Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial - REDUCE-IT

Contribution To Literature:

The REDUCE-IT trial showed that use of icosapent ethyl 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CV disease or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels.


The goal of the trial was to assess the safety and benefit of icosapent ethyl compared with placebo in reducing cardiovascular (CV) events among patients with high triglycerides (TGs).

Study Design

Eligible patients were randomized in a 1:1 fashion to either icosapent ethyl (2 g twice daily with food) (n = 4,089) or matching placebo (n = 4,090). Randomization was stratified by primary vs. secondary prevention, use of ezetimibe, and geographic region.

  • Total number of enrollees: 19,212
  • Duration of follow-up: 4.9 years
  • Mean patient age: 64.0 years
  • Percentage female: 28%

Inclusion criteria:

  • Age >45 years with established CV disease or age >50 years with diabetes and ≥1 additional risk factor
  • Fasting TG level from 150-499 mg/dl 
  • Low-density lipoprotein (LDL) cholesterol level from 41 and 100 mg/dl
  • Stable dose of statin for ≥4 weeks

Exclusion criteria:

  • Severe heart failure
  • Active severe liver disease
  • Glycated hemoglobin level >10.0%
  • Planned coronary intervention or surgery
  • History of acute or chronic pancreatitis
  • Known hypersensitivity to fish, shellfish, or ingredients of icosapent ethyl or placebo

Other salient features/characteristics:

  • Secondary prevention cohort: 70.7%
  • Ezetimibe use: 6.4%
  • Moderate- or high-intensity statin: 94%
  • Diabetes: 59%
  • Median TG levels at baseline: 216 mg/dl, LDL: 75 mg/dl, high-density lipoprotein: 40 mg/dl, high-sensitivity C-reactive protein: 2.2

Principal Findings:

The primary CV outcome of CV death, nonfatal myocardial infarction (MI), stroke, coronary revascularization, or unstable angina, for icosapent ethyl vs. placebo, was 17.2% vs. 22.0% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.68-0.83; p < 0.0001).

Secondary outcomes, for icosapent ethyl vs. placebo:

  • Change in TG levels at 1 year: -39.0 mg/dl vs. 4.5 mg/dl
  • Change in LDL at 1 year: 2 mg/dl vs. 7 mg/dl
  • CV death or MI: 9.6% vs.12.4%, p < 0.001
  • All MI: 6.1% vs. 8.7%, p < 0.001
  • Revascularization: 5.3% vs. 7.8%, p < 0.001
  • All-cause mortality: 6.7% vs. 7.6%, p = not significant
  • Atrial fibrillation/flutter: 5.3% vs. 3.9%
  • Serious adverse bleeding events: 2.7% vs. 2.1%, p = 0.06

Total and recurrent event analysis: 55.2% were first primary events. Total (first and subsequent) primary endpoint event rates were reduced to 61 from 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively (rate ratio [RR] 0.70, 95% CI 0.62-0.78, p < 0.0001). The first occurrence of a primary composite endpoint was reduced with icosapent ethyl versus placebo (HR 0.75, 95% CI 0.68-0.83, p < 0.0001) as was the second occurrence (HR 0.68, 95% CI 0.60-0.78, p < 0.0001). Similar effects were noted for key secondary endpoints.


The results of this trial indicate that the use of icosapent ethyl 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CV disease or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels. Rates of revascularization and MI were lower, while atrial fibrillation/flutter and bleeding were higher with icosapent ethyl.

These are very interesting findings, and come on the heels of several negative trials with n–3 fatty acid supplementation. One aspect of this medication is that it has a higher dose of purified eicosapentaenoic acid (EPA) (4 g/day) than what was tested in other clinical trials. Other trials with moderate to high doses of EPA are ongoing. This is one of the first non-LDL targeted trials to show a CV benefit, and will likely be featured in future guidelines.


Bhatt DL, Steg G, Miller M, et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol 2019;73:2791-802.

Editorial Comment: Granger CB, Nelson AJ, Pagidipati NJ. Risk of Total Events With Icosapent Ethyl: Can We Reduce It? J Am Coll Cardiol 2019;73:2803-5.

Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.

Bhatt DL, Steg G, Miller M, et al., on behalf of the REDUCE-IT Investigators. Cardiovascular Risk Reduction With Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.

Editorial: Kastelein JJ, Stroes ES. FISHing for the Miracle of Eicosapentaenoic Acid. N Engl J Med 2019;380:89-90.

Presented by Dr. Deepak Bhatt at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: ACC Annual Scientific Session, ACC19, AHA Annual Scientific Sessions, AHA18, Angina, Unstable, Atrial Fibrillation, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Eicosapentaenoic Acid, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Primary Prevention, Secondary Prevention, Stroke, Triglycerides

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