The Effects of Icosapent Ethyl on Total Ischemic Events: An Analysis from REDUCE-IT

By Aly Becraft, MS and Kevin C Maki, PhD


Statin therapy is highly effective for lowering low-density lipoprotein cholesterol (LDL-C), but many patients remain at risk for ischemic events, despite statin therapy.1 Elevated levels of triglycerides (TG) and TG-rich lipoproteins are independent risk factors for cardiovascular events and may play a casual role in the development of cardiovascular disease.2


Icosapent ethyl (VascepaÒ) is a highly purified derivative of EPA that is currently approved by the Food and Drug Administration for use as an adjunctive therapy in the treatment of hypertriglyceridemia in patients with TG levels ≥500 mg/dL.3 It has been shown to lower TG levels without raising LDL-C4,5 and may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties.6-9


Earlier this year, Bhatt et al. published results from the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) indicating that icosapent ethyl reduced risk for the first occurrence of the primary endpoint (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or hospitalization for unstable angina) by 25% in patients with elevated TG levels (≥500 mg/dL) receiving statin therapy during a median follow-up of 4.9 y.3 In this randomized, double-blind, placebo-controlled trial, a total of 8,179 statin-treated patients were given 4 g/day icosapent ethyl or a mineral oil-based placebo with meals. At baseline, patients had a median TG level of 216 mg/dL and a median LDL-C of 75 mg/dL. Seventy-nine percent of patients had history of atherosclerosis and 29% had a history of diabetes.


Recently, the REDUCE-IT investigators sought to determine the effect of icosapent ethyl on total ischemic events in the trial.10 For this analysis, the primary outcome was the total of first plus subsequent ischemic events (defined the same as for the primary outcome in the main analysis).  There were 1,606 first primary endpoint events and 1,303 additional primary endpoint events (727 second events, 272 third events, and 269 fourth or more events). Total ischemic event rate for the primary outcome was reduced by 30% with icosapent ethyl compared to placebo (rate ratio [RR] 0.70, 95% confidence interval [CI] 0.62-0.78, P < 0.0001). First events were reduced by 25%, second events by 32%, third events by 31%, and fourth or more events by 48%. The key secondary endpoint, defined for this analysis as hard major adverse cardiac outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke), was also significantly reduced with icosapent ethyl compared to placebo (RR 0.72, 95% CI 0.63-0.82, P < 0.0001). Several statistical models were used, and each demonstrated consistent effects of icosapent ethyl for reducing total ischemic events.


Comment: The results from this analysis demonstrate the benefit of icosapent ethyl as a therapy for the reduction of first and subsequent ischemic events in statin-treated patients. The present analysis of REDUCE-IT included patients from 11 different countries, yielding more conclusive outcomes for cardiovascular benefit than for interventions conducted in single countries.11-13


The efficacy of icosapent ethyl was numerically larger for second and higher events, which illustrates two important points.  First, those who have had a recent cardiovascular event are at high risk for subsequent events.  Second, the traditional analysis method of focusing only on first events markedly underestimates the impact of cardiovascular disease and often the benefit of the therapy under study.  Related to the second point, cost effectiveness analyses generally only consider first event reduction and may therefore underestimate cost effectiveness. 


Future analyses of biomarkers collected from REDUCE-IT patients may provide further insight into the mechanisms of action of icosapent ethyl and help to better explain the mechanisms responsible for the effects and identify additional potential clinical applications for this new therapy.



  1. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
  2. Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-63.
  3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
  4. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-90.
  5. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92.
  6. Bays HE, Ballantyne CM, Braeckman RA, et al. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13:37-46.
  7. Nelson JR, Wani O, May HT, Budoff M. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol. 2017;91:1-9.
  8. Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858:3131-40.
  9. Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipids. 2018;212:73-9.
  10. Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019; Epub ahead of print.
  11. Yokoyama M, Origasa H, Matsuzaki M, et al.; JELIS Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction appears in Lancet. 2007;370:220]. Lancet. 2007;369:1090-8.
  12. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico [published corrections appear in Lancet. 2001;357:642 and 2007;369:106]. Lancet. 1999;354:447-55.
  13. Tavazzi L, Maggioni AP, Marchioli R, et al.; GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223-30.





Photo by Kendal James

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