Omega-3 Fatty Acids and Cardiovascular Disease Prevention
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- Barringer, T.A. & Harris, W.S. Curr Nutr Rep (2012) 1: 115. doi:10.1007/s13668-012-0011-5
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Observational studies and early clinical trials indicated that long-chain n-3 fatty acids have a role in prevention of coronary heart disease, specifically fatal coronary heart disease. Results of recent trials have been inconsistent, although the study designs, patient populations, and n-3 doses have been quite different. Some studies have called into question whether there is any benefit from n-3 fatty acid therapy in patients who are receiving guideline-based treatment since their coronary event. Other recent trials suggest that certain patient subgroups, specifically those with diabetes or metabolic syndrome, may derive a significant benefit. Also, the only clinical trial to show a reduction in nonfatal coronary events used a higher n-3 fatty acid dose than used in the other studies, which raises the question of whether more is better for certain clinical outcomes. Only further research can resolve these questions.
Keywordsn-3 fatty acidsOmega-3 fatty acidsEPADHACardiovascularPreventionCardiovascular diseaseCoronary heart diseaseRandomized controlled trialDARTGISSI-PrevenzioneOMEGAAlpha OmegaSU.FOL.OM3JELISHeart failureGISSI-HF
Evidence from all types of research has accumulated over the past 40 years that the marine n-3 fatty acids (EPA and DHA) have beneficial effects in preventing and treating various cardiovascular disorders. The first large randomized clinical trials (RCTs) were published in 1989 and 1999 and demonstrated a profound effect on prevention of sudden cardiac death in patients with a history of myocardial infarction [1, 2]. This effect is strongly supported by findings from animal experiments as well as observational studies [3, 4]. Interestingly, these same trials did not demonstrate a reduction in nonfatal cardiovascular events. Consequently, most experts have endorsed the increased intake of long-chain n-3 fatty acids for the prevention of cardiovascular death, especially for individuals with a history of coronary heart disease (CHD) . In the past few years, however, several RCTs have yielded somewhat surprising results, raising new issues and questions about the exact role of these fatty acids in cardiovascular disease. This review focuses on the recent clinical trials and offers possible explanations for the observed outcomes. It does not discuss the various physiologic effects and molecular mechanisms that could account for the clinical outcomes. However, other recent reviews of n-3 fatty acids in cardiovascular disease elaborate on these presumed mechanisms of benefit [6–9].
Coronary Heart Disease
Recent randomized controlled trials of long-chain n-3 fatty acids and cardiovascular events
RR (95% CI)
3,851 patients with recent MI (≤2 weeks)
840 mg/d EPA+DHA vs placebo
Major CV events
Alpha Omega (2010)
4,837 patients with history of MI (median, 3.7 years)
376 mg/d EPA+DHA vs placebo and ALA (1.9 g/d) groups combined
Major CV events
2,501 patients with recent coronary or cerebral ischemic event (median, 101 d)
600 mg/d EPA+DHA vs placebo and B vitamin groups combined
Major CV events
18,645 patients with total cholesterol ≥6.5 mmol/L (with and without CHD history)
1.8 g/d EPA vs usual care
Three of these four trials were designed, at least partially, in response to the first two RCTs to study the effects of long chain n-3 fatty acids in CHD patients: the Diet and Reinfarction Trial (DART) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial. In the 1989 DART report, 2,033 male survivors of myocardial infarction (MI) were randomly assigned to one of three dietary advice interventions: low-fat, increased fiber, or increased n-3 fatty acids, either in the form of fatty fish (200–400 g/wk, providing 500–800 mg n-3 fatty acids/d) or fish oil capsules (∼900 mg EPA+DHA/d) . There was a 29% reduction in all-cause mortality at 2 years in the n-3 fatty acid group, with the benefit attributed to a reduction in CHD mortality. Then in 1999, the GISSI-Prevenzione study reported the effects of n-3 fatty acids (∼850 mg/d), vitamin E (300 mg/d), both, or neither in 11,324 patients enrolled within 3 months of an MI . After 3.5 years, there was a 15% reduction in the composite primary end point (death, nonfatal MI, or nonfatal stroke), with 21% and 30% reductions in total and cardiovascular mortality. This end point reduction was driven by a 45% reduction in sudden cardiac death, which was evident after only 4 months . There was no reduction in nonfatal MI. Over the next decade, three other European research groups conducted similar secondary prevention trials using similar doses of n-3 fatty acids, but they had different outcomes.
The German multicenter OMEGA (not an acronym) trial randomly assigned 3,804 patients—3 to 14 days after an MI—to either 840 mg of EPA+DHA or placebo “given in addition to current guideline-adjusted treatment” . The primary outcome was the rate of sudden cardiac death within 1 year after the infarct. Secondary end points were total mortality and nonfatal clinical events. Acute coronary angiography was performed in 94% and acute percutaneous coronary intervention (PCI) in 78% of all patients. There was no difference in the primary or either of the secondary end points. Sudden cardiac death occurred in only 1.5% of the patients in both the n-3 and placebo arms. This unexpectedly low rate was attributed to the aggressive medical care, which not only included PCI in almost 80% of patients (compared with 5% in GISSI-Prevenzione), but intensive pharmacologic treatment from the time of hospitalization to the end of the trial—antiplatelet agents in 96% of patients, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 90%, β-blockers in 95%, and statins in 95%. In GISSI-Prevenzione, each of these drugs, other than antiplatelet agents, was used in less than half of the participants. Another factor that could have reduced the difference between the two arms in sudden cardiac death was the number of study participants who reported consuming fish “several times a week.” By the end of the trial, this percentage was 45% and 44% in the n-3 and control groups, respectively. A significant shortcoming of this study was the unexpectedly low 1-year event rate. This resulted in the study being underpowered (ie, it had only a 19% chance of detecting a 25% benefit from n-3 treatment).
Alpha Omega Trial
The Alpha Omega trial, conducted in The Netherlands, also studied n-3 fatty acid therapy in the post-MI patient, but in a very different fashion . Patients (n = 4,837) with a history of MI within 10 years of enrollment (median interval, 3.7 years) were randomly assigned to receive one of four trial margarines: one supplemented with EPA+DHA (targeted for an additional daily intake of 400 mg of EPA+DHA), one supplemented with α-linolenic acid (ALA, targeted for an additional daily intake of 2 g of ALA), one supplemented with both EPA+DHA and ALA, and one nonsupplemented margarine to serve as the placebo. The primary end point was the rate of major cardiovascular events, defined as fatal and nonfatal cardiovascular events and cardiac interventions. It was a prerequisite for study participation that patients were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. In reality, the average consumption of margarine was 18.8 g/d, which resulted in additional intakes of 226 mg EPA +150 mg DHA, and 1.9 g ALA, or both, according to the assigned n-3 supplementation. During the 40-month follow-up period, a major cardiovascular event occurred in 13.9% of participants. Neither EPA+DHA nor ALA reduced this rate. In the prespecified subgroup of women, ALA, as compared with placebo and EPA+DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio [HR], 0.73; P = 0.07). In a post-hoc analysis, patients with diabetes who received EPA+DHA had a 49% reduction in death from CHD (HR, 0.51; P = 0.04) and a 49% reduction in ventricular arrhythmia-related events that did not quite reach statistical significance (HR, 0.51; P = 0.09), results that are similar to those from the GISSI-Prevenzione trial. Diabetic participants who received both EPA+DHA and ALA had a 72% reduction compared with placebo in the combined end point of ventricular arrhythmia-related events and fatal MI . The effects of EPA+DHA supplementation alone in this diabetic subgroup are difficult to interpret because the small dose of EPA+DHA may have been obscured by the larger amount of ALA administered in half of the comparison groups, and by the relatively high background intake of EPA+DHA in The Netherlands.
The SUpplementation with FOLic acid and/or OMega-3 fatty acids (SU.FOL.OM3) trial was designed to investigate whether B vitamins or n-3 fatty acids, or both, could prevent major cardiovascular events in patients who had a coronary or cerebral ischemic event within the preceding 12 months . Patients (n = 2,501) were recruited through a network of French physicians and were then randomly assigned to one of the following daily supplement packages: B vitamins (5-methytetrahydrofolate [560 μg], vitamin B6 [3 mg] and B12 [20 μg]), EPA+DHA (600 mg, 2:1 ratio), both B vitamins and EPA+DHA, or placebo. Major cardiovascular events were defined as a composite of nonfatal MI, stroke, or death from cardiovascular disease. Neither intervention had any effect on the composite end point. The authors speculated that a longer interval between the cardiovascular event and randomization (median, 101 days vs 16 days for GISSI-Prevenzione), the relatively low dose of n-3 fatty acids, or (as in OMEGA) the fewer than expected events may have yielded the null results.
The Japan EPA Lipid Intervention Study (JELIS) is the fourth RCT conducted in the “modern era” of CHD management. In contrast to the three trials just discussed, JELIS was not specifically designed to replicate GISSI-Prevenzione . There were, in fact, several important differences between this trial and all the preceding n-3 trials that have been discussed. First, of the 18,645 hypercholesterolemic patients enrolled in this trial, 14,981 had no history of cardiovascular disease. Although the main analysis combined patients without and with a cardiovascular disease history (3,664 secondary prevention participants), the large numbers allowed for subgroup analyses of each arm separately. Second, the n-3 dose was 1,800 mg/d. Third, the population studied had a much higher background intake of n-3 fatty acids. This dietary difference plus the larger study dose means that the n-3 tissue levels achieved were much higher than in any previous trial. Fourth, all patients were taking statins, and lastly, the n-3 fatty acid used was EPA alone. Unfortunately, it was not placebo controlled, although the data were analyzed blindly. How significant these study design differences were in producing the outcomes observed is open to speculation, but at least JELIS generated hypotheses that future studies using n-3 therapy will need to address.
The primary end point in JELIS was any major coronary event, including sudden cardiac death, fatal and nonfatal MI, unstable angina, and revascularization (angioplasty, stenting, and coronary artery bypass grafting). After a mean of 4.6 years, the EPA group had a 19% reduction in the primary end point. This was driven by a 19% reduction in the nonfatal events, which comprised 92% of all coronary events that occurred.
In contrast to DART (conducted in Wales) and GISSI-Prevenzione (conducted in Italy), there was no reduction in sudden cardiac death in JELIS. This latter finding may be best explained by an earlier analysis that showed that the effect of fish or fish oil on cardiac death rate is nonlinear . In a pooled analysis of prospective observational and clinical trial data, most risk reduction in cardiac death occurred at an intake of one to two servings of fatty fish per week, or about 250 mg of EPA+DHA/d. Above this threshold, little additional benefit was noted . In Japan, 90% of the population consumes at least this threshold amount, with an average intake of about 900 mg EPA+DHA/d [17, 18]. In comparison, the average daily intake of EPA+DHA in the United States is 100 to 125 mg. The JELIS investigators confirmed that their study population had the typical Japanese n-3 fatty acid status by measuring the baseline plasma EPA, which was 93 mg/L, or about 10-fold higher than that reported in the US population . As the vast majority of the JELIS population had an intake of n-3 fatty acids above the estimated threshold for preventing cardiac death, it is not surprising that the control group in JELIS had a cardiac death rate per 1,000 person-years of 2.5, whereas in GISSI-Prevenzione, it was 17.
JELIS was large enough to perform several subgroup analyses that provide additional insights into the role of n-3 fatty acids (ie, EPA) in cardiovascular disease. In patients with a history of coronary artery disease, EPA treatment reduced major coronary events by 19% (P = 0.048). Within this secondary prevention arm of the study, statistically and clinically significant reductions were seen in those with a previous revascularization (relative risk reduction [RRR], 35%; number needed to treat [NNT], 13), those with a prior MI (RRR, 27%; NNT, 19), those with both a prior MI and revascularization (RRR, 41%; NNT, 10) . Given that all participants were receiving statin therapy, these are remarkable results; however, the intensity of statin therapy in this study was much less than US guidelines recommend for secondary prevention. Achieving an low-density lipoprotein cholesterol level of only 130 mg/dL somewhat lessens the generalizability of the study.
In patients without a history of coronary artery disease (n = 14,981), EPA treatment reduced major coronary events by 18%, an almost identical point estimate as the secondary prevention group, although it was not statistically significant (P = 0.132). This was probably due to the very low event rate, which was 1.4% in the EPA group and 1.7% in the control group (compared with 8.7% and 10.7% in the secondary prevention arm). As would be expected, the incidence of major coronary events in this primary prevention group increased with the number of risk factors. The rate among individuals with three traditional risk factors was double that of the group with only hypercholesterolemia (which was required for study entry) . In the primary prevention cohort with multiple risk factors, large and statistically significant reductions were seen. One subgroup in particular, participants with triglycerides (Tg) of 150 mg/dL or greater and high-density lipoprotein cholesterol (HDL-C) less than 40 mg/dL (who often also had a body mass index >25 kg/m2 and/or hypertension), had an overall event rate of 3.3%, which was reduced by 53% by EPA treatment (P = 0.043) . The Tg level was reduced by 23% in the EPA arm, and by 18% in the control arm. While this difference was statistically significant, it is biologically implausible to attribute the 53% reduction in major coronary events to this 5% difference in Tg lowering, and there was no difference in the other lipid variables . Therefore, in statin-treated patients, high Tg/low HDL-C status identified participants who especially benefited from EPA therapy. A similar subgroup analysis was performed on those participants with impaired glucose metabolism (n = 4,565), which was defined as having diabetes or having a fasting glucose of 110 or greater at the time of enrollment or after 6 months. Treatment with EPA resulted in a 22% decrease in coronary artery disease incidence (P = 0.048) in the impaired glucose metabolism group . The median Tg level in this group was 175 mg/dL, and the mean HDL-C level was 55 mg/dL. There was a 10-mg/dL difference in Tg lowering between the EPA-treated and control arms (P < 0.01), but no significant difference was seen in fasting glucose and hemoglobin A1c levels during treatment. It is of some interest to compare the results of this subset of JELIS participants with those from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study. This study enrolled 5,518 individuals with diabetes and compared the effects of statin alone with statin plus fenofibrate on cardiovascular events. In the primary (composite) end point, there was no benefit of the combination over statin alone .
Other Coronary Heart Disease Trials
Two other published clinical trials evaluated the effect of n-3 fatty acid therapy on cardiovascular events and mortality. Although one of them showed a trend toward reduction in all-cause mortality in the n-3 group, both studies were too small (n = 300 and n = 563) and had inadequate duration of follow-up (1 and 3 years) to contribute to this discussion on the role of n-3 fatty acids in preventing CHD [30, 31].
Findings from epidemiologic studies have generally supported a protective effect of n-3 fatty acids in preventing heart failure. During 12 years of follow-up, the Cardiovascular Health Study of 4,738 adults 65 years of age or older showed that consumption of tuna and other broiled or baked fish was associated with a lower incidence of heart failure . Dietary n-3 fatty acid intake was also inversely associated with heart failure, with a 32% reduction in patients consuming the equivalent of at least 1 g/d of EPA+DHA. In contrast, patients consuming much lower quantities of n-3 fatty acids in the Rotterdam study had no significant risk reduction . The Japan Collaborative Cohort study, consisting of 57,972 Japanese men and women observed for almost 13 years, showed an inverse association between n-3 fatty acid intake and heart failure mortality . The Atherosclerosis Risk in Community (ARIC) study of 3,592 middle-aged adults observed for 14 years determined associations between plasma fatty acids and incident heart failure. Higher levels of saturated fatty acids were positively associated with heart failure, while higher levels of arachidonic acid (20:4 n6) and DHA (22:6 n3) were inversely associated with incident heart failure in women .
A post-hoc analysis of the GISSI-Prevenzione trial indicated that treatment with 1 g/d of n-3 fatty acids in post-MI patients had similar beneficial effects on total mortality in those with and without left ventricular systolic dysfunction; however, n-3 fatty acid treatment was more effective in preventing sudden cardiac death in patients with systolic dysfunction compared with those with a normal ejection fraction . This finding, along with the epidemiologic data, set the stage for the GISSI-Heart Failure (GISSI-HF) trial. Patients with New York Heart Association (NYHA) functional class II to IV heart failure (n = 6,975) were randomly assigned to 1 g/d n-3 fatty acids or placebo while continuing all therapies for usual heart failure care. In the intention-to-treat analysis after a median follow-up of 3.9 years, n-3 fatty acid treatment resulted in a 9% reduction in all-cause mortality and an 8% reduction in the composite of mortality and cardiovascular hospitalization . Because approximately 30% of the patients in both treatment groups were not taking their assigned study drug by the end of the study, a per-protocol analysis was undertaken on 4,994 fully compliant patients (defined as those who took the assigned drug at least 80% of the time). In compliant patients, the reduction in all-cause death was 14% (P = 0.004). An echocardiographic substudy in GISSI-HF also found a small but significant improvement in left ventricular ejection fraction with n-3 fatty acid treatment, but not with rosuvastatin .
The RRR achieved in GISSI-HF, though significant, is much less than demonstrated in the observational trials discussed above, which raises the question of whether treatment earlier in the course of heart failure might be more effective. The results of a subsequent small trial have prompted further speculation that this might indeed be the case . Nodari et al.  performed a mechanistic study in 133 patients with somewhat less advanced heart failure than GISSI-HF participants. All patients had nonischemic cardiomyopathy and NYHA functional class I or II symptoms (vs 40% with III or IV in GISSI-HF). The mean age was 63 (vs 67 in GISSI-HF), and the mean ejection fraction was 37% (vs 33% in GISSI-HF). All patients were receiving optimal medical care for heart failure and on stable doses for at least 6 months prior to study entry, at which time they were randomly assigned to receive 2 g/d of n-3 fatty acids or placebo. At the end of 12 months, there were significant differences between the n-3 and placebo group in the left ventricular ejection (increased by 10% and decreased by 5%, respectively), peak VO2 (increased by 6% and decreased by 4.5%, respectively), exercise duration (increased by 7.5% and decreased by 5%, respectively), and mean NYHA functional class (decreased from 1.88 to 1.61 and increased from 1.83 to 2.14, respectively). Although this small trial was not powered to assess clinical outcomes, hospitalization rates for heart failure were 6% in the n-3 fatty acid group and 30% in the placebo group (P = 0.0002). Multivariate analysis demonstrated that the time from diagnosis of heart failure correlated inversely with the improvement in left ventricular ejection fraction (ie, shorter duration of disease predicted more improvement from n-3 treatment). Considering the totality of data from these two trials as well as the epidemiologic data, it is plausible that earlier treatment, and perhaps a larger dose of n-3 fatty acids (2 g/d), would be more effective in reducing mortality and morbidity from heart failure, although a larger trial is needed to confirm this hypothesis.
As noted repeatedly in the previous discussion, more research is needed to define the utility of n-3 fatty acid therapy in cardiovascular disease prevention and therapy. However, many of the existing clinical trials have suffered from the same design flaw seen in contemporary vitamin/nutrition trials—namely no control for baseline and on-treatment tissue levels of the supplement being investigated. Observational data clearly indicate that the risk of various cardiovascular outcomes varies with tissue levels of EPA and DHA [16, 41–46]. Determining whether this association is causal or not, and determining what the “optimal” dose is (which will undoubtedly vary among individuals) will depend on clinical trials that incorporate knowledge of the pretrial and on-trial tissue levels. Without this knowledge, trials are merely testing whether supplementation is effective in a general population composed of many individuals who may already have sufficient, or protective, levels. This design flaw could easily account for discrepancies seen between the epidemiologic and clinical trial data. Examples abound among the vitamin supplement trials, in which results derived from the whole study population have often been opposite results from the “deficient” subpopulation [47, 48]. Only if future clinical trials of n-3 fatty acids incorporate baseline assessment of n-3 fatty acid status will it be possible to develop more definitive guidelines for using EPA+DHA in treating and preventing various diseases, as well as for measuring n-3 tissue levels in clinical practice. Such a trial is the VITAL (VITamin D and omegA-3 triaL), which is currently evaluating the effects of 840 mg/d (from Lovaza) and/or vitamin D (2,000 IU/d) versus placebo in 20,000 older adults in the United States on cardiovascular and cancer end points. Unlike many past studies, it will be tracking blood levels of both n-3 fatty acids and vitamin D over this 5-year trial, but neither a low n-3 fatty acid or vitamin D level was an inclusion criterion.
Given the strong safety profile of n-3 fatty acids, even at relatively high doses, and the potential for benefit, these agents will no doubt continue to be used in cardiovascular disease patients. It should be stressed, however, that future research will be significantly hampered if clinicians and patients are dogmatic in their belief that the value of n-3 fatty acids in cardiovascular disease is already well-established. If such unfounded certainty is widespread, it will become very difficult to find patients (and investigators and research ethics panel members) willing to participate in or approve the placebo-controlled clinical trials that are so desperately needed to properly evaluate the value of these nutrients in the treatment and prevention of cardiovascular disease.
For patients with systolic heart failure (ie, ejection fraction <50%), already receiving state-of-the-art care, n-3 fatty acid therapy has the potential to improve mortality outcomes. Future studies should address the issues of optimal dose and timing with respect to duration and severity of heart failure.
For acute MI patients who have not undergone coronary revascularization or are not receiving optimal secondary prevention care, it is reasonable to assume that 1 g EPA+DHA/day will reduce risk of sudden cardiac death.
Patients who have diabetes, metabolic syndrome, and/or high Tg may possibly have reduced risk of nonfatal coronary events with relatively high-dose (ie, 2–4 g/d) n-3 therapy. Future studies should determine whether there is a benefit in similar populations receiving optimal cardiovascular disease prevention therapy.
Dr. Barringer has served on the speakers’ bureau for GlaxoSmithKline and Abbott Laboratories.
Dr. Harris has served on boards for Aker Biomarine and Omthera, is an employee of Health Diagnostic Lab, has served on the speakers’ bureau for GlaxoSmithKline, has had travel expenses covered by Monsanto/Solae, and is the owner of OmegaQuant Analytics.