March 18, 2008 — The benefits, guidelines for use, and protective effect of omega-3 fatty acid intake on cardiovascular (CV) health are reviewed in the March issue of Mayo Clinic Proceedings. After briefly summarizing current scientific evidence supporting the benefits of omega-3 fatty acids to CV health, this review highlights indications for use and recommended guidelines for administration and dosing.

"The American Heart Association (AHA) has endorsed the use of omega-3 fatty acids for secondary prevention of cardiovascular (CV) events in people with documented coronary artery disease (CAD)," write John H. Lee, MD, from the Mid America Heart Institute and University of Missouri-Kansas City, and colleagues. "The recommendation calls for approximately 1 g/d of a mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Although the AHA statement identifies oily fish as the ideal source, fish oil (in capsules or liquid form) is also an acceptable option."

This recommendation is the first time that the AHA has recommended a nutritional supplement for CAD prevention, and it is supported by a large and growing body of evidence supporting the CV benefits and triglyceride-lowering effects of omega-3 oils.

Although the US Food and Drug Administration (FDA) has approved an omega-3 fatty acid ethyl ester formulation, at a dosage of 4.0 g/day, for the treatment of very high triglyceride levels, many clinicians and patients remain confused about the optimal formulation, indications, and dosing of omega-3 fatty acids for CV health.

In this review, the term omega-3 fatty acids refers only to DHA and EPA because the evidence for a CV benefit from the plant-derived omega-3 fatty acid, alpha-linolenic acid, is much weaker than it is for DHA and EPA.

No trials have yet been conducted comparing DHA and EPA with CAD as an endpoint, so neither of these omega-3 fatty acids has been proven to be more cardioprotective than the other. Current recommendations are that both DHA and EPA, either from fish or from supplements, be consumed in approximately equal amounts.

To date, the strongest evidence showing a CV benefit from omega-3 fatty acid intake derives from 3 large controlled trials in which a total of 32,000 participants were randomized to a control group or to receive omega-3 fatty acid supplements containing DHA and EPA. In these trials, the supplemented group had a 19% to 45% reduction in CV events vs the control group.

Based on these results, the review authors recommend increased intake of both DHA and EPA, whether from dietary sources or fish oil supplements, especially for individuals with or at risk for CAD. In the absence of known CAD, the target DHA and EPA consumption levels are at least 250 to 500 mg/day, and these levels should increase to approximately 1 g/day for persons with heart disease.

Patients with hypertriglyceridemia should consume 3 to 4 g/day of DHA and EPA, which can lower triglyceride levels by 20% to 50%. In patients with severely elevated triglyceride levels (> 500 mg/dL), 3 to 4 g/day of DHA and EPA typically lowers triglyceride levels by 45%. When added to baseline statin therapy in patients with triglyceride levels of 200 to 499 mg/dL, this dosage lowers triglyceride levels by an additional 23% to 29%.

Two meals of oily fish per week can provide 400 to 500 mg/day of DHA and EPA, but patients with hypertriglyceridemia must use fish oil supplements to reach target levels of 1 g/day of DHA and 3 to 4 g/day of EPA.

"Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone," the reviewers write. "Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations."

Standard over-the-counter fish oil concentrate contains 120 mg of DHA and 180 mg of EPA per 1-g capsule, so 1 to 2 capsules of standard fish oil per day contain 300 to 600 mg of DHA and EPA and meet the recommendations for primary prevention; 3 to 4 capsules per day contain 900 to 1200 mg of DHA and EPA and meet the recommendations for secondary prevention; and 5 to 7 capsules twice daily contain 3000 to 4200 mg of DHA and EPA and can be used to lower triglyceride levels.

Tasteless liquid products are also available that provide 1300 mg of DHA and EPA per teaspoon (3900 mg of DHA and EPA per tablespoon). One tablespoon of standard liquid fish oil twice weekly contains approximately the same amount of omega-3 fatty acids as 6 oz of salmon consumed twice weekly (500 mg/day of DHA and EPA).

"Omega-3 fatty acid supplements can be taken at any time, in full or divided doses, without raising concerns for interactions with any medications," the reviewers conclude. "Omega-3 fatty acids persist in cell membranes for weeks after consumption, and thus intermittent bolus dosing, ie, twice weekly intake of fish or fish oil, provides the same benefits as daily consumption of lower doses."

Some of the reviewers have disclosed various financial relationships with CardioTabs, Reliant Pharmaceuticals, the Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI) trial sponsored by Astra-Zeneca and Società Prodotti Antibiotici (SPA), the Rischio & Prevenzione trial sponsored by SPA, Sigma-Tau, Solvay Pharmaceuticals, Pronova BioPharma, and Monsanto.

Mayo Clin Proc. 2008;83:324-332.

Clinical Context

Study Highlights

• Evidence of efficacy:
  • DHA and EPA are the 2 omega-3 fatty acids studied together for efficacy in CV disease prevention mainly in patients with underlying CAD.
  • The original randomized trial in patients with myocardial infarction demonstrated a 29% reduction in all-cause mortality rate.
  • Evidence for alpha-linolenic acid, present in flaxseed, walnuts, other nuts, and some vegetables, has not been shown to be adequate because less than 5% is converted to EPA or DHA.
  • 2 major randomized clinical trials on secondary CV disease prevention, GISSI and the Japan EPA Lipid Intervention Study (JELIS), have since demonstrated significant reduced mortality rates and CV events associated with doses of 850 mg and 1.8 g/day of DHA and EPA.
  • In the GISSI trial, 4-month treatment reduced sudden cardiac death (SCD) by 45%.
  • Reduction in SCD with fish oil is more likely to be seen in populations with higher prevalence of SCD.
  • JELIS included patients without documented CAD who showed a nonsignificant 18% reduction in CV events vs a significant 19% reduction in those with underlying CAD.
  • 1700 mg/day of omega-3 fatty acids has been shown to benefit atrial fibrillation and some ventricular arrhythmias.
  • A dose of 4.0 g/day of both DHA and EPA has been associated with reduction of 1.7 mm Hg for systolic and 1.5 mm Hg for diastolic blood pressure, which can translate into reduced mortality rates.
  • Higher doses of 3.0 to 4.0 g/day have been shown to be required to reduce triglyceride levels, whereas lower doses of 0.5 to 1.0 g/day are sufficient to reduce SCD risk.
  • When used with statins for secondary prevention, DHA and EPA can reduce non–high-density lipoprotein cholesterol and triglyceride levels further by 29.5% and 9.0%, respectively.
  • No single study has examined the efficacy of EPA and DHA on primary CAD prevention.
  • A study of EPA and DHA on patients with chronic heart failure is expected to conclude on 2008 to examine the impact on patients with left ventricular dysfunction.
• Formulations and doses of DHA and EPA:
  • Both DHA and EPA are present in all oily fish, and commonly consumed fish such as salmon contain the 2 in a 2:1 ratio.
  • Standard fish oil capsules such as derived from menhaden, an oily fish of the herring family, contain DHA and EPA in a 2:3 ratio.
  • 1 capsule of over-the-counter fish oil is equivalent to 300 mg of EPA and DHA.
  • 1 tablespoon of standard liquid fish oil taken twice weekly provides the same amount of omega-3 fatty acids as 6 oz of salmon twice weekly (500 mg/day of EPA and DHA).
  • Modest consumption of 200 to 500 mg/day corresponding to 1 to 2 servings of oily fish weekly has been associated with reduced CAD death.
  • For primary prevention, a dose of 1 serving per week of oily fish may be sufficient to reduce risk by 15%, whereas 5 or more servings weekly may confer a 40% risk reduction.
  • Those without CAD can benefit from 1 to 2 capsules of fish oil daily, whereas those with CAD would need 3 to 4 capsules daily for secondary prevention.
  • For reduced triglyceride levels, 5 to 7 capsules twice daily (3 - 4 g/day of EPA and DHA, equivalent to 10 - 14 capsules) are needed to lower levels by 30% to 50%.
  • This dose may be added to statins for additive effect.
  • Omega-3 fatty acids may be taken at any time, and oils persist in cell membranes for weeks after consumption; thus, dosing interval may be as long as once weekly.
  • There are no head-to-head trials of EPA with DHA with controls with CAD as an endpoint; thus, neither fatty acid can be said to be more effective than the other.

Pearls for Practice

• A combination of EPA and DHA is beneficial for secondary CAD protection and risk reduction for SCD, arrhythmias, and treatment of hypertriglyceridemia.
• The dose equivalent for primary CAD protection is 1 to 2 capsules of EPA with DHA daily; for secondary protection, 3 to 4 capsules; and for hypertriglyceridemia, 10 to 14 capsules of EPA with DHA daily.

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