Daily omega-3 carboxylic acid does not reduce MACE in high-risk individuals

A daily dose of omega-3 carboxylic acid does not appear to reduce the incidence of major adverse cardiovascular events (MACE)*, according to the STRENGTH** trial presented at AHA 2020.

This multinational (22 countries) study included 13,078 adults (mean age 62.5 years, 35 percent female) on statin treatment who had or were at high risk for cardiovascular disease (CVD) due to low HDL-cholesterol (<42 and <47 mg/dL in men and women, respectively; median 36 mg/dL) and elevated hypertriglyceridaemia (180–500 mg/dL; median 240 mg/dL). They were randomized 1:1 to receive omega-3 carboxylic acid (containing eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 4 g/day) or corn oil (placebo) plus background therapy for ≤5 years.

Fifty-six percent of participants had established atherosclerotic disease, 70 percent had diabetes mellitus, and 50 percent were on high-intensity statins. Patients were followed up for a median 42 months and received the study drug for a median 38.2 months. 

Between baseline and follow-up, patients who received omega-3 carboxylic acid experienced a median 19 percent reduction in triglyceride levels (vs 0.9 percent reduction with corn oil) and a 20 percent reduction in high-sensitivity C-reactive protein (hsCRP) levels (vs -6.3 percent vs corn oil; p<0.001 for both). Omega-3 carboxylic acid recipients also had a median 268.8 percent increase in plasma EPA levels (vs a 10.5 percent reduction with corn oil), and a median 298.6 percent increase in red blood cell EPA levels (vs 8.7 percent reduction with corn oil; p<0.001 for both). [AHA 2020, abstract LBS4; JAMA 2020;doi:10.1001/jama.2020.22258]

The primary outcome of MACE did not significantly differ between patients who received omega-3 carboxylic acid and corn oil (12.0 percent vs 12.2 percent; hazard ratio [HR], 0.99, 95 percent confidence interval [CI], 0.90–1.09; p=0.84).

The findings were consistent regardless if patients had established CVD (secondary prevention) or were a primary prevention group (HRs, 0.94 and 1.16, respectively; nominal p_interaction=0.07).

The incidence of new-onset atrial fibrillation (AF) was higher in the omega-3 carboxylic acid compared with the corn oil group (2.2 percent vs 1.3 percent; HR, 1.69, 95 percent CI, 1.29–2.21; nominal p<0.001). New-onset heart failure or venous thromboembolism rates did not significantly differ between groups.

Drug-related adverse events (AEs) occurred more often in the omega-3 carboxylic acid than corn oil group (22.2 percent vs 12.9 percent), with AEs leading to drug discontinuation in 10.8 and 8.0 percent, respectively. Gastrointestinal disorders were more common in the omega-3 carboxylic acid than corn oil group (24.7 percent vs 14.7 percent), including nausea (3.2 percent vs 1.7 percent) and diarrhoea (11.9 percent vs 4.9 percent). Bleeding events (4.9 percent in both groups) and new-onset diabetes mellitus rates (14.8 percent vs 14.2 percent) were comparable between groups.

The trial was prematurely ceased due to lack of apparent benefit of omega-3 carboxylic acid vs corn oil.

Findings remain inconclusive 

“These findings do not support use of this omega-3 fatty acid formulation to reduce MACE in high-risk patients,” said the researchers.

“These findings, in the context of the increased risk of AF seen in this and other omega-3 trials, cast uncertainty regarding whether there is net benefit or harm with any omega-3 fatty acid preparation,” pointed out Professor A. Michael Lincoff from the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings on behalf of the investigators at AHA 2020. He noted the lack of benefit despite a 269 percent increase in plasma EPA levels.

The increased AF incidence, which also occurred in icosapent ethyl recipients in the REDUCE-IT*** trial, warrants additional research, he added. Furthermore, whether omega-3 carboxylic acid would exert benefits in a lower risk population remains to be seen.

The lack of increase in LDL-cholesterol, apolipoprotein B, or hsCRP levels in the corn oil group (median change -1.1, -1.0, and -6.3 percent, respectively) as opposed to the 10.2, 7.8, and 32 percent respective increases noted with mineral oil in the REDUCE-IT trial, hints at the neutrality of corn oil as a comparator, he continued.

“Adding STRENGTH to the list of null trials with a mixed omega-3 fatty acid is a reminder that the widespread use of over-the-counter mixed omega-3 products lacks evidence for clinical utility,” contributed Professor Roger Blumenthal and colleagues from the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, US. [JAMA 2020;doi:10.1001/jama.2020.22387]

As for the reasons for the discordant findings between the STRENGTH and REDUCE-IT trials, several mechanisms could be at play. These include differences in study drug formulations, differences between EPA and DHA, and choice of placebo, they said.