The randomized clinical trial, which evaluated the outcomes of 13,078 statin-treated patients with high cardiovascular risk, high triglycerides, and low HDL cholesterol levels, was stopped early due to a lack of significance in the composite outcomes of major adverse cardiovascular events. The observational study was conducted across 675 centers in 22 countries. Considerable interest in the potential cardiovascular benefits of omega-3s has been garnered through a number of large-scale epidemiological studies, the most similar being REDUCE-IT which have found that omega-3s supplementation can have favorable effects on inflammatory, oxidative, thrombotic, vascular, and arrhythmogenic factors involved in cardiovascular disease, all of which have been leading reasons driving the use of omega-3 fatty acid supplements.
The American Heart Association reports that this clinical trial will be the subject of debates over its recommendations on fish oil supplementation, following an advisory from AHA in 2017 which noted that fish oil supplements prescribed by a healthcare professional may help prevent cardiovascular mortality in patients who’ve recently had a heart attack, and may prevent death and hospitalizations in patients with heart failure, despite a lack of scientific research supporting the clinical use of these supplements by AHA’s specifications.
“Many people continue to take fish oil supplements to prevent heart disease. However, the fish oil medication we tested in the STRENGTH trial was not effective for that purpose,” lead author A. Michael Lincoff, MD, vice chairman for Research of the Department of Cardiovascular Medicine and interventional cardiologist in the Heart, Vascular, and Thoracic Institute at the Cleveland Clinic, said. “We believe the 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.”
In REDUCE-IT, 8,179 patients with elevated triglycerides were administered either 4 grams of EPA daily, or a mineral oil placebo for a median duration of 4.9 years. The authors of STRENGTH believe that the mineral oil may have exaggerated the benefits seen among those who were administered EPA, due to the fact that there was a greater than 30% increase in C-reactive protein levels in the placebo group.
“A possible explanation for the different outcomes relates to the comparators used,” the authors concluded. “The decision was made with the design of this trial to administer corn oil because it was considered to be a neutral comparator with the least effects on a range of biochemical parameters associated with cardiovascular risk. In contrast, the cardiovascular effects of icosapent [the highly-purified EPA used in REDUCE-IT and STRENGTH] were compared with mineral oil, with adverse effects, compared with baseline, on alipoprotein B, LDL cholesterol, and hs-CRP levels. These effects were not observed with the corn oil group in this trial, highlighting differences between the comparator used in the studies […] However, the FDA subsequently awarded a label claim for cardiovascular event reduction for icosapent ethyl based on analyses that concluded that the effects of mineral oil could not entirely explain the observed differences in outcome.”
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.