Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Abstract

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol (LDL‐C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High‐dose eicosapentaenoic acid (EPA) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT; NCT01492361) is a phase 3b randomized, double‐blinded, placebo‐controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk. REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and <500 mg/dL and LDL‐C >40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary‐efficacy endpoint events have occurred.

High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk

“…Unique identifier: NCT01492361) is expected to be the first of these trials to present results, which are expected in the second half of 2018. This phase 3b, international, multicenter, prospective, double‐blind, placebo‐controlled, parallel‐group trial randomized ≈8000 high‐risk patients receiving stable statin therapy with triglycerides 1.69 to 5.64 mmol/L (150–499 mg/dL) to the highly purified omega‐3 fatty acid icosapent ethyl (ethyl ester of eicosapentaenoic acid) 4 g/d or matching placebo 33. Patients in this trial are required to have a history of cardiovascular disease or diabetes mellitus plus an additional cardiovascular risk factor.…”

Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin‐controlled LDL cholesterol

“…Stronger evidence is needed. In addition to the REDUCE‐IT study, the Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia (STRENGTH) and the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides In Patients With Diabetes (PROMINENT) studies are ongoing large CV outcomes trials involving high‐risk CVD patients, including a large percentage of patients with diabetes, undergoing statin therapy, with the results from the REDUCE‐IT study (EPA vs placebo) to be presented first in 2018 …”

Sex Differences in Omega‐3 and ‐6 Fatty Acids and Health Status Among Young Adults With Acute Myocardial Infarction: Results From the VIRGO Study

“…The 2 trials that suggested benefits of omega‐3 FA supplementation enrolled older patients (average age of 60) and focused only on clinical outcomes as opposed on patient‐reported outcomes . Another 3 clinical trials of omega‐3 FA supplementations are currently ongoing, which are also focusing on older patients . A recent American Heart Association Advisory report recommends replacement of saturated fat with polyunsaturated vegetable oils that consist of high omega‐6 linoleic acid to lower cardiovascular disease risk, largely based on evidence from middle‐aged and elderly population .…”