Role of Fish Oil in Secondary Cardiovascular
By Rahul Gupta, MD, MPH, FACP Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV. Dr. Gupta reports no financial relationships relevant to this field of study.
Synopsis: In patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity.
Source: Risk and Prevention Study Collaborative Group. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013;368:1800-1808.
Based on several randomized trials and other epidemiological studies, sufficient evidence of a protective effect of n-3 fatty acids against cardiovascular diseases has traditionally been presented in the scientific literature. In patients with a history of myocardial infarction or heart failure, data have shown that n-3 fatty acids reduce cardiovascular mortality and morbidity1,2. The anti-inflammatory, anti-atherogenic, and anti-arrhythmic effects of n-3 fatty acids may be the plausible mechanisms for reduction in the risk of cardiovascular disease in these patients. Based on the evidence, some may even hypothesize that such beneficial effects of n-3 fatty acids could be extrapolated to reducing cardiovascular risk among patients with multiple cardiovascular risk factors or atherosclerotic disease but no previous myocardial infarction.
To test this hypothesis, Italian researchers with the Risk and Prevention Study Collaborative Group conducted a double-blind, placebo-controlled, community-based, clinical trial of men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. The eligible study participants qualified in at least one of three different ways: multiple cardiovascular risk factors, clinical evidence of atherosclerotic vascular disease, or any other condition placing the patient at high cardiovascular risk in the opinion of the patient's general practitioner. Of the 12,513 patients included in the study, 6244 were randomly assigned to 1 g daily of n-3 fatty acids (polyunsaturated fatty-acid ethyl esters with eicosapentaenoic acid and docosahexaenoic acid content not less than 85%) and 6269 patients were randomized to placebo (olive oil). While initially the primary efficacy endpoint was defined as the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke, the primary efficacy endpoint had to be revised to the composite of time to death from cardiovascular causes or hospital admission for cardiovascular causes due to a lower than expected event rate.
The researchers found that during average follow-up of 5 years, the incidence of the primary endpoint — cardiovascular-related death or hospital admission related to cardiovascular causes was approximately 12% in both groups, and n-3 fatty acid supplementation did not lower the incidence of any of the secondary endpoints. While there were several subgroups based on enrollment criteria (such as diabetes, multiple non-diabetic cardiovascular risk factors, and clinical atherosclerosis), none benefited from the supplementation either. There was also no statistically significant difference between the two groups in terms of adverse side effects such as abdominal pain, nausea, and diarrhea. The researchers concluded that no evidence of the usefulness of n-3 fatty acids exists for preventing cardiovascular death or disease in a cohort of individuals with multiple cardiovascular risk factors or atherosclerotic disease but no previous myocardial infarction or heart failure.
The supplemental use of n-3 fatty acids does not reduce the risk of cardiovascular morbidity and mortality in patients with multiple cardiovascular-disease risk factors. The above research highlights this changing paradigm and conforms to similar findings from the most recent randomized trials of secondary prevention. While there is no doubt that this issue is far from being settled, a recent meta-analysis by Kwak et al examining data from 14 randomized, placebo-controlled studies found no reduction in cardiovascular events (risk ratio, 0.99; 95% confidence interval, 0.89-1.09) as well as no improvement in other relevant endpoints.3 However, the analysis by Kwak et al did not include two large randomized, controlled trials favoring the use of n-3 fatty acids reportedly because these trials had an open-label study design without the use of placebo. Inclusion of these two trials seems to have tilted the weight toward favoring n-3 fatty acids in secondary prevention in other meta-analyses.
So, to summarize, we have older studies favoring use of n-3 fatty acids, while the more recent data demonstrate insufficient evidence of a secondary preventive beneficial effect of n-3 fatty acid supplements for overall cardiovascular events among patients with a history of cardiovascular disease. Some would argue that with little harmful effects, continuing to recommend such treatment may not do any significant harm until we get more scientific evidence to base a decision upon. I would recommend that we begin to educate our patients, especially those who do not have a history of myocardial infarction or heart failure, that n-3 fatty acid supplementation with fish oil is not effective.
1. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455.
2. GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): A randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-1230.
3. Kwak SM, et al for the Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: A meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med 2012;172:686-694.