Fishing for Further Reductions in Residual Cardiovascular Risk

Volume 1, Issue 4

The saga of fish oils products, which are commonly comprised of various omega-3 fatty acid preparations, is a long and serpentine one which is both perpetually bolstered by optimism while simultaneously marred by setback. Omega-3 products have several proposed mechanisms to support cardiovascular health, including antioxidant and anti-inflammatory properties, and while many trials have proven these agents effective in reducing levels of serum triglycerides, only one has shown efficacy in reducing rates of major adverse cardiovascular events (MACE). The REDUCE-IT trial, published in November of 2018, showed that higher dose of purified eicosapentaenoic acid (EPA), icosapent ethyl, at 4g daily reduced the rates of MACE among a group of high-risk patients. In this week’s issue of Talking Therapeutics, we review two of the latest trials evaluating this still controversial topic, and attempt to get the bottom of this murky pond of conflicted evidence. 

Point 1: There Remains Only One

Unfortunately, both of the recently published trials came up short. The STRENGTH trial randomized 13,078 individuals to either 4g daily of omega-3 carboxylic acid (EPA plus DHA) or a corn oil placebo. Similar to REDUCE-IT, patients in this trial were high-risk, with elevated serum triglyceride levels despite maximally tolerated statin doses. Over a median follow-up period of approximately 3.4 years, there was no significant difference in rates of MACE between the treatment and placebo arms (12.0% vs 12.2%, P=0.84). Similarly, the OMEMI trial assessed the efficacy of 1.8g daily of n-3 PUFA (930mg EPA and 660mg DHA) compared with a corn oil placebo among older adults (mean age 75 years) after acute myocardial infarction. Of note, all participants in this study were from Norway, where baseline plasma EPA concentrations in the population are overall higher compared to those in North America. Within a follow-up period of 2 years, there was no significant difference between the omega-3 treatment group compared with the placebo control with respect to rates of MACE (21.4% vs. 20.0%; p=0.06).

Reasons for these discrepant findings are likely multifactorial. The REDUCE-IT trial used high doses of a pure EPA product, which is relevant as EPA has unique pleotropic properties compared to DHA. It’s therefore possible that the doses of EPA used in the two recent studies may simply have been too low. The REDUCE-IT trial also used mineral oil as the placebo agent, which is germane as mineral oil can potentially interfere with statin absorption and hence falsely inflate the perceived omega-3 benefit seen in that study. These considerations aside, the bottom line is that the high-dose EPA prescription product (ie icosapent ethyl) remains the only one with proven cardiovascular benefits, and that other mixed omega-3 products—despite being less expensive and generically available—should not be substituted.

Point 2: Fear the Fib 

Both of the recently published STRENGTH and OMEMI trials showed a signal for higher rates of atrial fibrillation, which was also noted in the REDUCE-IT trial. Importantly no increased incident of stroke was observed in these trials. While the rates of new-onset atrial fibrillation were low, this potential safety signal underscores the point that non-evidence-based omega-3 products (ie any product not named icosapent ethyl) should not be recommended at this time pending publication of additional data.

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