Topline Results from REDUCE-IT Show a Significant Reduction in Cardiovascular Outcomes with Omega-3 Fatty Acid
By Kevin C Maki, PhD and Mary R Dicklin, PhD
Exciting topline results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT) were recently announced by Amarin, the maker of Vascepa®.1 The full results are scheduled to be presented on November 10, 2018 at the American Heart Association’s (AHA) Scientific Sessions in Chicago, IL. REDUCE-IT was a randomized, controlled trial that examined the effects of 4 g/d Vascepa vs. placebo on cardiovascular outcomes in statin-treated adults at elevated cardiovascular risk.2 Topline results indicated an ~25% relative risk reduction (p < 0.001) in the primary composite endpoint of the first occurrence of a major adverse cardiovascular event, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization, after a median follow-up of 4.9 y.1
These results will take some by surprise, based on the abundance of unfavorable interpretations of the effects of omega-3 fatty acids on cardiovascular outcomes from other recently published trials and meta-analyses.3,4 However, as my colleagues and I previously speculated,5 a failure to show benefit in some of those other studies has likely been due, at least in part, to study design issues, including administration of low dosages and absence of a clear pathophysiologic target for the intervention. Unlike previous studies, many of which gave 1 g/d Omacor®/Lovaza®, containing ~850 mg EPA + docosahexaenoic acid (DHA),6 in REDUCE-IT subjects received a high dosage of 4 g/d Vascepa (roughly 3,700 mg of EPA).2 Subjects in REDUCE-IT were also required to have elevated baseline triglycerides (TG) of ≥150 mg/dL and <500 mg/dL (lower limit later changed to ≥200 mg/dL), resulting in a median baseline TG level of 216 mg/dL. Results from our meta-analysis suggested that medications which substantially lower TG reduce cardiovascular risk in those with elevated TG, especially if accompanied by low high-density-lipoprotein cholesterol.7 Thus, REDUCE-IT directly addressed the issue of TG-lowering as a target of therapy.
Our separate meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acids on cardiac death showed an 8% lower risk with omega-3 supplementation vs. controls, although the effect was much larger (29%) in studies where the dosage employed was >1 g/d of EPA + DHA.8 It is uncertain whether REDUCE-IT will have enough cardiac deaths to show a benefit for that outcome, although it should add a substantial number of events to the aggregate database of studies using higher dosages.
Results from another large-scale clinical trial of omega-3 fatty acids, the Vitamin D and Omega-3 Trial (VITAL), are also scheduled to be presented at AHA. In VITAL, subjects received 1 g/d of Omacor/Lovaza and were not required to have elevated TG levels at baseline.9 The results from VITAL and another recently reported trial (A Study of Cardiovascular Events in Diabetes; ASCEND)4 will facilitate a more complete assessment of the effects of low-dosage EPA + DHA on the risk of cardiac death, which has important public health implications.
The Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) is another high-dosage study (4 g/d) of the carboxylic acids (free fatty acids) form of EPA + DHA, and the last of the large-scale omega-3 trials underway. Subjects in STRENGTH were required to not only have elevated TG (≥180 mg/dL and <500 mg/dL), but also to have low levels of high-density lipoprotein cholesterol (<47 mg/dL for women and <42 mg/dL for men).10 STRENGTH is scheduled to complete in the fall of 2019.
- Amarin Corporation. REDUCE-IT™ cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at https://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent.
- Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-148.
- Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.
- ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.
- Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).
- Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.
- Maki JC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.
- Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.
- Manson JE, Bassuk SS, Lee IM, et al. The Vitamin D and Omega-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin trials. 2012;33:159-171.
- Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018; Epub ahead of print.