The landmark Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT®) was a global outcomes study designed to assess the cardioprotective efficacy and safety of VASCEPA® (icosapent ethyl) as an add-on to statin therapy in reducing major cardiovascular (CV) events in a high-risk patient population.
Based on the groundbreaking results from REDUCE-IT, VASCEPA received U.S. Food and Drug Administration (FDA) approval as the first and only medication for reducing cardiovascular risk beyond cholesterol lowering therapy in high-risk adults on maximally tolerated statins with TG ≥150 mg/dL and established CVD or diabetes and ≥2 CVD risk factors.
This prospective, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed 8,179 patients who received either 4 grams daily of VASCEPA or placebo and were assessed for major CV events (CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina). Patients with an elevated CV risk, defined as patients with established CV disease or diabetes with at least one additional risk factor, were eligible to participate. During enrollment, all study participants exhibited elevated triglyceride (TG) levels (150-499 mg/dL), despite being on optimized statin therapy and under LDL-control (41-100 mg/dL).1
REDUCE-IT results were first presented as a late breaker at the 2018 Scientific Sessions of the American Heart Association (AHA) on November 10, 2018 in Chicago, Illinois2, coinciding with the original publication in The New England Journal of Medicine (NEJM).1 These and subsequent publications and presentations can be found HERE.
A key finding of the study showed that at a median of 4.9 years, patients receiving VASCEPA on top of statin therapy had a 25% relative risk reduction (RRR) and a 4.8% absolute risk reduction (ARR) of 5-point major adverse cardiovascular events (MACE) compared to the placebo group in the primary endpoint time to first event analysis.
When considering all events over the course of the trial (first and subsequent), patients treated with VASCEPA experienced 30% fewer total events relative to those taking placebo. For every 1,000 patients treated with VASCEPA for 5 years, approximately 159 total primary endpoint events could be prevented.3
VASCEPA was well tolerated and adverse events were generally similar to placebo. There were no significant differences in the overall rate of treatment emergent adverse events or serious adverse events leading to withdrawal of study drug in the VASCEPA treatment group versus the placebo group. There was a trend towards increased bleeding (2.7% with VASCEPA versus 2.1% with placebo), and an increase in hospitalizations for atrial fibrillation or flutter with VASCEPA (3.1% versus 2.1%).
In December 2019, the FDA approved a new indication and label expansion for VASCEPA based on the REDUCE-IT results. After more than a decade of development and testing, VASCEPA is now the first and only drug approved by the FDA as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated TG levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease. More information can be found in this press release.
Prespecified analyses have demonstrated results consistent with the primary analysis, including subgroup analyses of patients with diabetes and U.S. participants. As presented at the 80th Scientific Sessions of the American Diabetes Association, Type 2 diabetes affected 58% of participants in REDUCE-IT. This analysis showed that administration of 4 g/day of VASCEPA resulted in significant 23% reductions in both first and total primary composite MACE in people with diabetes. Reductions of 30% and 29% were observed in both first and total hard (3-point) MACE, the key secondary composite endpoint, respectively, and a significant 23% reduction in the primary composite endpoint was reported for patients receiving treatment with VASCEPA compared with placebo2. The leading cause of morbidity and mortality in type 2 diabetes mellitus continues to be cardiovascular disease, especially in those patients who already have established atherosclerotic cardiovascular disease (ASCVD).4 Above normal blood levels of triglycerides are common in patients with diabetes,5,6 and have been associated with increased ASCVD (30% and 23% higher risk for non-fatal myocardial infarction and non-fatal stroke, respectively) in this patient population, despite statin therapy.7 More information can be found here.
The study was not designed to be powered for subgroup analyses. While cardiovascular risk category (established cardiovascular disease or diabetes plus risks) were stratification factors, the presence of diabetes within the established cardiovascular disease cohort was not. These data include both pre-specified and post hoc analyses. The study was not designed for in-depth biomarker analyses. Glucose and HbA1c were infrequently collected, generally on an annual basis.
An additional prespecified and exploratory analysis showed that administration of 4 g/day of VASCEPA resulted in a significant 34% reduction in first coronary revascularizations versus placebo. The analyses from the REDUCE-IT study included several types of coronary revascularization events in statin-treated patients with persistent elevated triglycerides (135-499 mg/dL), who also had either cardiovascular disease or diabetes and additional cardiovascular risk factors. Prespecified tertiary endpoint analyses showed that times to first revascularization events were significantly reduced by VASCEPA versus placebo across subtypes of intervention, including urgent, emergent, and elective revascularizations, which were reduced by 34%, 38%, and 32%, respectively. In post hoc analyses, VASCEPA significantly reduced percutaneous coronary intervention (PCI) by 32% and coronary artery bypass grafting (CABG) by 39% relative to placebo. More information can be found here.
The cardiovascular benefit observed in REDUCE-IT appears to be highly correlated with the observed increase in serum EPA levels. An analysis demonstrated that on-treatment serum EPA levels from VASCEPA, administered at 4 g/day, strongly correlated with reductions in cardiovascular events in the REDUCE-IT study.9 More information can be found here.
The clinical program that predates, and supports, REDUCE-IT includes the exploration of VASCEPA lipid effects in patients with very high and elevated TGs (MARINE and ANCHOR). In brief, both Phase 3 biomarker studies met the primary endpoints of TG lowering. More information is shown below and the peer reviewed publications can be found here.
1 Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz C, Tardif J, Ballantyne CM. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.
2 Bhatt DL, Steg G, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz C, Tardif, JC, Ballantyne CM. The primary results of the REDUCE-IT trial [abstract 19515]. Circulation. 2018;138:e752-e753. https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000636
3 Bhatt DL, Steg PG, Miller M, et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol 2019;73(22):2791-2802. https://wwwsciencedirect.com/science/article/pii/S0735109719337969?via%3Dihub=
4 Arnold SV, Bhatt DL, Barsness GW, et al. Clinical Management of Stable Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus: A Scientific Statement From the American Heart Association. Circulation. 2020;141(19):e779‐e806. doi:10.1161/CIR.0000000000000766
5 Fan W, Philip S, Granowitz C, Toth PP, Wong ND. Residual Hypertriglyceridemia and Estimated Atherosclerotic Cardiovascular Disease Risk by Statin Use in U.S. Adults With Diabetes: National Health and Nutrition Examination Survey 2007-2014. Diabetes Care. 2019;42(12):2307‐2314.
6 Rana JS, Liu JY, Moffet HH, et al. Metabolic dyslipidemia and risk of coronary heart disease in 28,318 adults with diabetes mellitus and low-density lipoprotein cholesterol <100 mg/dl. Am J Cardiol. 2015;116:1700-1704.
7 Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab. 2019;21(2):366‐371.
8 Peterson BE, Bhatt DL, Steg PG, et al. Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses. Circulation. 2021;143(1):33-44.