Omega-3 Fatty Acids: Do Cardiovascular Benefits Exist?
Ben Hierlmeier, Pharm.D., Park Nicollet
Background: Omega-3 fatty acids have been widely used and recommended due to the belief that increased intake would prevent cardiovascular (CV) disease. Compounds with potential benefit are the long-chain omega-3 fatty acids (LCn3) from oily fish including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant sourced alpha-linolenic acid (ALA). Many proposed mechanisms by which LCn3 might improve CV health exist including: membrane-stability effect by enrichment of the myocardial membrane, electrophysiologic effects on various ion channels, autonomic effects such as reduction in heart rate variability and increased vagal tone, reduction in perfusion arrhythmias, anti-inflammatory effects, and antithrombotic effects. It is well established that high doses of DHA and EPA effectively treat hypertriglyceridemia (TG>500 mg/dL). This therapy is currently recommended by most major guidelines as a first line option, primarily to reduce the risk of pancreatitis. However, CV benefits in the wider population are less well established. There has been some promising evidence supporting the use of fish oil, however recent reviews and meta-analyses seem to conclude there is no benefit with regards to CV outcomes.
Evidence: The most recent update on the potential role for fish oil was a large 2018 systematic Cochrane review by Abdelhamid et al. The review encompassed 79 randomized controlled trials lasting at least 12 months, totaling 112,059 patients. The included study interventions were LCn3 supplementation and/or advice to increase LCn3; and the comparison groups were usual or lower intake of LCn3. The results showed little or no effect of increasing LCn3 on all-cause mortality (RR 0.98 [95% CI 0.90-1.03]), CV mortality (RR 0.95 [95% CI 0.87-1.03]), CV events (RR 0.99 [95% CI 0.94-1.04]), coronary heart disease (CHD) mortality (RR 0.93 [95% CI 0.79-1.09]), stroke (RR 1.06 [95% CI 0.96-1.16]), or arrhythmia (RR 0.97 [95% CI 0.90-1.05]). Results were graded based on moderate- and high-quality evidence. When the authors conducted a sensitivity analysis retaining only trials with a low risk of bias, the effect sizes for LCn3 on all primary outcomes, with the exception of arrhythmia, moved the RR toward 1.0 suggesting no difference.
The Agency for Healthcare Research and Quality performed a review in 2016, which also suggested no CV benefits with LCn3 supplementation (Balk et al). However, previous systematic reviews have suggested CV protection in specific patient populations such as post heart surgery patients (He et al. 2013) and post myocardial infarction patients (Zhao et al. 2009).
Public health advice from professional organizations on LCn3 supplementation is also variable.The UK’s National Institute for Health and Clinical Excellence supports dietary fish intake, but does not support using dietary supplements. The American Heart Association encourages patients with CHD to consult with their doctor, as they may benefit from omega-3 supplements.
Discussion: While the 2018 Cochrane review seems quite convincing, it may not tell the whole story for LCn3 supplementation. Generally a large sample size is desirable, however the patient populations in the various studies included in this meta-analysis may be too heterogeneous. Patients included had variable baseline CV risk and medical histories. An overly heterogeneous patient population could mean that specific populations who do benefit from increased LCn3 intake are not seen in the analysis because of large numbers of patients with different baseline characteristics. Additionally, many of the trials included in the meta-analysis had limitations such as not controlling for dietary intake in control populations, having too short of a follow-up period when evaluating long term outcomes, and using inadequate doses of LCn3s. Most recent evidence has suggested little to no benefit when supplementing with LCn3; however, the conclusions of the Cochrane review may be too broad.
Clinical Impact: The body of evidence allows for few conclusions related to the use of LCn3s. It is likely that most patients would benefit from a healthy diet, including fish rich in omega 3 fatty acids, instead of consuming omega 3 dietary supplements. However, evidence suggests that specific populations, such as those with TG>500 mg/dL, could benefit from increased LCn3 intake. Increased LCn3 intake may also benefit other patient populations, such as those identified in the aforementioned reviews, in addition to other patient populations currently being investigated.
Additional studies are needed to identify appropriate patients for LCn3 supplements. Several ongoing randomized controlled trials may provide better evidence for the role of LCn3s in cardiovascular prevention. The Reduction of Cardiovascular Events With EPA – Intervention Trial (REDUCE IT) and Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) trials are long-term studies comparing CV morbidity and mortality for patients using statin medications plus high dose prescription LCn3 compared to a placebo group. The Study of Cardiovascular Events iN Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) are ongoing studies looking at supplement doses of LCn3 one gram per day for primary prevention of cardiovascular outcomes. Results of these trials may provide further guidance and recommendations with regards to LCn3 supplementation. Pharmacists should consider LCn3 supplements for patients with elevated triglycerides, however current evidence suggests they are not useful for everyone, and money may be better spent on healthy food consumption, including fatty fish.
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 DOI: 10.1002/14651858.CD003177.pub3
Balk EM, Adam GP, Langberg V, et al. Omega-3 fatty acids and cardiovascular disease: an updated systematic review. Rockville (MD): Agency for Healthcare Research and Quality; 2016. Evidence report/technology assessment no. 223. AHRQ Publication No.16-E002-EF. www.effectivehealthcare.ahrq.gov/reports/final.cfm. DOI: 10.23970/AHRQEPCERTA223
He Z, Yang L, Tian J, Yang K, Wu J, Yao Y. Efficacy and safety of omega-3 fatty acids for the prevention of atrial fibrillation: a meta-analysis. Can J Cardiol, 2013;29(2):196–203.
Zhao YT, Chen Q, Sun YX, et al. Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: a meta-analysis of randomized controlled trials. Ann Med 2009;41 (4):301–10.
Trikalinos TA, Moorthy D, Chung M, et al. Concordance of randomized and nonrandomized studies was unrelated to translational patterns of two nutrient-disease associations. J Clin Epidemiol 2012;65(1):16–29.