Association Between Achieved Omega-3 Fatty Acid Levels And Major Adverse Cardiovascular Outcomes In Patients With High Cardiovascular Risk A Secondary Analysis Of The Strength Trial

IMPORTANCE In patients treated with omega-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes.OBJECTIVE To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of omega-3 fatty acids compared with corn oil placebo.DESIGN, SETTING, AND PARTICIPANTS A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020).INTERVENTIONS Participants were randomized to receive 4 g daily of omega-3 carboxylic acid (CA) or an inert comparator, corn oil.MAIN OUTCOMES AND MEASURES The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the omega-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization.RESULTS Of the 13 078 total participants, 6539 (50%) were randomized to receive omega-3 CA and 6539 (50%) randomized to corn oil. omega-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 omega-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in omega-3 CA patients were 89 mu g/mL (interquartile range [IQR], 46-131 mu g/mL) for EPA and 91 mu g/mL (IQR, 71-114 mu g/mL) for DHA with top tertile levels of 151 mu g/mL (IQR, 132-181 mu g/mL) and 118 mu g/mL (IQR, 102-143 mu g/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results.CONCLUSIONS AND RELEVANCE Among patients treated with omega-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.