n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction
Open accessAbstract
BACKGROUND: Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS: In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS: The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. CONCLUSIONS: Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.).
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The STRENGTH, VITAL, ASCEND, ORIGIN, OMEGA, ALPHA-OMEGA, GISSI-HF and GISSI-P trials randomized patients to receive either a combination of EPA and DHA or placebo; yet only the GISSI trials noted a statistically significant effect on cardiovascular events and mortality.
“The STRENGTH, VITAL, ASCEND, ORIGIN, OMEGA, ALPHA-OMEGA, GISSI-HF and GISSI-P trials randomized patients to receive either a combination of EPA and DHA or placebo; yet only the GISSI trials noted a statistically significant effect on cardiovascular events and mortality [96–103].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [101]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMore recent trials have shown no benefit of low-dose n-3 PUFA supplements in middle-aged post-MI populations.
“while more recent trials have shown no such benefit in middle-aged post-MI populations with low-dose n-3 PUFA supplement 7-9”
From Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction (2021) · cites this paper as [9]
The Discussion (p. 2026) reports that a low dose of EPA-DHA had no effect on major cardiovascular events after myocardial infarction. But the trial participants averaged 69 years of age, so this paper does not establish the claim specifically for a middle-aged post-MI population. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEven among omega-3 fatty acid studies, there are marked differences with respect to the relatively low doses of omega-3 administered and the ratio of EPA to DHA.
“Even among omega‐3 fatty acid studies, there are marked differences with respect to the relatively low doses of omega‐3 administered and the ratio of EPA to DHA.16, 17, 18, 19, 20, 21, 22, 23, 24”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [20]
The Study Design and Patients section describes this trial’s low-dose intervention and specifies an EPA-to-DHA ratio of 3:2; Study Intervention reports average daily intakes of 226 mg EPA and 150 mg DHA. The Discussion notes that earlier trials used EPA with or without DHA, but our copy does not establish marked differences in dose or EPA-to-DHA ratios across the studies cited in the sentence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMore recent omega-3 therapy outcome studies conducted in the presence of statins have been less encouraging, but evaluated nonhypertriglyceridemic patient populations and administered low doses of long-chain omega-3 fatty acids.
“Other more recent omega‐3 therapy outcome studies conducted in the presence of statins have been less encouraging, but these studies were characterized by evaluating nonhypertriglyceridemic patient populations (eg, TG <200 mg/dL) and administering low doses of long‐chain omega‐3 fatty acids (eg, eicosapentaenoic acid [EPA] and/or docosoahexaenoic acid [DHA]).19, 20, 21, 22, 23, 24”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [20]
The initial manuscript's results were skewed because its search strategy missed significant studies and included trials that mostly used EPA and DHA combinations rather than IPE.
“Our initial manuscript included Trials such as ORIGIN8, ASCEND9, Alpha Omega10, and JELIS5; among these trials, only one trial had IPE, and the rest of the trials had a combination of EPA and DHA, so our results were skewed as search strategy missed significant studies.”
From Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials (2024) · cites this paper as [10]
Even lower doses of omega-3 fatty acid supplementation have shown a potential signal for increased risk for atrial fibrillation.
“Even lower doses of O3FA supplementation has shown a potential signal for increased risk for AF,2,4,5”
From Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials (2021) · cites this paper as [4]
The Abstract describes a low-dose omega-3 trial, but it does not report atrial fibrillation risk. The End Points section and Subgroup Analyses report ventricular-arrhythmia-related events, which are distinct from atrial fibrillation; searches for atrial fibrillation and adverse-event incidence found no passage establishing the claimed signal. (LLM, conf=0.75)
Experimental — accuracy not yet measuredRegardless of the dose of omega-3 fatty acid supplementation implemented in the trials and potential-related benefits on cardiovascular outcomes, omega-3 fatty acid supplementation may increase the risk for atrial fibrillation.
“proposing that regardless of the dose of O3FA supplementation implemented in the trials and potential-related benefits on CV outcomes, O3FA supplementation may increase the risk for AF.”
From Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials (2021) · cites this paper as [4]
Our copy discusses ventricular arrhythmias and cardiovascular outcomes (Abstract, End Points, and Subgroup Analyses), but the retrieved passages do not address atrial fibrillation risk. Searches for atrial fibrillation and adverse events found no passage supporting a dose-independent increase in that risk. (LLM, conf=0.75)
Experimental — accuracy not yet measuredLow-dose supplementation with n-3 polyunsaturated fatty acid margarine (400 mg/day) or alpha-linolenic acid (2 g/day) did not significantly reduce triglycerides or major cardiovascular events in a randomized trial of 4837 post-myocardial infarction patients.
“a low dose supplementation of a margarine with n-3 PUFAs (400 mg/day) or a-linolenic acid (2 g/day) did not significantly reduce TG levels in an RCT involving 4837 post-MI patients; neither did this supplementation reduce the rate of major CV events.92”
From ESC/EAS Guidelines for the management of dyslipidaemias (2011) · cites this paper as [92]
Consumption of n-3 PUFAs, as oily fish or purified n-3 acid ethyl ester, reduced mortality in MI survivors in one study but not in another.
“The consumption of n-3 PUFAs, as either increased (oily) fish intake or a highly purified n-3 acid ethyl ester prescription medication, has in one study been shown to reduce mortality in survivors of MI, 178 but not in another.92”
From ESC/EAS Guidelines for the management of dyslipidaemias (2011) · cites this paper as [92]
A recent observational analysis found that saturated fat intake was linked to a trend of higher coronary heart disease risk compared with low-glycemic, higher-fiber carbohydrates.
“In a recent observational analysis, SFA consumption was associated with a trend toward higher CHD risk than low-glycemic, higher-fiber (eg, whole grain) carbohydrates and with lower CHD risk when it replaced high-glycemic (eg, highly refined) carbohydrates.145”
From Components of a Cardioprotective Diet: New Insights (2011) · cites this paper as [145]
Some evidence supports cardiovascular benefits of plant-derived omega-3 fats, but compared with seafood omega-3, the potency of plant-based omega-3 appears weaker, and mixed findings preclude strong conclusions.
“Some evidence supports cardiovascular benefits of plant-derived omega-3 fats, but compared with naturally occurring omega-3 from seafood, the potency of plant-based omega-3 appears weaker, and mixed findings preclude strong conclusions.137,138”
From Components of a Cardioprotective Diet: New Insights (2011) · cites this paper as [138]
When saturated fat replaced high-glycemic carbohydrates, it was linked to lower coronary heart disease risk.
“In a recent observational analysis, SFA consumption was associated with a trend toward higher CHD risk than low-glycemic, higher-fiber (eg, whole grain) carbohydrates and with lower CHD risk when it replaced high-glycemic (eg, highly refined) carbohydrates.145”
From Components of a Cardioprotective Diet: New Insights (2011) · cites this paper as [145]
Nicotinic acid derivatives have Lp(a)-lowering effects.
“Nicotinic acid derivatives also have Lp(a)-lowering effects689–691).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [691]
In one Dutch trial, 40 months of an ALA-containing margarine led to a nonsignificant reduction in major cardiovascular events RR=0.91; 95% CI: 0.78-1.05.
“Few long-term trials of ALA and clinical events have been conducted; in one Dutch trial, 40 months of an ALA-containing margarine led to a nonsignificant reduction in major cardiovascular events RR=0.91; 95% CI: 0.78-1.05).373”
From Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity: A Comprehensive Review (2016) · cites this paper as [373]
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“Our initial manuscript included Trials such as ORIGIN [8] , ASCEND [9] , Alpha Omega [10] , and JELIS [5] ; among these trials, only one trial had IPE, and the rest of the trials had a combination of EPA and DHA, so our results were skewed as search strategy missed signi fi cant studies.”
Background
- Authors
- Kromhout, D., Giltay, E. J., & Geleijnse, J. M.
- Affiliations
- Wageningen University & Research (NL)
- Leiden University Medical Center (NL)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-11-18
- Volume
- 363
- Issue
- 21
- Pages
- 2015-2026
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2026310866
- Semantic Scholar
- 20dbd82117553651dfad3bb4509147dc0f5a7f1e
- Cited by
- 936
- References
- 29
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 23 · 2023: 39 · 2022: 39 · 2021: 51 · 2020: 55 · 2019: 61 · 2018: 58 · 2017: 63 · 2016: 62 · 2015: 62 · 2014: 83 · 2013: 93 · 2012: 117
- FWCI
- 91.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- omega-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid, myocardial infarction, cardiovascular events, women, cardiovascular disease prevention, dietary intervention, omega-6 fatty acids, LDL cholesterol, triglycerides, HDL cholesterol
- MeSH terms
- Aged, Aged, 80 and over, Cardiovascular Diseases, Docosahexaenoic Acids, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Margarine, Middle Aged, Myocardial Infarction, Eicosapentaenoic Acid, Fatty Acids, Omega-3, alpha-Linolenic Acid, Dietary Supplements, Kaplan-Meier Estimate
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