Results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial) USA

by | Jan 18, 2021 | 2020, Blood Lipids, Cardiovascular Health, EPA (Eicosapentaenoic Acid)

Written by Joyce Smith, BS. Icosapent ethyl, a highly stable and purified formulation of EPA significantly reduced cardiovascular events and triglyceride levels in elderly patients with cardiovascular risk factors who were on statin therapy.

cardiovascularSome international trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial) is a multicenter, randomized double-blind placebo-controlled trial involving 8,179 patients at 473 sited in eleven countries. The participants, all on statin therapy and with a history of cardiovascular disease, diabetes or other risk factors, were randomized to receive 2 grams twice per day of icosapent ethyl (a highly purified ethyl ester of eicosapentaenoic acid [EPA]) or a mineral oil placebo. Primary end point included cardiovascular (CV) death, nonfatal myocardial infarct (MI) or stroke, coronary revascularization or unstable angina. Secondary endpoint was CV death, and non-fatal MI or stroke.

The study, consisting of three separate analysis, found a consistent reduction in the primary and secondary efficacy endpoints in patients from both within and outside the US. In 2019, Bhatt and colleagues found that EPA significantly reduced cardiovascular events by 25% (HR, 0.75, 95% CI, 0.68–0.83; P=.00000001) and triglycerides in patients with modestly elevated triglycerides (135–499 mg/dL) and elevated cardiovascular risk. That analysis was published in The New England Journal of Medicine 1. A subsequent analysis, published in the Journal of the American College of Cardiology, revealed that total ischemic events (first events plus recurrent events) were reduced by 30% (P=.00000000036) 2. The following (and final) REDUCE-IT was a subgroup analysis 3 done specifically to determine the degree of benefit of ecosapent ethyl to United States participants.

The 3,146 US patients (38.5% of the total trial) consisted of 32.3% female participants, 9.7% Hispanic. After a 4.9 mean year follow up, the primary endpoint was reached in 24.7% of the mineral oil placebo group vs 18.2% of the ecosapent ethyl group (P=0.000001). Those in the ecosapent ethyl group who had modestly elevated triglycerides (135–499 mg/dL) and elevated cardiovascular risk had a 31% significant reduction in the number of cardiovascular events (HR, 0.75, 95% CI, 0.68–0.83; P=.00000001) compared to the placebo group. The secondary composite end point was reached in 16.6% (placebo group) versus 12.1% of ecosapent ethyl group (P=0.00008) with the ecosapent ethyl group reaching significant reductions in cardiovascular death (P=0.007), myocardial infarct (p=0.01), stroke (P=0.02) and all-cause mortality P=0.004. Compared to the other participating countries, the all-cause mortality reduction in the US was Pintereaction=0.02. The main secondary endpoint results were at least as strong in the US as outside the US, perhaps because US patients had more risk factors such as obesity and lower baseline levels of EPA than participants from the other countries. In all three analysis, the REDUCE-IT participants (both inside and outside the US) experienced an increase in atrial fibrillation or flutter, which was also seen in the STRENGTH and OMEMI trials that used DHA/EPA combinations. Tolerability and safety were similar for both US and full study participants.

According to available metabolic data, ecosapent ethyl supplementation does not raise LDL cholesterol levels while DHA -based formulas do; thus, treatment cannot be generalized to other n-fatty acid formulas, particularly dietary supplements that contain a variety of unregulated n-3 fatty acid mixtures. Researchers believe the achieved cardiovascular benefits of pure EPA were independent of the decrease in triglyceride levels 4 and may be due to a potential membrane stabilizing effect or even a stabilization or regression of coronary plaques 5,6. A C-reactive protein (CRP) level may also contribute to the benefit. In addition, the highly purified and stable EPA (ecosapent ethyl) used in REDUCE-IT was considerably higher than the EPA (used in combination with DHA) in the Strength and OMEMI studies. A future study duplicating ecosapent ethyl’s effects is warranted.

Source: Bhatt, Deepak L., Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Ph Gabriel Steg, Steven B. Ketchum, Ralph T. Doyle Jr et al. “REDUCE-IT USA: results from the 3146 patients randomized in the United States.” Circulation 141, no. 5 (2020): 367-375.

© 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License.

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Posted January 18, 2021.

Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from  the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.

References:

  1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine. 2019;380(1):11-22.
  2. 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.
  3. Bhatt DL, Miller M, Brinton EA, et al. REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States. Circulation. 2020;141(5):367-375.
  4. Tobbia P, Brodie BR, Stuckey T, et al. Are adverse events following an invasive strategy in patients with non-ST-segment elevation acute coronary syndromes more frequent at US sites versus non-US sites? Analysis from the ACUITY trial. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2013;82(4):E365-374.
  5. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine. 2009;361(11):1045-1057.
  6. Metra M, Mentz RJ, Hernandez AF, et al. Geographic Differences in Patients in a Global Acute Heart Failure Clinical Trial (from the ASCEND-HF Trial). Am J Cardiol. 2016;117(11):1771-1778.

Primary end point occurred in 17.2% of EPA group compared to 22% in the placebo group. The EPA group had significantly more atrial fibrillation or flutter compared to the placebo group (3.1% vs 2%; P=0.004).