Trial Reference
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380:11-22.
Expert Comment
Maria Eliane Campos Magalhães and Andréa Araujo Brandão
Background
A long-standing association exists between elevated triglyceride levels and cardiovascular disease (CVD). However, the evidence for an independent relationship of triglycerides to the risk of future CVD events has long been controversial. If triglycerides directly promote CVD or represent a biomarker of risk has been debated for decades.
Icosapent ethyl, a highly purified eicosapentaenoic acid (EPA) ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
REDUCE-IT trial included a total of 8179 patients (70.7% for secondary prevention of cardiovascular events) followed-up for a median of 4.9 years. 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 endpoints were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic endpoints 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 was hospitalized for atrial fibrillation or flutter compared to the placebo group (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).
Conclusion
Numerous studies have investigated the potential effect of treating triglyceride levels in order to reduce CVD risk. This is due to the fact that the rates of cardiovascular events still remain high among patients with cardiovascular risk factors who are receiving treatment for secondary or primary prevention (residual risk).
In randomized trials, medications that reduce triglyceride levels, such as extended-release niacin and fibrates, have not reduced the rates of cardiovascular events when administered in addition to appropriate medical therapy, including statins. Similarly, contemporary trials and recent metanalyses of n−3 fatty acid products have not shown a benefit in patients receiving statin therapy. However, the Japan EPA Lipid Intervention Study (JELIS), which compared low-intensity statin therapy plus 1.8 g of pure EPA daily or statin therapy alone, showed that the risk of major coronary events was significantly lower (19%) in the group that received EPA plus statin therapy than in the group that received statin therapy alone.
Findings of Reduce-IT trial confirm the clinical benefits with icosapent ethyl. They may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA). Both the formulation (a highly purified and stable EPA ethyl ester) and the total dose of 4 g used in this trial were different from those used in previous outcome trials. The mechanisms responsible for the benefit of icosapent ethyl observed in REDUCE-IT trial are currently unknown.
In conclusion, the results of this large trial clearly suggest the effect of EPA on triglycerides and clinical endpoints. These data along with the results from the JELIS trial should be considered as a supporting evidence for the hypothesis that high doses of EPA (not to be generalized to other n-3 fatty acid preparations) may have an effect on cardiovascular disease events.