cardiovascular events would require large and perhaps impractical sample sizes and/or follow-up periods. In an early randomized trial of men who had already experienced a myocardial infarction (MI), Burr et al. (1989) reported that dietary advice, including advice to increase consumption of seafood, was associated with a significant reduction (29 percent) in 2-year all-cause mortality (p<0.05). An extended follow-up of these subjects, however, did not suggest any substantial long-term survival benefit (Ness et al., 2002). In contrast, in a separate study of male subjects over age 70 with stable angina, Burr et al. (2003) reported higher, and not lower, cardiovascular mortality in the group assigned to receive advice to consume seafood or n-3 fatty acid supplements (p=0.02). The reports by Burr et al. (2003) and Ness et al. (2002) seemed to some researchers a serious challenge to the idea that patients with coronary artery disease (CAD) and those at increased risk for heart disease should be advised to increase consumption of seafood rich in EPA/DHA or to take fish-oil supplements (Marckmann, 2003). A more detailed review of the literature considered by the committee is provided in Appendix B-2.

The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-Prevenzione) trial (GISSI Prevenzione Investigators, 1999) examined associations between dietary supplementation with EPA/DHA from fish oil, vitamin E, or combined treatment, and incidence of a second MI. From October 1993 to September 1995, 11,324 Italian patients surviving recent (≤ 3 months) MI were randomly assigned supplements of EPA/ DHA (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy measurement endpoints of death, nonfatal MI, and nonfatal stroke were significantly reduced by EPA/DHA treatment; the relative risk reduction (RRR) was 15 percent for death, nonfatal MI, or nonfatal stroke (RR=0.85; 95% CI 0.74-0.98). Intention-to-treat analyses were done according to a (two-way) factorial design and by a (four-way) treatment group.

Results showed that EPA/DHA, but not vitamin E supplementation, significantly reduced risk of death, nonfatal MI, and nonfatal stroke (RR=0.90, 95% CI 0.82-0.99, two-way analysis; RR=0.85, 95% CI 0.74-0.98, four-way analysis). A decrease was found in the risk of all-cause mortality (14 percent [95% CI 3-24] two-way, 20 percent [95% CI 6-33] four-way) and cardiovascular death (17 percent [95% CI 3-29] two-way, 30 percent [95% CI 13-44] four-way). There was no significant effect between the combined treatment and EPA/DHA for the primary endpoints listed above. This study showed that dietary supplementation with fish oil as a source of EPA/DHA led to a statistically significant benefit in people with a history of MI; however, effects on fatal cardiovascular events require further exploration.

The percentage of patients who experienced at least one cardiac event (cardiac death, resuscitation, recurrent MI, or unstable angina) was 28 in



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