OXFORD, UK — Another meta-analysis has suggested that daily supplementation with marine-derived omega-3 fatty acids (FAs) does not significantly reduce the rate of fatal or nonfatal CHD or any major vascular events in high-risk individuals.[1]

After examining data from 10 randomized trials following 77,917 participants with prior CHD or stroke or at high-risk for CVD, British researchers found that at least 12 months of supplementation had no significant effect on rates of any CHD events (rate ratio [RR], 0.96; P =0.12), including nonfatal MI (RR, 0.97; P=0.40) or CHD death (RR, 0.93; P =0.05).

Omega-3 FAs also were not significantly associated with rates of major vascular events (RR, 0.97; P =0.10), stroke (RR, 1.03; P =0.56), or revascularizations (RR, 0.99; P =0.61).

"The results of these 10 trials involving 78,000 participants treated for 4 years provide no support for the current AHA guidelines that patients with prior CHD should take omega-3 FA for prevention of CVD," senior author, Dr Robert Clarke (University of Oxford, UK), told theheart.org | Medscape Cardiology in an email.

In an updated scientific statement last year, the AHA said omega-3 FA supplementation is reasonable in patients with prior CHD or HF with reduced ejection fraction but made no recommendation for use in primary prevention because of a lack of randomized data. In contrast, European guidelines say it is debatable whether omega-3 FAs exert a protective effect and that more evidence is needed to justify their use, note the authors.

The study, led by Dr Theingi Aung (University of Oxford) for the Omega-3 Treatment Trialists' Collaboration, was published January 31 in JAMA Cardiology.

Commenting for theheart.org |Medscape Cardiology, Dr Carl 'Chip' Lavie (Ochsner Heart and Vascular Institute, New Orleans, LA) said it is still very reasonable for physicians to recommend omega-3 FAs for CV protection and that he would to do so after MI and in patients with systolic HF or high LDL cholesterol or triglycerides.

"This paper will hardly be a death sentence as omega-3 is very safe and relative inexpensive, and several studies have shown at least modest or even quite profound benefits," he said.

Lavie noted that many of the trials in the meta-analysis were "either too small, too underpowered, too low dose, or too short to show any effects. Even still, almost all of the endpoints leaned toward a trend for benefit and the 7% reduction in CHD death was of borderline significance, with a P value of 0.05."

Given the safety and low cost of omega-3 FAs, Lavie argues the evidence doesn't have to be at nearly the same level of that for expensive and risky medications and devices.

"The fact is that a lot of our patients who oppose many therapies are very happy to use things like omega-3 supplements, and this should not be ignored," he said.

Clarke pointed out that the present meta-analysis is different from previous meta-analyses in that it assessed the effects of omega-3 FAs on prespecified CVD subtypes and CVD in a range of patient populations.

"The results demonstrated no beneficial effects of treatment with omega-3 FA on any CVD, or on any subtype of CVD, or on any CVD in any subgroup of the population," he said.

Nevertheless, the authors write that the 95% CIs in the analysis "cannot exclude a 7% lower risk of major vascular events and a 10% lower risk of CHD associated with omega-3 FA supplements."

The meta-analysis included several high-profile trials, such as ORIGIN, JELIS, GISSI-HF, and GISSI-P—all with at least 500 participants and an average duration of 1 to 6.2 years. All but one trial tested a daily dose of omega-3 FA of 226 to 1800 mg of eicosapentaenoic acid (EPA) and 0 to 1700 mg of docosahexanoic acid (DHA), with one using 1800 mg/d EPA alone.

About 23% of participants had prior CHD, prior diabetes, total cholesterol of 193.1 mg/dL or greater, or triglycerides greater than 150.4 mg/dL, and about 15% reported prior statin use.

Clarke observed that two large ongoing trials—VITAL in the United States and ASCEND in the United Kingdom—will provide additional evidence later this year on the effects of 1 g of omega 3 FA per day in a further 40,000 patients.

"Most experts would await the results of these trials before revising the guidelines. However, in the light of the consistent null findings from the 10 previous trials, there is little expectation that the results of the ongoing trials will differ from the results of the present meta-analysis," he said. "Patients are still advised to eat fish at least two per week, but taking fish oil supplements has no beneficial effects."

VITAL principal investigator, Dr JoAnn Manson (Brigham and Women's Hospital, Harvard Medical School, Boston) said in an email, "When effects of an intervention remain inconsistent and inconclusive despite extensive study, it is often because effects are modest in the populations tested."

In the case of omega-3 FAs, the agents have been tested predominantly in secondary prevention and high-risk populations, often in the setting of concomitant use of other medications, such as aspirin, statins, ACE inhibitors, and β-blockers. Also, many of the trials were of short duration and tested low doses, she said.

A key unanswered question is whether marine omega-3 FAs reduce the risk for MI, stroke, CV mortality, and other CVD events in a primary prevention setting, among those at "usual" risk of CVD.

VITAL, the first such large-scale randomized trial, is being conducted in 25,874 participants who were selected only on age (men aged 50 years or older and women aged 55 years or older), were free of CVD at baseline, and did not have high use of aspirin or statins (less than 50% for each). The mean trial duration is 5 years; results are expected this fall.

Other trials, such as ASCEND, DO-HEALTH, STRENGTH, and REDUCE-IT, will also add importantly to the evidence base, Manson said.

"While awaiting additional data, it remains important to meet guidelines for dietary fish intake (or plant-based sources of omega-3s, if vegetarian), which will not only provide these nutrients but also replace less healthful foods in the diet," she added.

Lavie expressed concern that patients in VITAL may be too healthy, controls may have decent omega-3 levels, and event rates may be low and called for further research with 2 to 4 g/d omega-3 FA in CHD and HF. REDUCE-IT and STRENGTH are assessing 4 g/d in addition to statins in hypertriglyceridemia, but these are with prescription products.

Clarke reports no relevant conflicts of interest. Coauthor disclosures are listed in the paper. Lavie reports having served as a speaker and consultant for DSM, the Global Organization for EPA and DHA Omega-3S (GOED), and Amarin.

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