Reference: JAMA. 2020 Nov 15
Replicating naturally occurring omega-3 fatty acids to mirror the dietary benefits for cardiovascular health suffers from the same problem as many other attempts to copy nature - things don’t always turn out as you might expect. The REDUCE-IT trial published in 2019 suggested that supplementing statins with a proprietary form of eicosapentaenoic acid (EPA) might help secondary prevention of cardiovascular events. Researchers recently conducted a nearly identically designed trial (STRENGTH) for Astra-Zeneca’s carboxylic acid formulation, called omega-3 CA, which combines EPA and docosahexaenoic acid (DHA).
Researchers looked at major adverse cardiovascular events (MACE) in a multi-site group of 13,078 patients already taking statins, about half of them at high risk of a primary event (due to age, family history, smoking, diabetes, elevated high-sensitivity C-reactive protein [hsCRP], or hypertension) and the other half needing secondary prevention after a primary event. Upon randomization, half the group received omega-3 CA and the other half were given corn oil tablets as a comparator. Groups were followed for several years with contact every three months, but the trial was stopped prematurely for futility because the drug didn’t seem to be working. The study was adequately powered to detect a 15% difference between groups, and 1580 of a planned 1600 events were recorded.
There were no significant differences between groups in MACE, including cardiovascular death, myocardial infarction, stroke, and admission for unstable angina (hazard ratio [HR] 0.99, 95% CI 0.9-1.09), with similar results in subgroup analyses of primary and secondary events. One tertiary outcome stood out, however—the rate of new-onset atrial fibrillation in omega-3 CA patients versus corn oil: 2.2% vs. 1.3% (HR 1.69, 95% CI 1.29-2.21).
This attempt to replicate the benefits of secondary prevention with fish oil found in the REDUCE-IT trial not only didn’t pan out but may have harmed patients by inducing atrial fibrillation (increased incidence of atrial fibrillation was also seen in the REDUCE-IT trial). One criticism of both the STRENGTH and REDUCE-IT trials is the use of corn oil and mineral oil, respectively, as comparators because of possible uncharacterized effects of these oils. Omega-3 CA tablets were associated in this trial with significant reductions in triglycerides, non-HDL cholesterol levels, and hs-CRP, so hypothetically, supplementation should have reduced events in real life. The question remains whether people who consumed an equivalent amount of omega-3 CA in their diet rather than in a pill would have had clinical benefit, as is seen with dietary calcium vs. supplementation. Or perhaps the benefit of statins for secondary prevention is so great that an added benefit from omega-3 CA is too small to realistically measure. As annoying as this must be to the folks at Astra-Zeneca, this study suggests that the addition of omega-3 CA to a statin does no good and has a risk of harm.
For more information, see the topic Omega-3 Fatty Acids and Fish Oil in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.