secondary prevention. I believe the jury is still out on fish oils, especially for primary prevention, but if tolerated they don't appear to be harmful and have the potential to be beneficial.
EPA treatment added to statins reduces nonfatal CHD events in hypercholesterolaemic Japanese patients.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content