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New Updates on Fish Oil in Heart Failure Prevention

  • Authors: News Author: Marlene Busko; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 8/30/2019
  • Valid for credit through: 8/30/2020
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

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Target Audience and Goal Statement

This article is intended for primary care physicians, cardiologists, nurses, pharmacists, and other physicians who treat and manage adults at risk for heart failure.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Analyze outcomes of a high dose of a precursor to eicosapentaenoic acid on cardiovascular outcomes among adults with hypertriglyceridemia
  • Evaluate the effect of plasma concentrations of omega-3 polyunsaturated fatty acids on the risk for heart failure
  • Outline implications to the healthcare team


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News Author

  • Marlene Busko

    Freelance writer, Medscape and Heartwire


    Disclosure: Marlene Busko has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD, FAAFP

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California


    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Genentech; GlaxoSmithKline
    Served as a speaker or a member of a speakers bureau for: Shire

Editor/CME Reviewer

  • Esther Nyarko, PharmD

    Associate CME Clinical Director, Medscape, LLC


    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

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  • Hazel Dennison, DNP, RN, FNP, CPHQ, CNE

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Hazel Dennison, DNP, RN, FNP, CPHQ, CNE, has disclosed no relevant financial relationships.

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New Updates on Fish Oil in Heart Failure Prevention

Authors: News Author: Marlene Busko; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 8/30/2019

Valid for credit through: 8/30/2020


Clinical Context

Research regarding the effects of supplementation with omega-3 polyunsaturated fatty acids (PUFAs) on cardiovascular outcomes has been mixed, but the REDUCE-IT trial by Bhatt and colleagues was a breakthrough in terms of sound methodology and significant results. This study, published in the January 3, 2019, issue of the New England Journal of Medicine, included patients at high risk for cardiovascular events who were already treated with a statin and had hypertriglyceridemia.[1] They were randomly assigned to receive either 2 g of icosapent ethyl (IE) twice daily or placebo. Icosapent ethyl is a precursor of eicosapentaenoic acid (EPA).

During a mean of nearly 5 years of follow-up, the IE treatment group experienced a significant 25% reduction in the risk for a composite of cardiovascular death and major cardiovascular events. Rates of stroke and myocardial infarction were significantly lower in the IE group, and the hazard ratio for cardiovascular death in comparing the IE and placebo groups was 0.80 (95% confidence interval [CI], 0.66-0.98). IE was associated with a higher risk for atrial fibrillation than placebo, and it was associated with a nonsignificant increase in the risk for serious bleeding events.

Research into the effects of omega-3 PUFAs on heart failure have also been mixed. The current study evaluates how plasma concentrations of omega-3 PUFAs might affect the risk for heart failure.

Study Synopsis and Perspective

High plasma levels of the kinds of fatty acids found in fish oil were associated with a lower long-term risk for new heart failure (HF), whether with reduced or preserved ejection fraction (HFrEF or HFpEF), in a community-based cohort of more than 6000 people.

The higher the plasma levels of EPA (a prevalent n-3 PUFA also called omega-3 PUFA) were, the lower the risks for both forms of HF during a median follow-up of 13 years.

Similar independent observations were made for plasma levels of docosahexaenoic acid (DHA) and of EPA and DHA combined, suggesting that increased levels of n-3 PUFA in general may confer cardiovascular (CV) benefits, observe the study's authors, led by Robert C. Block, MD, MPH, from the University of Rochester School of Medicine and Dentistry, New York.

The findings from the Multi-Ethnic Study of Atherosclerosis (MESA), published July 10 in JACC: Heart Failure, supports existing data on the CV effects of elevated levels of n-3 PUFA, whether achieved by diet, supplements or prescription.[2]

The MESA cohort consists of initially middle-aged adults and is noteworthy for being about evenly divided between women and men and including large proportions of African Americans and other nonwhite groups.

The analysis "may reopen the discussion on the role of omega-3 fatty acids in the context of prevention and treatment of HF," writes Aldo P. Maggioni, MD, from the Heart Care Foundation, Florence, Italy, in an accompanying editorial.[3]

"This study clearly demonstrated a significant independent inverse correlation between circulating levels of omega-3 fatty acids, specifically [EPA], and the occurrence of HF over a long median follow-up period of 13 years."

To reap the any such benefits, "shall we have to go to the fish market or to the pharmacy to elevate our circulating levels of omega-3 fatty acids and, in this way, to try to prevent (or treat) HF?" Dr Maggioni asked.

He argues in favor of the pharmacy. CV outcomes from OMEGA-REMODEL and REDUCE-IT, the current results, and studies in mice "suggest that just with very high plasma levels of omega-3 fatty acids we can obtain a reduction of major CV events, a prevention of HF occurrence and a favorable effect on the left ventricular remodeling processes."

Moreover, "High plasma levels of omega-3 fatty acids can be probably achieved just with the use of purified pharmacological preparations."

"Most Americans, regardless of race or ethnicity," have insufficient levels of n-PUFAs, and "would benefit from increased intake," senior author Gregory C. Shearer, PhD, from Pennsylvania State University, University Park, said in emailed comments to | Medscape Cardiology.

Fish oil supplements would likely be more effective than eating more fish to achieve the n-3 PUFA levels that may be of benefit, Dr Shearer and coauthor Timothy D O'Connell, PhD, from the University of Minnesota, Minneapolis, speculated in a joint interview.

As both the report and editorial note, n-3 PUFA supplementation at the fairly low dosage of 1 g/d, added to standard therapy, was associated with reduced all-cause mortality and HF hospitalization rates over the course of about 4 years in the 2008 GISSI-HF trial.

In the 2015 trial OMEGA-REMODEL, patients who took a proprietary n-PUFA preparation at 4 g/d for 6 months after an MI showed reductions in ventricular remodeling, fibrosis, and inflammatory markers.

More recently, in the REDUCE-IT trial, patients with raised triglycerides and CV disease or diabetes plus 1 other CV risk factor showed a 25% reduction in the composite outcome of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina over the course of 5 years while receiving icosapent ethyl at 4 g/d. The agent acts as a precursor of EPA.

The current analysis classified 65,632 high-risk MESA participants according to their plasma percent-EPA levels.

Levels were lower than 1.0% or insufficient compared with adjusted levels that prevented HF in animal models in 73.1% of participants.

They were 1% to 2.5%, or marginally sufficient, in 2.4% of participants, and 4.5% of the cohort had sufficient levels, at >2.5%.

Only 1.4% of Hispanic participants had sufficient percent-EPA levels; the proportions were 4.4% for African Americans, 4.9% for whites, and 9.8% for participants of Asian descent.

There were 292 HF events (128 involving HFrEF, 110 in HFpEF, and 54 with in people with unknown ejection fractions) during a median of 13 months. Participants who did not vs those who did develop HF showed mean percent-EPA levels of 0.76% vs 0.69%, respectively (P=.005).

In an analysis adjusted for age, sex, race, body mass index, smoking status, type 2 diabetes, blood pressure, lipids, lipid-lowering therapy, albuminuria, and types of PUFA, percent-EPA was inversely associated with risk for HF at a hazard ratio of 0.73 for each log-unit difference (P=.001).

"Clinical trials using 1 g/day omega-3 fatty acids," such as GISSI-HF, "seem to reduce HF risk by about 10%," said Dr Shearer. But this dose would likely only increase the average percent-EPA from 0.7% to the marginally sufficient range, between 1% and 1.5%.

Any forthcoming trials should be designed "to achieve a goal of greater than 3.5% EPA, or greater than 12% EPA plus DHA," he said. "Based on the results from MARINE and ANCHOR, we are optimistic that a larger [n-3 PUFA supplement] dose such as 4 g/day" would result in an average percent-EPA of 4% and about a 35% reduced risk for HF.

"[I]f we want to move from hypotheses to more reliable evidences," Dr Maggioni writes, "it is probably the time to design again adequately sized randomized clinical trials testing high dosages of omega-3 fatty acids on top of current optimized pharmacological and non-pharmacological therapies."

Their goals, he writes, should be to determine whether the intervention has an effect on clinical outcomes in patients with overt HF, as well as the ability to avert HF in patients with structural heart disease but without signs or symptoms of HF.

"Considering the very favorable tolerability and safety profile of this therapeutic approach, any positive results of these trials could provide us with an additional strategy to improve the outcomes of patients with HF or at high risk to develop it."

Dr Block has disclosed no relevant financial relationships. Dr Shearer has received honoraria from Amarin Pharmaceuticals. Disclosures for the other authors are listed in the report. Dr Maggioni has received honoraria for participation in committees of studies sponsored by Bayer, Novartis, and Fresenius outside the scope of the current study.

JACC: Heart Fail. Published online July 10, 2019.

Study Highlights

  • Researchers used MESA to assess their study question. This study enrolled 6814 adults between the ages of 45 and 84 years between 2000 and 2002.
  • All participants underwent a battery of tests at baseline, including measurement of plasma fatty acids.
  • The main outcome of the current study was HF. Participants were assessed for this outcome every 2 years during follow-up, with events adjudicated in the medical record.
  • Researchers divided participants with HF into preserved ejection fraction (ejection fraction of 45% or more; HFpEF) and reduced ejection fraction (ejection fraction, <45%; HFrEF) groups.
  • The main study analysis featured the relationship between plasma fatty acids and HF. The researchers performed multiple analyses to account for confounders in this relationship.
  • Data were available for 6562 participants. The mean age at baseline was in the midsixth decade, and the study cohort was evenly split between female and male.
  • During a median follow-up period of 13 years, 292 participants were identified with HF, with a fairly equal representation of HFpEF and HFrEF.
  • On the basis of animal models, less than 5% of participants had plasma levels of EPA thought to be sufficient to prevent HF. Hispanic participants had the lowest rate of sufficient EPA levels, which were exceeded nearly 10-fold among persons of Chinese descent.
  • Concentrations of EPA and DHA in the plasma were inversely associated with the risk for HF in initial analyses. EPA and DHA concentrations were strongly correlated among individual participants.
  • Sensitivity analyses demonstrated that plasma EPA concentrations remained inversely associated with the rates of both HFpEF and HFrEF. Further analyses that adjusted for demographic and other CV risk variables failed to alter this main study conclusion.
  • For each log increase in the concentration of plasma EPA, the hazard ratio for HF was 0.73 (95% CI, 0.60-0.91).
  • The respective final adjusted hazard ratio for DHA concentration and risk for HF was 0.51 (95% CI, 0.38-0.70). Combining DHA and EPA concentrations, the hazard ratio for HF per log increase in plasma concentration was 0.54 (95% CI, 0.39-0.73).

Clinical Implications

  • REDUCE-IT demonstrated that the icosapent ethyl (IE) treatment group experienced a significant 25% reduction in the risk for a composite of CV death and major CV events compared with placebo. Rates of stroke and myocardial infarction were significantly lower in the IE group, and the hazard ratio for CV death in comparing the IE and placebo groups was 0.80 (95% CI, 0.66-0.98). IE was associated with a higher risk for atrial fibrillation than placebo, and it was associated with a nonsignificant increase in the risk for serious bleeding events.
  • The current study finds that plasma concentrations of both EPA and DHA are inversely associated with the risk for HF.
  • Implications for the Healthcare Team: There is growing evidence that both dietary and supplemental omega-3 PUFAs are associated with better CV outcomes. The healthcare team should encourage consumption of a diet which includes these fatty acids and suggest supplements for high-risk patients.


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