Omega-3 Fish Oil: Cardioprotective or Not?

Often there is a dichotomy regarding information published in the lay press versus what is presented in the medical literature. So it’s nice when both agree, except on those rare occasions, when both get it wrong.

Despite numerous epidemiologic and observational studies to the contrary, Men’s Health had a recent article titled “Is Fish Oil the New Snake Oil?”1–4 They based that on several recent “high-profile reviews” in “trusted medical journals” that no longer supported the original health claims regarding fish oil. They were referring to two review articles recently published in the medical literature.5,6 The result is an uncertainty for both physicians and the public regarding the use of omega-3 fish oil.

The problem, though, is not a lack of benefit from using omega-3 fatty acids (OM3), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The problem is that there was a lack of quality fish oil studies included in these two review articles.5,6 When looking at OM3 trials, there are six things to be aware of:

1. Was the study trying to show short-term or long-term benefits? Short-term benefit: (One to two years on OM3) a reduction in fatal cardiovascular events, generally because of a reduction in ischemic, induced ventricular tachyarrhythmias.7 Potential anti-arrhythmic actions of OM3:

  • A membrane-stability effect by enrichment of the myocardial membrane with OM3
  • Electrophysiologic effects on various ion channels
  • Autonomic effects, such as reduction in heart-rate variability and increased vagal tone
  • Reduction in perfusion arrhythmias
  • An anti-inflammatory effect

Long-term benefit: (>3 years on OM3) a reduction in non-fatal or fatal cardiac events, such as acute coronary syndrome. Potential mechanisms include an anti- inflammatory and/or an antithrombotic effect. Do not look for a reduction in long- term benefits when examining studies with a short time span.

2. Was the patient receiving an appropriate dose? Short-term benefit trials need at least 0.5–1.0 gm/day of OM3, while the long-term trials generally require ≥1.5–2.0 gm/day.

3. Were OM3 blood levels obtained to show that the treated group had an adequate OM3 blood level vs. the control group? People have different OM3 absorption abilities, different genetic handling of OM3, and the fish they eat may contain significantly different levels of OM3. OM3 levels cannot be assumed to be adequate.8,9

4. Was the population large enough for the study? Primary prevention trials need to have a much larger study population than secondary prevention trials.

5. Was there a limitation on fish intake by the control group? Too much intake by the control group could mask any benefit seen in the treated group.

6. What was the concurrent therapy used? Aggressive revascularization and multiple drug therapies may lessen the incidence of fatal cardiac events to such an extent that it is hard to demonstrate benefit in short- term studies. Long-term trials are not as affected by concurrent therapy.

Men’s Health seems to have keyed on the two recent review articles that claimed there was insufficient evidence of secondary prevention with OM3 use. Kwak evaluated 14 studies, while Rizos looked at the same 14 plus six additional studies.5,6 Both meta-analyses had numerous shortcomings: 11 studies had follow-up ≤2.5 years, 11 had samples sizes of only 50–550, nine had no fish restriction, 14 had no measured omega-3 level, and most were not designed to detect cardiovascular endpoints.10

Of the eight studies in the review articles that had more than 550 patients:

Those showing benefit:
DART randomized 2,033 men with recent myocardial infarction (MI) to OM3 — either oily fish or fish capsules — vs. the control.11 There was a 29 percent reduction in all-cause mortality (primarily cardiac) over two years. The best reduction in events was seen in those taking fish capsules vs. simply increasing fish intake, which may indicate a threshold effect for OM3.

GISSI Prevenzione had 11,323 patients <3 months post-MI randomized to 1 gm of OM3 vs. the control. Sudden cardiac death (SCD) was reduced by 47 percent at four months (p=0.048).12 Note: There was minimal invasive treatment post-MI and only moderate medication use.

JELIS involved 18,645 high-risk or vascular-disease patients put on placebo vs. 1.8 gm of EPA.13 A five-year follow-up showed a 19 percent reduction (p=0.011) in major coronary events, primarily unstable angina and nonfatal MIs. Most risk reduction occurred after 2.5 years. Post-hoc analysis: 53 percent reduction in cardiovascular (CV) events in patients with elevated triglycerides and low HDL-C.14

GISSI-HF involved 6,988 patients with New York Heart Association (NYHA) class II-IV and an average ejection fraction of 33 percent, randomized to placebo vs. 1 gm OM3. Follow-up was 3.9 years.15 There was a significant 9 percent reduction in mortality (p=0.041) and 8 percent reduction in mortality and admissions for chronic heart failure (CHF) (p=0.009).  Survival curves started to diverge after two years.

Those showing no benefit:
OMEGA
randomized 3,804 immediate post-MI patients to OM3 1 gm vs. olive oil.16 There was no difference in SCD at one year. Problems: The study was underpowered. Aggressive post-MI therapy, including percutaneous coronary intervention in 78 percent, dropped the expected SCD rate of 3.5 percent down to 1.5 percent. Also, 44 percent of placebo patients were ingesting fish several times a week.

Alpha Omega Trial had 4,837 participants with prior MI.17 Participants were randomized to placebo or 400 mg OM3 and followed for 3.5 years. Overall, there was no reduction in CV event rates, but diabetics had a 50 percent reduction in coronary heart disease (CHD) events and rate of arrhythmic events similar to GISSI. Problems: Participants were given an inadequate dose of OM3 and follow-up was too short. The JELIS curve didn’t start to diverge until 2.5 years.

ORIGIN randomized 12,536 high-risk patients with impaired fasting glucose to placebo vs. 900 mg of OM3 with a 6.2- year follow up.18 There was no difference in event rates. Problems: Patients received an inadequate dose for long-term benefits. The placebo group was ingesting 40–568 mg of OM3 a day. There was no measured OM3 level.

SU.FOL.OM3 had 2,501 patients with a history of cardiovascular disease randomized to OM3 600 mg vs. placebo.19 They were followed for 4.7 years. There was no difference in cardiovascular events. Problems: Patients received an inadequate dose. There was no fish restriction in the placebo group. It was underpowered.

So despite the inclusion of these suboptimal “no benefit” studies, omega-3 use in the larger of the two meta-analyses still favored a reduction in all-cause mortality, sudden death, and MI, although these reductions were not statistically significant. What was significant was the reduction in cardiac death (p=0.01) seen in the meta-analysis. The usual p-value for significance is ≤0.05 so this result was impressive. Rizos, et al., for arguable reasons, decided to set the p-value for significance at 0.006 and claimed, therefore, that the finding was not significant (Figure 1).6

Summary: A meta-analysis is only as good as the studies it includes, which gives an idea of the validity of these two recent meta-analyses. Yet, for some reason, they have been accepted by the public and various physicians as evidence that there is no cardiovascular benefit from OM3 use. We need to keep sight of the numerous other reviews and studies that have described the advantages of using OM3 for cardiovascular benefits and continue to use OM3 for cardiovascular risk reduction (see table with citations).

Disclosure statement: Dr. Moran is a speaker for Amgen, Repatha, Sanofi, and Regeneron.

References are listed on page 46 of the PDF.

 

Article By:

Omega-3 Fish Oil: Cardioprotective or Not?

Director, Advance Lipid Management Program
Tyler Heart Institute, Community Hospital of the
Monterey Peninsula
Monterey, CA

Diplomate, American Board of Clinical Lipidology

0
No votes yet