July 15, 2018, Dr Chee L Khoo
I must declare my personal interest in this discussion. I have been taking omega-3 fish oil supplements for years to reduce my triglycerides. I am also on a statin for my hypercholesterolaemia and the fish oil is to treat the residual hypertriglyceridaemia. A recent study confirm the efficacy of this approach1. However, does the addition of fish oil and reduction of triglycerides translate to improvement in cardiovascular (CV) outcomes? What does the evidence say?
Observations of lower rates of coronary heart disease (CHD) in populations who consumed large amount of foods rich in omega 3 oils led to suggestions that perhaps, consumption of fish or omega 3 fatty acid supplements may be protective of heart disease.
Indeed, the initial DIET and Reinfarction Trial-1 which examined men who have had myocardial infarction, found that fish consumption was associated with a significant reduction in fatal CHD and all-cause mortality but had no association with nonfatal myocardial infarction (MI) recurrence2. The Gruppo Italiano per lo Studio della Soprav vivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial, an open-label trial involving 11 323 recent survivors of MI, reported that patients who received supplementation with omega-3 FAs experienced a 10% reduced risk of major cardiovascular events compared with untreated controls3.
The Japan EPA Lipid Intervention Study (JELIS) trial, an open-label trial involving 18 645 participants (20% with prior CHD) reported that supplementation with fish oil was associated with a 19% reduction in major CHD events.
This is great. However, 8 other large scale trials did not find any benefit though! In fact, DIET and Reinfarction Trial-2 found that consumption of fish or fish oil supplements in men with angina actually increased the risk of CHD death5. Now, is the discrepancy of results due to difference in omega 3 sources, different outcomes between primary vs secondary prevention or increasing use of statins these days which dilute improvement in outcomes in patients with CV risks? Previous meta-analysis of the trials suggests a significant beneficial association of omega-3 fatty acids (FA) with fatal CHD but not non-fatal CHD. All too confusing when our patients ask about whether they should be on fish oils, isn’t it?
The Omega-3 Treatment Trialists’ Collaboration is a meta-analysis based on aggregated study-level data obtained from the principal investigators of all large randomised clinical trials of omega-3 FA supplements for the prevention of cardiovascular disease6. They assessed the associations of supplementation with omega-3 FAs on (1) fatal CHD, nonfatal MI, stroke, major vascular events, and all-cause mortality and (2) major vascular events in prespecified subgroups. The pre-specified eligibility criteria were randomised clinical trials of marine derived very-long-chain omega-3 FA supplements vs placebo or open-label control, with a sample size of at least 500 participants and a scheduled duration of treatment of at least 1 year. All eligible trials required use of supplements, but no minimum daily dose of eicosapentaenoic acid (EPA) or docosahexanoic acid (DHA) was specified.
A total of 77 917 participants were involved, and trials ranged in size from 563 to 18645 participants. Of the 10 trials, 8 had a double-blind design and used a placebo control, and 2 trials had an open-label design.
What did they find?
Omega3 supplementation had no significant association with any CHD events including CHD deaths, non-fatal MI, major vascular events, strokes or re-vascularisation events.
What about subgroups of patients?
Even after adjusting for by sex, history ofCHD, history of diabetes, pretreatment levels of total cholesterol, high-density lipoprotein cholesterol levels, low-density lipoprotein cholesterol levels, triglyceride levels, or prior use of statin therapy, there were still no significant association with any major vascular events. There were some association after adjusting for age (p= 0.02) and by history of stroke (p= 0.06).
This study once again add to the conflicting results thus on whether omega 3 supplement have a protective effect against cardiovascular disease. 2016 European Society of Cardiology and European Atherosclerosis Society guidelines for prevention of cardiovascular disease indicated that it is debatable whether omega-3FAs may exert a protective effect, and the 2016 guidelines on the management of dyslipidaemia indicated that more evidence on the efficacy of omega-3 FA supplements for prevention of clinical outcomes is needed to justify their prescription.
In contrast, the American Heart Association recommended that the use of omega-3 FAs for prevention ofCHDis probably justified in individuals with prior CHD and those with heart failure and reduced ejection fractions.
We await several large trials to complete – ASCEND (late 2018), VITAL (late 2018), STRENGTH (mid 2018) and REDUCE-IT (July 2018). Watch this space.
Access the abstract here
Reference:
- Chee Hae Kim et al. Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial. Clinical Therapeutics/Volume 40, Number 1, 2018
- Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2(8666):757-761.
- GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Soprav vivenza nell’Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E After myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177): 447-455.
- Yokoyama M, Origasa H, Matsuzaki M, et al; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567): 1090-1098.
- Burr ML, Ashfield-Watt PA, Dunstan FD, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr. 2003;57(2):193-200.
- Theingi Aung, Jim Halsey, Daan Kromhout et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. 2018;3(3):225-234.