Icosapent ethyl decreases CVD risk after MI

Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction

Literature - Gaba P, Bhatt, DL, Steg PG, et al. - J Am Coll Cardiol. 2022 May 3;79(17):1660-1671. doi: 10.1016/j.jacc.2022.02.035

Introduction and methods


Despite the variety of treatment options to lower LDL-c and triglyceride levels, it has proven difficult to fully eliminate CVD risk. However, this is of great importance in patients with prior MI, who have an increased risk of recurrent ischemic events [1]. Recently, icosapent ethyl (IPE) has emerged as an additive agent to further reduce CVD risk. This ethyl ester of eicosapentaenoic acid (an omega-3 fatty acid) reduces plaque volume and mitigates inflammation, among others [2-8].

Aim of the study

The authors assessed the effect of IPE on ischemic events in statin-treated patients with prior MI and hypertriglyceridemia.



This was a post-hoc analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial), a multinational, double-blind, phase 3b RCT in which 8179 statin-treated patients with established CVD or diabetes mellitus plus other risk factors were randomized to IPE (2 g twice daily) or placebo [9]. Patients had to have controlled LDL-c levels and moderately elevated triglyceride levels at baseline. Of the 8179 patients in REDUCE-IT, 3693 (45%) had a history of MI, of whom 1870 had received IPE and 1823 placebo. Their median follow-up time was 4.8 years (IQR: 3.2–5.3).


The primary endpoint was defined as a composite outcome of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, and unstable angina requiring hospitalization. The key secondary endpoint was the composite of CV death, nonfatal MI, and nonfatal stroke. Additional prespecified, blindly adjudicated endpoints included some of the individual component of the primary endpoint, as well as sudden cardiac death and cardiac arrest.

Main results

Primary endpoint

  • In patients with prior MI, IPE treatment significantly reduced the incidence of the primary composite endpoint from 26.1% to 20.2% compared with placebo (hazard ratio (HR): 0.74; 95% CI: 0.65–0.85; P = 0.00001), equating to a relative risk reduction (RRR) of 26%.
  • The absolute risk reduction (ARR) in the primary endpoint was 5.9%.
  • History of coronary revascularization had no effect on the primary endpoint.

Key secondary endpoint

  • IPE also significantly reduced the incidence of the key secondary composite endpoint from 18.0% to 13.3% compared with placebo (HR: 0.71; 95% CI: 0.61–0.84; P = 0.00006), indicating an RRR of 29%.
  • The ARR in the key secondary endpoint was 4.7%.
  • Similar reductions in the key secondary endpoint were observed upon stratification by history of coronary revascularization.

Additional endpoints

  • Significant RRRs for IPE versus placebo were also seen in cardiac arrest (56%), sudden cardiac death (40%), total ischemic events (35%), fatal or nonfatal MI (34%) and CV death (30%). The RRR for all-cause mortality was 20%(P = 0.054).


  • The incidence of hospitalization for atrial fibrillation was significantly higher in IPE-treated patients than in the placebo group (3.6% vs. 2.2%; log-rank P = 0.01).
  • The bleeding rate was significantly higher in IPE-treated than in placebo-treated patients (10.6% vs. 8.7%; Fisher’s exactP = 0.05), but there was no significant difference in the frequency of serious bleeding (2.7% vs 2.2%; Fisher exact’s P = 0.46).


In statin-treated patients with prior MI and hypertriglyceridemia, IPE treatment resulted in substantial relative and absolute risk reductions in ischemic events, including CV death. There were small increased risks of atrial fibrillation and minor bleeding.


1. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–1357.

2. Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerideson statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020;41:3925–3932.

3. Budoff MJ, Muhlestein JB, Bhatt DL, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results. Cardiovasc Res. 2021;117:1070–1077.

4. Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2020;40:1135–1147.

5. Sherratt SCR, Juliano RA, Copland C, Bhatt DL, Libby P, Mason RP. EPA and DHA containing phospholipids have contrasting effects on membrane structure. J Lipid Res. 2021;62:100106.

6. Olshansky B, Bhatt DL, Chung MK. Omega-3 fatty acids effect on major cardiovascular events in patients at high cardiovascular risk. JAMA. 2021;325:1332–1333.

7. Sherratt SCR, Dawoud H, Bhatt DL, Malinski T, Mason RP. Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability. Prostaglandins Leukot Essent Fatty Acids. 2021;173:102337.

8. Kosmopoulos A, Bhatt DL, Meglis G, et al. A randomized trial of icosapent ethyl in ambulatory patients with COVID-19. iScience. 2021:103040.

9. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.

Find this article online at J Am Coll Cardiol.

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