Omega-3

Title: Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Disease Protection

Clinical CV Protection
Although data are accumulating to support benefits of omega-3 PUFA in many CV conditions, including atherosclerosis, atrial fibrillation, and complex ventricular dysrhythmias, probably the most impressive data thus far have been in CHD patients post-MI, high-risk hypercholesterolemia, those with advanced heart failure (HF), and, particularly, patients with hypertriglyceridemia.

Post-MI. Two large-scale studies, including Diet and Reinfarction Trial (DART)7 and GISSI-Prevenzione,8 which together included over 13,000 post-MI patients, demonstrated reductions in total mortality of nearly 30%. In GISSI-Prevenzione,8 which assessed the effects of Lovaza containing 850 mg of combined EPA/DHA in a 1.2:1 ratio versus usual care, patients taking Lovaza had major reductions in CV endpoints ( Slide 3).9 Other studies, including a recent underpowered OMEGA trial, have not demonstrated such benefits.10

Hypercholesterolemia. In the JELIS trial,11 18,645 patients (nearly 80% primary prevention) with hypercholesterolemia were randomized to statin alone or statin plus highly purified EPA 1800 mg/day. At the end of 5 years, EPA produced a 19% reduction in major CV events (Slide 4).11

Lovaza in HF. Several recent epidemiological studies support the benefits of omega-3 PUFA for protection against HF.1,12 A recent major trial (GISSI-HF)13 randomized nearly 7,000 HF patients to Lovaza versus placebo. After correcting for baseline factors (Slide 5),13 Lovaza therapy showed small, but statistically significant reductions in total mortality (9%; p < 0.05) and total mortality or CV hospitalizations (-8%; p < 0.01). These benefits translate into 56 patients needing to be treated for 4 years to avoid one death or hospital CV admission.

In an editorial, Dr. Greg Fonarow noted that omega-3 PUFA "should join the short list of evidence-based life-prolonging therapy for HF,"14 and my colleagues and I agree with this assertion.1,12

Omega-3 PUFA and Hypertriglyceridemia. Perhaps the most proven and accepted role of omega-3 PUFA and specifically Lovaza, a formulation approved by the Food and Drug Administration (FDA), is for the treatment of dyslipidemia, especially severe hypertriglyceridemia. In patients with triglycerides =500 mg/dl, Lovaza 4 g reduced triglycerides by 45% and non–high-density lipoprotein (HDL) cholesterol by 14%, with a 9% increase in HDL15; in patients with triglycerides between 200-499 mg/dl, this dose of Lovaza lowered triglycerides by 30%.16 Although clinical event reduction has not been proven when using this dose of Lovaza to treat hypertriglyceridemia, as noted previously, lower doses (Lovaza 1 g) have reduced clinical events post-MI8 and in advanced HF13 (Lovaza does not have FDA indications for post-MI or HF, however).

Clinical Recommendations
For those without CHD, the American Heart Association (AHA) recommends two oily fish meals per week, which has been shown to be equivalent to about 500 mg/day of combined EPA and DHA17; this dosage could also be obtained by one or two over-the-counter (OTC) fish oil capsules, depending on the exact concentrations of EPA and DHA. Other organizations have also endorsed guidelines that address increasing consumption of fish. 1

The current AHA guidelines recommended combined EPA and DHA in a dose of approximately 1000 mg/day in patients with CHD.17 This dose may also now be appropriate for patients with HF.1,12,14 Since few patients eat four or more oily fish meals per week, this dosage of EPA + DHA would generally require two or three OTC fish oil capsules, depending on the exact concentrations of EPA and DHA (equivalent to one Lovaza, which is not FDA-approved for this indication). In patients with elevated triglycerides, 3-5 g/day of EPA + DHA would be needed, which generally would require between 6-12 OTC fish oil capsules (or 4 Lovaza, the FDA-approved preparation).

Conclusions
Based on considerable evidence, the target EPA + DHA consumption should be at least 500 mg/day for individuals without overt CV diseases, and at least 800-1000 mg/day for individuals with known CHD and HF. As was recently reviewed in detail, 1 further studies are needed to determine optimal dosing and the relative ratio of DHA and EPA that provides maximal CV protection in those at risk of CV diseases, as well as in the treatment of atherosclerosis, arrhythmias, and primary myocardial disorders. However, the constellation of data suggests that this story represents a "fish tale with growing credibility."1



 
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