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

REDUCE-IT

Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.

• a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter)
• patients were randomly assigned to receive 2 g of icosapent ethyl (icosapent ethyl or ethyl eicosapentaenoic acid is a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid) twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina
• key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
  
  
• total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years
  • patients were enrolled mostly on the basis of secondary prevention (71%), and almost 60% had diabetes
  • at baseline
    • low-density lipoprotein (LDL) cholesterol levels were well controlled among the patients (median value,1.94 mmol per liter [75.0 mg per deciliter]), and triglyceride levels were slightly elevated (median value, 2.44 mmol per liter, [216.0mg per deciliter])
  • a primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001)
    • a 25% lower risk in the icosapent ethyl group
  • rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03)
  • a larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004)
    • serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06)
      
      
• study authors concluded that "..among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo."

Commentary:

• the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), in which 8179 high-risk patients who had elevated triglyceride levels and had been receiving statin therapy were randomly assigned to receive 2 g of icosapent ethyl twice daily or placebo containing mineral oil
  • patients were enrolled mostly on the basis of secondary prevention (71%), and almost 60% had diabetes
  • after a median follow-up of 4.9 years, the primary efficacy end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina in a time-to-event analysis) was reported in 22.0% of the patients in the placebo group and in 17.2% of the patients in the icosapent ethyl group - a 25% lower risk in the icosapent ethyl group
  • risk of the prespecified key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis) was similarly lower in the icosapent ethyl group
  • hierarchical statistical testing inferred consistent effects on all individual end points except death from any cause
• the levels of triglycerides, LDL cholesterol, and non-HDL cholesterol in the placebo group increased by 2.2%, 10.9%, and 10.4%, respectively, at 1 year, and the levels of apolipoprotein B and C-reactive protein increased by 7.8% and 32.3%, respectively, at 2 years
  • this may imply that true cardiovascular effects of icosapent ethyl might be less than that observed in this trial, although a post hoc analysis suggested a similar benefit with respect to major adverse cardiovascular events regardless of whether LDL cholesterol level increased in the placebo group
    
    
• results reported by Bhatt et al. are similar to those of the Japan EPA Lipid Intervention Study (JELIS), an open-label trial (2)
  • JELIS reported that the risk of major adverse cardiovascular events was 19% lower with statin therapy plus 1.8 g of eicosapentaenoic acid daily than with statin therapy alone
    
    
• the cardiovascular benefits of icosapent ethyl were greater than would be predicted on the basis of the changes in triglyceride levels
  • observed median reduction of 0.36 mmol per liter (14 mg per deciliter) in non-high-density lipoprotein (HDL) cholesterol level from baseline with icosapent ethyl would be expected to translate into a lower risk of cardiovascular events of only 6 to 8% - not the 25% observed in REDUCE-IT
  • also results were similar regardless of whether a normal triglyceride level was attained
  • results from REDUCE-IT argue against the theory that triglyceride lowering per se lowers cardiovascular risk
    • speculations that a reduction in triglyceride level is a proxy for the metabolic effects of eicosapentaenoic acid
      • separation of the Kaplan-Meier curves at 2 years is consistent with a lipoprotein-mediated mechanism and less so with an antithrombotic or an antiinflammatory mode of action

A randomised controlled trial (n=3884 aged 20-79 yrs with chronic coronary artery disease) found addition of icosapent ethyl to statin resulted in numerically lower risk of cardiovascular events versus control that did not reach statistical significance (9.1% vs 12.6%, HR 0.79, 95%CI 0.62-1.00; P=0.055) (3):

• treatment consisted of 1800 mg highly purified eicosapentanoic acid (EPA) daily (icosapent ethyl) as either 900 mg twice a day or 600 mg 3 times a day after meals, or control. Both intervention and control patients received statins prescribed by their attending physician
• primary end point was a composite of cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina requiring emergent hospitalization and coronary revascularization, and coronary revascularization, over a median period of 5 years

Reference:

1. Bhart DL et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.N Engl J Med. 2018 Nov 10.
2. Yokoyama M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.
3. Myauchi K et al. Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid (RESPECT-EPA). Circulation 2024; 150 (6).