Abstract
It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%). Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.
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Key Points
This study assessed whether adding a carboxylic acid formulation of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) to background therapy improve cardiovascular outcomes i n statin-treated patients with high cardiovascular risk, high triglycerides, and low HDL cholesterol levels. In this randomized clinical trial of 13 078 patients that was stopped early, daily supplementation with omega-3 fatty acids, compared with corn oil, resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in patients with high cardiovascular risk.
This was a large-scale clinical trial called STRENGTH (Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High CV Risk Patients with Hypertriglyceridemia aimed to assess major adverse cardiovascular events associated with daily administration of 4 mg of an omega-3 EPA/DHA formulation compared to participants who received a matching corn oil placebo. The observational study was conducted across 675 centers in 22 countries. Many people continue to take fish oil supplements to prevent heart disease. However, the fish oil medication tested in the STRENGTH trial was not effective for that purpose. Questions surrounding the benefit versus risk of fish oil will remain unanswered unless another trial using a neutral placebo such as corn oil is able to definitively show cardiovascular benefits for an omega-3 fatty acid medication. The authors said that it remains uncertain whether cardiovascular benefits would be achieved in a lower-risk population, rather than the level of risk experienced by the participants in the study who were at high risk of future cardiovascular events and were required to have a background in statin therapy in order to enroll.