n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes

OBJECTIVE

We carried out a secondary analysis in high-risk patients with a previous myocardial infarction (MI) and diabetes in the Alpha Omega Trial. We tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid (ALA) will reduce the incidence of ventricular arrhythmias and fatal MI.

RESEARCH DESIGN AND METHODS

A subgroup of 1,014 post-MI patients with diabetes aged 60–80 years was randomly allocated to receive one of four trial margarines, three with an additional amount of n-3 fatty acids and one placebo for 40 months. The end points were ventricular arrhythmia–related events and fatal MI. The data were analyzed according to the intention-to-treat principle, using multivariable Cox proportional hazards models.

RESULTS

The patients consumed on average 18.6 g of margarine per day, which resulted in an additional intake of 223 mg EPA plus 149 mg DHA and/or 1.9 g ALA in the active treatment groups. During follow-up, 29 patients developed a ventricular arrhythmia–related events and 27 had a fatal MI. Compared with placebo patients, the EPA-DHA plus ALA group experienced less ventricular arrhythmia–related events (hazard ratio 0.16; 95% CI 0.04–0.69). These n-3 fatty acids also reduced the combined end-point ventricular arrhythmia–related events and fatal MI (0.28; 0.11–0.71).

CONCLUSIONS

Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia–related events in post-MI patients with diabetes.There is strong evidence from prospective cohort studies and randomized trials that >250 mg/day of the fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will reduce fatal coronary heart disease (CHD) by as much as 36% (1). There is also evidence, although less conclusive, that EPA-DHA reduces sudden death (2,3). Prospective cohort studies have provided evidence that the plant food–derived n-3 fatty acid α-linolenic acid (ALA) may reduce fatal CHD (4). Animal experiments showed that n-3 fatty acids reduce the vulnerability to cardiac arrhythmias (5). The Alpha Omega Trial tested the hypothesis that an additional intake of 0.4 g/day of EPA-DHA or 1.9 g/day of ALA will reduce fatal CHD and ventricular arrhythmia–related events in stable postmyocardial infarction (post-MI) patients (6). However, this hypothesis was not confirmed in the main analysis of the trial (7).A post hoc analysis of the Alpha Omega Trial showed that in post-MI patients with diabetes, EPA-DHA reduced both fatal CHD and ventricular arrhythmia–related events by 49% (7). The reduction in these end points was in accord with that obtained in the Gruppo Italiano per lo Studio della Sopravvivenza nell''Infarto miocardico (GISSI)-Prevenzione trial for fatal coronary and sudden death (8). In the Alpha Omega Trial, an even stronger reduction of 61% of ventricular arrhythmia–related events was observed for ALA. This evokes the question of whether post-MI patients with diabetes are particularly susceptible to protective effects of n-3 fatty acids on fatal CHD and ventricular arrhythmia–related events.In a cohort study of diabetic women, a dose-response relation was observed between fish consumption and CHD mortality (9). Women who consumed fish five or more times per week had a 64% lower risk of CHD mortality compared with those who consumed fish less than once per month. In a trial of heart failure patients with diabetes, a supplement of 0.9 g EPA-DHA per day reduced the composite end point of all-cause mortality or admission to the hospital for cardiovascular reasons significantly with 11% (10). Although evidence of the effect of fish consumption and EPA-DHA supplementation on fatal CHD in patients with diabetes is small, the available data are compatible with the hypothesis that EPA-DHA may protect against fatal CHD.The life expectancy of a 50-year-old patient with diabetes is 6 years shorter than that of a person without diabetes (11). This difference is largely due to an increased risk of macrovascular diseases among diabetic patients. In addition, they have an increased risk of fatal CHD (12) and an increased risk of sudden death (13,14). A previous MI in combination with diabetes especially makes patients prone to fatal CHD and ventricular arrhythmia–related sudden death (12,15). Therefore, post-MI patients with diabetes are a suitable group to test the hypothesis that n-3 fatty acids protect against fatal CHD and ventricular arrhythmia–related events.Overlap in the definitions of ventricular arrhythmia–related events and in fatal CHD was present in the main publication of the results of the Alpha Omega Trial (7). Both end points included fatal cardiac arrest and sudden death. In the present analysis, mutually exclusive definitions will be used; therefore, fatal CHD is limited to fatal MI. In the main publication, the two groups that received EPA-DHA were compared with the two groups that did not receive EPA-DHA. The same strategy was used for ALA. This was done because in the analysis of the primary end-point major cardiovascular events, the cumulative incidence of the four treatment groups did not differ. Here we present the results of an in-depth analysis of the effects of different n-3 fatty acids compared with placebo on ventricular arrhythmia–related events and fatal MI in stable post-MI patients with diabetes.