More research supporting the protective benefit of omega-3 fatty acids—in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—on cardiovascular (CV) end points was presented at major medical meetings in 2005. The largest CV clinical trial was JELIS (Japan EPA Lipid Intervention Study), presented during the American Heart Association (AHA) Scientific Sessions by Dr. Mitsuhiro Yokoyama, Chief, Department of Cardiovascular and Internal Medicine, Kobe University Graduate School of Medicine, Japan.
    The JELIS trial involved over 18,000 patients, all of whom were taking low-dose statin therapy, mostly either pravastatin 10 mg or simvastatin 5 mg. Approximately half of the cohort were also assigned to 1800 mg/day of highly purified EPA, a preparation that has long been available in Japan and which is used to treat lipid abnormalities and peripheral artery disease (PAD). As reported by theheart.org, of patients taking both the low-dose statin therapy and the EPA supplement, 2.8% had a major coronary event over a mean follow-up of 4.6 years compared with 3.5% of the statin alone group, for a 19% relative risk reduction in the incidence of major coronary events in favour of the combination group. In JELIS, major coronary events were defined as sudden cardiac death (SCD), fatal or nonfatal myocardial infarction (MI), unstable angina or the need for revascularization.

The relative risk reduction was very similar for both primary and secondary prevention cohorts, although results did not achieve statistical significance in the primary prevention group. According to principal investigator Dr. Yokoyama, the benefit of additional EPA in this large cohort of patients appeared to be independent of its effects on cholesterol, for there was a 26% reduction in LDL-C in both study cohorts. Interestingly, EPA supplementation in JELIS had no effect on the incidence of SCD.
    This is in direct contrast to several other clinical studies including the landmark GISSI-Prevention Trial (Lancet 1999;354:447-55) where after 3.5 years of follow-up, there was a 45% reduction in SCD in patients with pre-existing coronary artery disease (CAD) randomized to a supplement of highly purified omega-3 fatty acids 1 g of EPA/ DHA compared with non-omega-3 fatty acid controls. Findings also demonstrated that EPA/DHA supplementation led to a 15% reduction in the primary end point of death, nonfatal MI and nonfatal stroke and a 20% reduction in all-cause mortality.
    A second Japanese study, also presented during AHA 2005 AHA, supports evidence that the addition of a low-dose statin to a diet already rich in omega-3 fatty acids—as typically seen in a Japanese diet—reduces the risk of CAD in the primary prevention setting. Again as reported by

theheart.org, results from the MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) study showed that diet plus low-dose statin reduced CAD risk by approximately one-third compared with individuals who did not take a statin. Patients in MEGA had moderately elevated cholesterol levels, with a baseline LDL-C of 156 mg/dL (4.0 mmol/L) and might be compared with those in AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study), another landmark primary prevention trial.
    MEGA investigators suggested that the cardioprotective benefit observed with low-dose pravastatin (10 mg) might be attributed to the traditional Japanese diet as well as relatively high baseline HDL-C levels in study participants, both of which are cardioprotective.

At the Canadian Cardiovascular Congress in Montreal, Dr. Paul Dorian, Professor of Medicine, University of Toronto, Ontario, and colleagues provided insights into how omega-3 polyunsaturated fatty acids (PUFAs) might help prevent SCD. As researchers indicated, there is fairly good evidence that the long-chain omega-3 PUFAs have antiarrhythmic effects, at least in patients who have already sustained an MI, although the mechanisms are not well understood. “The purpose of our work was therefore to try to better understand in an experimental model why it might be that fish oils are directly or indirectly antiarrhythmic,” Dr. Dorian said in an interview.
    Using an anesthetized rabbit model, researchers infused both low and high doses of a parenteral fish-oil emulsion (EPA/ DHA) over 20 minutes and measured ventricular effective refractory period at various cycle lengths both at baseline and after infusion. All post-infusion measurements were repeated three times at 15-minute intervals and averaged investigators noted.
    As the researchers reported, results showed that the fish oils used in their experimental model have properties that are similar to those of the class III antiarrhythmic drugs, “all of which have the property of prolonging cardiac refractoriness and potential duration,” Dr. Dorian observed. However, fish oils did not slow cardiac conduction, an expected property, according to researchers.
    “We also found—which I think is really important from a pharmacology perspective—that the effect was dose- and concentration-dependent, and that at higher doses, the potential beneficial effect was lost,” Dr. Dorian told delegates.

This latter observation is essentially true for any agent, he added, “so just because you take more of a drug doesn’t mean it’s necessarily better.” Indeed, the discrepancy in the experimental effects of low- and high-dose fish oils used in this model might explain some of the contradictory observations reported for fish oils in different cardiac populations.
    The most contradictory findings appear to be in patients who have received an implantable cardioverter defibrillator (ICD). Raitt et al. (JAMA 2005;293(23):2884-91) suggested that fish oils did not protect patients against ventricular tachycardia or ventricular fibrillation (VT/VF) if they had received an ICD because of a recent sustained ventricular arrhythmia. Moreover, Raitt et al. postulated that fish oils might be proarrhythmic in this subgroup of cardiac patients. But as Dr. Dorian countered, “These are not the same patients and it’s not the same disease.” As he has previously pointed out, patients in whom fish oils appear to increase the incidence of VT might be a select group of individuals where the mechanism of VT/VF is secondary to a fixed arrhythmogenic substrate. In contrast, patients with ischemic-mediated VT/VF appear to be very responsive to the antiarrhythmic properties of fish oils, according to Dr. Dorian. “There are many different kinds of arrhythmias and a substance that prevents one kind of arrhythmia may not prevent another kind of arrhythmia, it may even make it worse, so it’s not illogical or paradoxical that fish oils can prevent one type of arrhythmia and not another.”
    Indeed, in the Raitt et al. study, fish oil supplementation did not increase the incidence of VF or mortality, but rather shortened the time to recurrent VT.

As Harper and colleagues have recently written in an overview of omega-3 fatty acids and CAD prevention (Am J Cardiol 2005;96(11):1521-29), a systematic review of 14 randomized trials, six of them including fish oils, showed that in the aggregate, fish oils including EPA/DHA reduce total mortality and SCD but not nonfatal MI—findings which the authors suggested support a role for EPA/DHA or fish in the secondary prevention setting.
The AHA itself has recommended patients without CAD eat a variety of preferably oily fish at least twice a week, along with foods rich in alpha-linolenic acid such as flaxseed. For CAD patients, the AHA recommends they consume approximately 1 g of EPA/DHA per day. If patients have high triglycerides, the AHA recommends 2 to 4 g of EPA/DHA per day, with medical supervision.