The REDUCE-IT verdict on eicosapentaenoic acid and cardiovascular outcome challenged with STRENGTH

• STRENGTH,1 an industry-sponsored, double-blind, randomized, controlled trial investigated the effects of a carboxylic acid (CA) formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (omega-3 CA) vs. corn oil in 13 078 participants with high cardiovascular (CV) risk, hypertriglyceridaemia, and low levels of high-density lipoprotein cholesterol. • Eligible patients were randomized to receive 4 g/day of omega-3 CA or corn oil in addition to standard preventive therapies, including statins (high-intensity in 50%), renin-angiotensin-aldosterone system (RAAS) blockers (in 81%), and antiplatelet agents (in 71%). • The primary efficacy outcome was a composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The trial required adjudication of 1600 primary events to provide 90% power to detect a 15% relative risk reduction in the omega-3 CA group. • After a median follow-up of 42 months, omega-3 CA did not reduce the incidence of the primary endpoint compared to corn oil [hazard ratio 0.99, 95% confidence interval (CI) 0.90–1.09; P ¼ 0.84]. Similarly, there were no significant differences between the treatment groups with regard to the risk of individual components of the primary endpoint nor in a number of secondary endpoints. • The incidence of drug-related gastrointestinal adverse events was greater among patients treated with omega-3 CA than with corn oil (24.7% vs. 14.7%). A higher rate of investigator-reported new-onset atrial fibrillation was observed with the use of omega-3 CA than corn-oil (2.2% vs. 1.3%; nominal P < 0.001)

The observation of lower rates of cardiovascular disease (CVD) in populations that consumed large amount of foods rich in very-longchain polyunsaturated fatty acids (FA) containing omega-3 FA triggered interest in assessing whether supplementation of omega-3 FA may be cardioprotective. During the past 20 years, at least 14 RCTs in over 132 000 participants, mostly at high CV risk, have assessed the efficacy and safety of long-term omega-3 FA supplementation for CV prevention