Source: Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2018;7:CD003177.
Study Population: Adults (age ≥18 years) with varying levels of cardiovascular risk
Efficacy Endpoints: All-cause mortality, cardiovascular mortality, cardiovascular events, arrhythmia, stroke
Harm Endpoints: Nausea, abdominal pain or discomfort, diarrhea, reflux, any gastrointestinal side-effect, headache or worsening migraine, joint and muscle pain, skin problems, gastrointestinal hospitalization, bleeding, pulmonary embolus or deep venous thrombosis
Narrative: Non-communicable diseases have overtaken communicable diseases as the world's major disease burden, with circulatory and cardiovascular diseases (CVD) remaining the leading cause of death globally.1 Researchers have long investigated the health effects of omega-3 (Ω-3) polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA; C20:5) and docosahexaenoic acid (DHA; C22:6), on CVD prevention. Dietary fatty acids may be oxidized for energy, stored in adipose tissue, or further metabolized to various long-chain PUFAs. Membrane derived PUFA’s serve as substrates for formation of eicosanoid effectors (Ω-3 and Ω-6).2 The effectors derived from Ω-3 PUFAs are less inflammatory and platelet aggregating than their Ω-6-derived counterparts.2
The primary source of nonprescription Ω-3 PUFA supplements is fish oil.3 In 2012, 7.8% of U.S. adults (18.8 million) reported consuming a fish oil dietary supplement within the prior 30 days.4 An American Heart Association (AHA) report suggested that Ω-3 PUFA supplements may reduce coronary heart disease (CHD) death, possibly through a reduction in ischemia-induced sudden cardiac death (SCD), among patients with prior CHD, but does not reduce the incidence of recurrent nonfatal MI. As benefits likely outweigh the risks, the AHA report offered a Class IIa recommendation (Benefits >> Risk. Additional studies with focused objectives needed. It is reasonable to administer treatment) for the use of Ω-3 PUFA supplements for the secondary prevention of CHD death.3
The meta-analysis discussed here analyzes the effectiveness of dietary Ω-3 PUFA supplementation with EPA (fish-derived; C20:5), DHA (fish-derived; C22:6) and alpha-linolenic acid (ALA; plant-derived; C18:3) to improve all-cause mortality, cardiovascular deaths, cardiovascular events, arrhythmias, and stroke. The meta-analysis included 79 randomized controlled trials (RCT) enrolling 112,059 participants published before April 2017.5 Twenty-seven on-going trials were excluded. Thirty-three trials included subjects with prior cardiovascular risk (secondary prevention), and 46 trials enrolled patients with no prior cardiovascular risk (primary prevention). The follow-up period varied from 12 to 72 months. Ω-3 PUFA supplementation was performed via capsule or medicinal oils, Ω-3 PUFA-enriched foods, or via dietary advice to increase Ω-3 PUFA intake. Due to small number of trials assessing long-chain Ω-3 (LCn3) fatty acids, EPA and DHA were analyzed in aggregate.5
Long-Chain Polyunsaturated Fatty Acids
No significant benefits were noted with LCn3 PUFA (EPA, DHA) supplementation for preventing all-cause mortality (39 RCTs; 92,653 participants), cardiovascular mortality (25 RCTs; 67,722 participants), cardiovascular events (38 RCTs; 90,378 participants), arrhythmia (28 RCTs; 53,796 participants), or stroke (28 RCTs; 89,358 participants).
Alpha-Linolenic Acid (ALA)
No significant benefits were noted with ALA supplementation for preventing all-cause mortality (5 RCTs; 19,327 participants; 459 deaths), cardiovascular mortality (4RCTs; 18,619 participants), cardiovascular events (5 RCTs; 19,327 participants; 884 CVD events), arrhythmia (1 RCT; 4,837 participants), or stroke (5 RCTs; 19,327 participants).5
The meta-analysis assessed both non-serious side-effects (nausea, abdominal pain or discomfort, diarrhea, reflux, any gastrointestinal side-effect, headache or worsening migraine, joint lumbar and muscle pain, or skin problems) and serious side-effects (gastrointestinal hospitalization, bleeding, pulmonary embolus (PE) or deep venous thrombosis (DVT).
Long-Chain Polyunsaturated Fatty Acids
There was no suggestion that LCn3 significantly increased non-serious side effects (aggregate) with high heterogeneity.5 Nausea was increased in the LCn3 PUFA group (RR 1.76, 95% CI 1.25 to 2.48; I2 =0%; 5 RCTs; 1,234 participants). All other non-serious side effects were not statistically different.5
Serious adverse events were not increased with LCn3 intake.
ALA supplementation did not increase side-effect mediated study withdrawal.5 Insufficient data was available to assess other non-serious adverse effects.
Data was insufficient for assessing the risk of PE or DVT (1 RCT; 708 participants; 1 event). No data was available for any other serious adverse events.
Caveats: Ω-3 PUFA enriched foods (e.g. dietary fish) may have different health effects than capsule or medicinal oil Ω-3 PUFA, as it may replace less healthy foods (leading to reduced saturated fat intake) and provides other additional nutrients (e.g. protein, selenium, iodine, calcium, magnesium). The sub-group analysis performed in the meta-analysis was underpowered to detect a statistically significant difference between the dietary advice subgroups (enriched food vs. capsule or medicinal oil). Daily Ω-3 PUFA intake in such studies is not quantifiable as dietary practices vary across patients. Thus, it remains unclear whether studies using this design skewed the potential effects of studies utilizing a more traditional design. Furthermore, the assessment of EPA and DHA in aggregate potentially masked the benefit of any singular agent.
The follow-up duration of at least 12 months may not have been long enough to detect any significant impact on mortality and cardiovascular outcomes.
Evidence from funnel-plots reported in the meta-analysis suggest some small study-bias, suggesting some smaller studies showing increased risk of CVD outcomes with Ω-3 PUFA use may be missing. Additionally, the data is limited by significant heterogeneity. This likely reflects the variable means by which data points were collected across trials.
Lastly, this analysis5 did not collate data on cancers and neurological problems associated with polychlorinated biphenyls (PCBs) or mercury in fish oils.
Conclusion: In summary, high-quality evidence suggests that long-chain Ω-3 PUFA do not prevent mortality (all-cause or cardiovascular) or cardiovascular disease events when used as primary or secondary prevention. Because of lack of any benefit but relative safety, we have assigned a color recommendation of RED (no benefit) to this treatment.
The original manuscript was published in Medicine by the Numbers, American Family Physician as part of the partnership between TheNNT.com and AFP.
Author: Anna Tomdio, MD; Michael Ritchie, MD; Andrew C Miller, MD
Published/Updated: April 15, 2019
The title bar is color-coded with our overall recommendation.