• Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

      Gaba, Prakriti; Bhatt, Deepak L; Giugliano, Robert P; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; et al. (Elsevier Inc., 2021-10-04)
      Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. Objectives: The purpose of this study was to determine the effects of IPE on investigator-reported events. Methods: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. Results: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. Conclusions: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
    • Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT

      Bhatt, D.L.; Steg, P.G.; Miller, M. (Elsevier USA, 2019)
      Background: In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events. Objectives: Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events. Methods: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial)randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl /dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients)or diabetes (29% patients)to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent)primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina)and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis. Results: In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%)first primary endpoint events and 1,303 (44.8%)subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001). Conclusions: Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361) Copyright 2019 The Authors
    • Icosapent Ethyl Reduces Ischemic Events in Patients with a History of Prior Coronary Artery Bypass Grafting: REDUCE-IT CABG

      Verma, Subodh; Bhatt, Deepak L; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Dhingra, Nitish K; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; et al. (American Heart Association, 2021-10-28)
      Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk following coronary artery bypass grafting (CABG) surgery. Methods: In the multicenter, placebo-controlled, double-blind trial REDUCE-IT, statin-treated patients with controlled low-density lipoprotein cholesterol (LDL-C) and mild to moderate hypertriglyceridemia were randomized to 4g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint (cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The present analysis reports on the subgroup of patients from the trial with a history of CABG. Results: Of the 8,179 patients randomized in REDUCE-IT, a total of 1,837 (22.5%) had a history of CABG, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.92; P=0.004), in the key secondary endpoint (HR, 0.69; 95% CI, 0.56-0.87; P=0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64; 95% CI, 0.50-0.81; P=0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%-10.2%) in first events, with a number needed to treat of 16 (95% CI, 10-44) over a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs. 3.1%; P=0.03) and a non-significant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of CABG, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events.
    • Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.

      Gaba, Prakriti; Bhatt, Deepak L; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; Doyle, Ralph T; et al. (Elsevier, 2022-05-03)
      BACKGROUND: REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. OBJECTIVES: Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. METHODS: We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. RESULTS: A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. CONCLUSIONS: Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).
    • Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

      Peterson, Benjamin E; Bhatt, Deepak L; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; Doyle, Ralph T; et al. (Wolters Kluwer Health, 2020-11-05)
      A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005).
    • Treatment With Icosapent Ethyl to Reduce Ischemic Events in Patients With Prior Percutaneous Coronary Intervention: Insights From REDUCE-IT PCI.

      Peterson, Benjamin E; Bhatt, Deepak L; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; Doyle, Ralph T; et al. (Wiley-Blackwell, 2022-03-09)
      Background Patients who undergo percutaneous coronary intervention (PCI) are at increased risk for recurrent cardiovascular events despite aggressive medical therapy. Methods and Results This post hoc analysis focused on the subset of patients with prior PCI enrolled in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, randomized, double-blind, placebo-controlled trial of icosapent ethyl versus placebo. Icosapent ethyl was added to statins in patients with low-density lipoprotein cholesterol <100 mg/dL and fasting triglycerides 135-499 mg/dL. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. There were 8179 patients randomized in REDUCE-IT followed for a median of 4.9 years, and 3408 (41.7%) of them had a prior PCI with a median follow-up of 4.8 years. These patients were randomized a median of 2.9 years (11 days to 30.7 years) after PCI. Among patients treated with icosapent ethyl versus placebo, there was a 34% reduction in the primary composite end point (hazard ratio [HR], 0.66; 95% CI, 0.58-0.76; P<0.001; number needed to treat4.8 years=12) and a 34% reduction in the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR, 0.66; 95% CI, 0.56-0.79; P<0.001; NNT4.8 years=19) versus placebo. Similarly, large reductions occurred in total coronary revascularizations and revascularization subtypes. There was also a 39% reduction in total events (rate ratio, 0.61; 95% CI, 0.52-0.72; P<0.001). Conclusions Among patients treated with statins with elevated triglycerides and a history of prior PCI, icosapent ethyl substantially reduced the risk of recurrent events during an average of ~5 years of follow-up with a number needed to treat of only 12. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.