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

Contribution To Literature:

Highlighted text has been updated as of August 26, 2022.

The REDUCE-IT trial showed that use of IPE 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CVD 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 (IPE) 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 IPE (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 screened: 19,212
  • Total randomized: 8,179
  • 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 (CVD) or age >50 years with diabetes and ≥1 additional risk factor
  • Fasting TG level from 135-499 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 IPE or placebo
  • Estimated glomerular filtration rate (eGFR) <30 or need for renal replacement therapy

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 (HDL): 40 mg/dl, high-sensitivity C-reactive protein (hs-CRP): 2.2

Principal Findings:

The primary CV outcome of CV death, nonfatal myocardial infarction (MI), stroke, coronary revascularization, or unstable angina, for IPE 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 IPE 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 = 0.09
  • 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 IPE vs. 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 IPE vs. 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.

USA subanalysis (n = 3,146 [38.5%]): Primary endpoint, for IPE vs. placebo: 18.2% vs. 24.7%, p = 0.0001); CV death: 4.7% vs. 6.7%, p = 0.007; MI: 6.7% vs. 8.8%, p = 0.01; stroke: 2.6% vs. 4.1%, p = 0.02; all-cause mortality: 7.2% vs. 9.8%, p = 0.004. Safety endpoints were similar to the overall cohort.

Cost-effectiveness analysis: The assumed cost of IPE = $4.16/day. The quality-adjusted life-years for IPE and placebo during the trial period were 3.34 and 3.27 and lifetime were 11.61 and 11.35, respectively. IPE was cost-saving in the majority of simulations. Overall, IPE appeared to be cost-dominant compared with placebo.

Eicosapentaenoic acid (EPA) levels and CV outcomes: Benefit of IPE vs. placebo was maintained across baseline EPA level tertiles (<20, 20-34, >34 mcg/ml) for primary and key secondary endpoint; p for interaction = 0.91. Median baseline EPA level 26.1, increased by ~400% at 1 year and was sustained out to 5 years in the IPE arm (p < 0.0001), while it remained more or less unchanged in the placebo arm. On-treatment EPA levels via IPE correlated with the primary endpoint, key secondary endpoint, and most other CV endpoints. Benefits noted were beyond those that could be explained by degree of TG or other biomarker changes such as LDL cholesterol, HDL, or hs-CRP.

Impact on revascularization: A total of 920 patients underwent coronary revascularization during the trial. Time to coronary revascularization was significantly lower with IPE compared with placebo (11.4% vs. 16.7%, HR 0.66, 95% CI 0.58-0.76, p < 0.0001: number needed to treat [NNT] = 24). Emergent or urgent revascularization: 5.3% vs. 7.8% (p < 0.0001); similar benefit for percutaneous coronary intervention and coronary artery bypass grafting.

Diabetes subset (n = 4,787): Median glycated hemoglobin (HbA1c), 7.0%. Primary endpoint for IPE vs. placebo: 22.2% vs. 29.2% (p < 0.0001). Effect is consistent among patients with and without established CVD at baseline. Key secondary composite endpoint (CV death/MI/stroke): 15.3% vs. 21.2% (p < 0.0001). Time to first and total events similarly lower with IPE. All-cause mortality: 7.5% vs. 8.4% (p = 0.15); CV death/MI: 10.2% vs. 13.5% (p < 0.0001); urgent/emergent revascularization: 5.7% vs. 7.2% (p = 0.02); stroke: 2.6% vs. 3.8% (p = 0.009); atrial fibrillation/flutter: 3.5% vs. 2.2% (p = 0.01). No significant changes in HbA1c or glucose.

Need for revascularization procedures: First coronary revascularization for IPE vs. placebo: 9.2% vs. 13.3% (p < 0.0001), NNT = 24. PCI: 7.7% vs. 10.9% (p < 0.001), CABG: 1.9% vs. 3.0% (p = 0.0005). Reductions were noted in both elective and urgent/emergent revascularizations. Results were consistent across tertiles of TG levels (p for interaction = 0.07). Total revascularizations were similarly reduced with IPE vs. placebo.

Patients with prior MI (n = 3,693): Primary endpoint for IPE vs. placebo: 20.2% vs. 26.1%, HR 0.74 (0.65-0.85); p = 0.00001; CV death or MI: 11.5% vs. 15.6%, p = 0.0002; fatal or nonfatal MI: 7.9% vs. 11.6%, p = 0.00009; all-cause mortality: 7.3% vs. 8.9%, p = 0.05; CV death: 4.5% vs. 6.4%, p = 0.01 (reductions noted in sudden cardiac death and cardiac arrest). Results similar by prior revascularization status.

Comparison of investigator-reported and adjudicated endpoints: The Kappa statistic between Clinical Endpoint Committee (CEC)-adjudicated vs. site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. For the primary endpoint, event rates were similar by both methods: investigator-reported (23.4% vs. 30.6%, HR 0.74, p < 0.0001) and CEC-adjudicated (21.7% vs. 28.3%, HR 0.75, p < 0.0001) for IPE vs. placebo, respectively.

Effect across eGFR categories: 22.2% had eGFR <60 at baseline (patients with GFR <30 or on renal replacement therapy were excluded from the trial). Effect of IPE vs. placebo for the primary endpoint was consistent across GFR categories; <60: 27.2% vs. 35.6%, p = 0.0002; 60-<90: 21.4% vs. 27.5%, p = 0.001; ≥90: 17.2% vs. 23.2%, p = 0.003; p for interaction = 0.41. Similar results were noted for the key secondary composite endpoint (p for interaction = 0.77), for CV death, and for the safety endpoints of atrial fibrillation/flutter and serious bleeding.

Reduction in MI: Overall MI incidence for IPE vs. placebo: 8.6% vs. 12.0% (p < 0.0001); ST-segment elevation MI (STEMI): 2.7% vs. 3.9% (p = 0.0008); NSTEMI: 5.9% vs. 7.8% (p = 0.001); fatal or nonfatal MI: 6.1% vs. 8.7% (p < 0.0001). At least one bleeding event among STEMI patients: 19.4% vs. 14.5% (p = 0.41).


The results of this trial indicate that the use of IPE 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. Results were consistent among patients with diabetes and those with prior MI, and across the spectrum of kidney function. Rates of revascularization and MI (all types) were lower, while atrial fibrillation/flutter and bleeding were higher with IPE. Results were maintained in the US cohort, and whether events were investigator-reported vs. CEC-adjudicated.

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 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.


Presented by Dr. Deepak Bhatt at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 26, 2022.

Gaba P, Bhatt DL, Steg PG, et al., on behalf of the REDUCE-IT Investigators. Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction. J Am Coll Cardiol 2022;79:1660-71.

Editorial Comment: Boden WE, Andersson C. Optimizing Dyslipidemic Cardiovascular Residual Risk Reduction With Icosapent Ethyl in Post-MI Patients. J Am Coll Cardiol 2022;79:1672-4.

Majitha A, Bhatt DL, Friedman AN, et al. Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL. Circulation 2021;144:1750-9.

Gaba P, Bhatt DL, Giugliano RP, et al. Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT. J Am Coll Cardiol 2021;78:1525-37.

Editorial Comment: Greene SJ, Butler J. Investigator-Reported Versus Adjudicated Clinical Events: 2 Versions of the Truth? J Am Coll Cardiol 2021;78:1538-40.

Presented by Dr. Deepak L. Bhatt at the European Society of Cardiology Virtual Congress, August 23, 2021.

Peterson BE, Bhatt DL, Steg PG, et al., on behalf of the REDUCE-IT Investigators. Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT REVASC. Circulation 2021;143:33-44.

Presented by Dr. Deepak L. Bhatt at the American Diabetes Association Virtual Scientific Sessions, June 13, 2020.

Presented by Dr. Benjamin E. Peterson at the virtual SCAI 2020 Scientific Sessions, May 14, 2020.

Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Bhatt DL, Miller M, Brinton EA, et al., on behalf of the REDUCE-IT Investigators. REDUCE-IT USA: Results From the 3,146 Patients Randomized in the United States. Circulation 2020;141:367-75.

Presented by Dr. William S. Weintraub at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019 (cost-effectiveness analysis).

Presented by Dr. Deepak L. Bhatt at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019 (REDUCE-IT USA subanalysis).

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, Stable Ischemic Heart Disease, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and SIHD, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Vascular Medicine, Chronic Angina

Keywords: ESC22, ESC21, ESC Congress, acc20, ACC Annual Scientific Session, AHA19, AHA Annual Scientific Sessions, ACC19, 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, ST Elevation Myocardial Infarction, Stroke, Triglycerides

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