Beyond the Mediterranean Diet: The Role of Omega-3 Fatty Acids in the Prevention of Coronary Heart Disease

Charles R. Harper, MD, Terry A. Jacobson, MD


Prev Cardiol. 2003;6(3) 

In This Article

Randomized Controlled Secondary Prevention Trials

Large randomized controlled secondary prevention trials with hard clinical end points (CHD death and nonfatal MI) have also been conducted. Trials with clinical end points have been recently completed with both marine-(EPA) and plant-(ALA) based sources of n-3 PUFA ( Table II ).

One of the earliest trials with clinical end points was the Diet and Reinfarction Trial (DART).[22] This trial involved 2033 Welsh men who recovered from an MI. Participants were randomized to receive advice on one or several dietary changes: a reduction in fat intake, an increase in fish intake, and an increase in cereal fiber intake. Total mortality was the primary end point and the participants were followed for 2 years. The advice on fat or fiber intake was not associated with any change in mortality. The subjects in the fish advice group were instructed to eat mackerel two times per week or to take fish oil capsules if they could not tolerate the fish. Those advised to eat fish had a 29% reduction in 2-year all-cause mortality compared with the non-fish groups (p<0.05). Consuming fish up to two times per week resulted in an absolute risk reduction of 3.5% with the number needed to treat (NNT) to prevent one death equal to 28 over the 2-year length of the trial.

In another smaller secondary prevention trial, the Indian Experiment of Infarct Survival (EIS),[23] 360 patients who were less than 1-day post-MI were studied. These patients were randomized to one of three arms: a group receiving fish oil capsules (1.08 g/day of EPA and 0.72 g/day of DHA), a group receiving 20 g/day of mustard seed oil (2.9 g/day of ALA), and a control group (100 mg/day of aluminum hydroxide). After 1 year, total cardiac events (total cardiac deaths and nonfatal MIs) were significantly less in the fish oil and mustard oil groups compared with the placebo group (24.5% and 28% vs. 34.7%; p<0.01).[23]

In another secondary prevention trial, the Lyon Diet Heart Study,[24] the plant-derived n-3 PUFA ALA was supplemented in a canola oil margarine, along with a Mediterranean style dietary pattern. The rationale for this study was derived from the landmark dietary study, The Seven Country Study,[25] where a cohort from Crete was found to have a lower mortality rate from CHD compared with similar cohorts in other countries. Cretan subjects had three-fold higher serum concentrations of ALA compared with a similar cohort from the Netherlands.[26] With this background, the Lyon Diet Heart Study was conducted to evaluate the effect of a Cretan Mediterranean diet, high in fruits and vegetables, rich in monounsaturated fatty acids (olive oil), and high in ALA on CHD morbidity and mortality. The sources of ALA in the Cretan diet are thought to be leafy vegetables such as purslane in addition to walnuts and legumes. Because olive oil was not gastronomically acceptable to the study population in France, a customized margarine was used that had a fatty acid composition similar to olive oil in being rich in monounsaturated fat, yet supplemented with ALA. The composition of the margarine included 4.8% ALA and 48% monounsaturated fat (oleic acid).[26]

After an initial MI, 605 patients were randomly assigned to the Mediterranean style diet or control group receiving a diet similar to the National Cholesterol Education Program (NCEP) step I diet. Follow-up at 27 months revealed a 76% relative risk reduction in the major primary end points of cardiovascular death and nonfatal MI. The NNT to prevent a second MI or cardiac death was 23.[26] It should be noted that this level of risk reduction occurred without significant changes in low-density lipoprotein (LDL), high-density lipoprotein (HDL), or total cholesterol. The Lyon results compare favorably to other secondary prevention trials with lipid-lowering drugs such as the Scandinavian Simvastatin Survival Study (4S)27 (NNT=12) and the Cholesterol and Recurrent Events (CARE) trial[27] with pravastatin (NNT=34). The risk reduction seen in the Lyon Diet Heart Study was also maintained at the 46-month follow-up visit. Although these results are impressive, one limitation to the Lyon Study is that there were numerous other changes made in the diet of the treatment group so as to resemble a Mediterranean-style dietary pattern. In addition to a three-fold higher dietary intake of ALA, the treatment group was also noted to have significantly higher oleic acid intake (olive oil), a lower saturated fat intake, and a decreased n-6 (LA) intake. This makes it difficult to ascertain whether the cardioprotective effects were from the ALA supplemented margarine or other features of the Mediterranean diet. Although difficult to verify, the study investigators suggest that the majority of the risk reduction was from the ALA supplementation.[26]

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) Prevenzione trial,[29] a secondary prevention trial, enrolled 11,324 post-MI patients in Italy and followed them for 3.5 years. Participants were randomized to one of four groups: one receiving 1 g/day of a fish oil supplement containing 850 mg of EPA and DHA, a group receiving a vitamin E supplement (300 mg/day), a group receiving both, and a control group receiving neither. The primary combined end point was death, nonfatal MI, and stroke. Vitamin E did not demonstrate any clinical benefit, while supplementation with EPA and DHA (850 mg/day) provided significant benefit. Supplementation with fish oil reduced the primary end point 15% by four-way analysis. That this degree of risk reduction could occur in Italian MI survivors on a prototypical Mediterranean diet suggests that greater benefits may be seen with n-3 fatty acids in a Western-style diet typified by high consumption of saturated fats and low intake of n-3 fatty acids.

In a recent post hoc analysis of the time course of the benefit of n-3 fatty acids in the GISSI Prevenzione trial,[30] an early and highly significant reduction of sudden cardiac death was found. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk, 0.59; 95% CI, 0.36-0.97; p=0.037). The reduction in risk of sudden death was statistically significant at 4 months (relative risk, 0.47; 95% CI, 0.219-0.995; p=0.048). This early effect of low-dose n-3 fatty acids (1 g/day) on total mortality and sudden death supports the theory of an antiarrhythmic effect.

Finally, a meta-analysis[31] of 11 randomized controlled trials that compared dietary or supplemental intake of n-3 fatty acids with a control diet or placebo in patients with CHD was recently published.

The risk ratio of nonfatal MI in patients who were on n-3 fatty acid-enriched diets compared with control diets or placebo was 0.8 (95% CI, 0.5-1.2; p=0.16), and the risk ratio of fatal MI was 0.7 (95% CI, 0.6-0.8; p<0.001). Only five of the trials reported the incidence of sudden death. Sudden death was associated with a risk ratio of 0.7 (95% CI, 0.6-0.9; p<0.01). This analysis suggests that n-3 fatty acids, both plant-and fish-based, reduce sudden death in patients with CHD while having little effect on the incidence of nonfatal MI.


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