Icosapent ethyl reduces risk of CV death in patients with CV disease, low LDL, and high triglycerides (REDUCE-IT)

Reference

Bhatt DL, Steg PG, Miller M, et al, for the REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380(1):11-22.

Synopsis

Icosapent ethyl is a purified derivative of eicosapentaenoic acid (an omega-3 fatty acid) that can lower triglyceride levels. However, previous studies of other agents that lower triglyceride levels have failed to identify a reduction in cardiovascular events. In this study, researchers identified a very-high-risk group of patients: 45 years or older with established cardiovascular (CV) disease, or 50 years or older with diabetes and at least one other CV risk factor. They were all taking a statin, had a low-density lipoprotein level of 41 to 100 mg/dL (1.06 - 2.59 mmol/L), and had a serum triglyceride level of 150 to 499 mg/dL (1.69 - 5.63 mmol/L). Most of the study sites recruited white patients in Eastern Europe, so generalizability may be limited to other settings. Halfway through the enrollment the lowest allowable triglyceride level was increased to 200 mg/dL (2.26 mmol/L). Patients with a serious comorbidity or an allergy to seafood were excluded. A total of 8179 patients were randomized to icosapent ethyl 2 g twice daily with food or to matching placebo. The placebo included mineral oil to mimic the appearance and consistency of the active drug. Groups were balanced at the start of the study, with a mean age of 64 years, 71% men, a median triglyceride level of 216 mg/dL, and 71% of patients having established CV disease. Patients were followed up for a median of 4.9 years, with 9% withdrawing consent or being lost to follow-up. The primary outcome was a very broad composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina, and it was less likely in the treatment group (17.2% vs 22.0%; hazard ratio [HR] 0.75; 95% CI 0.68 - 0.83; NNT = 21 over 4.9 years). In a post hoc analysis the researchers added a narrower and more appropriate composite outcome of CV death, acute MI, or nonfatal stroke, and again patients in the intervention group were less likely to experience it (11.2% vs 14.8%; HR 0.74; 0.65 - 0.83; NNT = 28 over 4.9 years). This benefit was only seen in patients with existing CV disease, and not in the primary prevention group of patients with diabetes. The individual endpoints, including CV death (4.3% vs. 5.2%; HR 0.80; 0.66 - 0.98; NNT = 111 over 4.9 years to prevent one CV death), were also improved. The absolute difference in all-cause mortality was similar to the reduction in CV mortality (6.7% vs 7.6%), but was not statstically significant. Overall rates of adverse events were similar, but atrial fibrillation (5.3% vs 3.9%) and peripheral edema (6.5% vs 5.0%) were more common with icosapent ethyl, and anemia was less common (4.7% vs 5.8%). The cost of icosapent ethyl is approximately $245 per month on www.goodrx.com in the United States.