PracticeUpdate Cardiology March 2019

TOP STORIES 2018 7

Cardiovascular Outcome Studies: REDUCE-IT By Benjamin Morgan Scirica MD

F or cardiovascular outcome studies, 2018 was a banner year. Many of the large tri- als of novel strategies for lipids, diabetes, inflammation, anticoagulation, and devices that reported last year truly deserve the label “land- mark,” and will change practice. But, among themall, my choice for the story of the year is the

Reduction of Cardiovascular Eventswith Icosapent Ethyl–Intervention (REDUCE-IT) trial, 1 which demonstrated that this purified formulation of eicosapentaenoic acid (EPA) markedly reduced cardiovascular events in 8179 patients whose fasting triglyceride levels were 135– 499 mg/dL and LDL levels were 41–100 mg/dL, as either a primary or secondary prevention strategy. EPA lowers triglycerides, and several formulations, including the one used in REDUCE-IT, are approved for use to lower triglycerides in patients with triglycerides >500 mg/dL. Before REDUCE-IT, though, no study ever demonstrated a cardiovascular benefit with targeted triglyceride-lowering, despite the clear association between elevated triglycerides and poor outcomes. The effect of EPA on cardiovascular events was greater than expected (HR, 0.75; P < .001 for the primary composite endpoint of CV death, MI, stroke, coronary revasculari- zation, and unstable angina) and was remarkably consistent among the individual components, including MI (HR, 0.69; P < .001), stroke (HR, 0.72; P = .01), coronary urgent or emergent revascularization (HR, 0.65; P < .001), and cardiovascular death (HR, 0.80; P = .03). Notably, the cardiovascular benefit of EPA was consistent regard- less of baseline LDL and triglyceride levels. EPA also lowered hsCRP by almost 40% compared with placebo, indicating that, in addition to lowering triglycerides, a reduction in inflammation may also be part of the mechanism by which EPA improves out- comes. There was some talk about the potential that the placebo, which contained mineral oil in order to maintain blinding, may have increased LDL and thus tilted the scale for EPA; however, the 5-mg/dL difference in LDL between the two groups would not explain the divergent rates of clinical events. How EPA will be incorporated into clinical guidelines and practice is still not clear. For the first time, there is now strong evidence for cardiovascular benefit with a non-LDL lowering lipid strat- egy. The triglyceride entry criteria of REDUCE-IT (135–499 mg/ dL) is much lower than the typical threshold for initiating triglycer- ide-lowering therapy and thus increases the size of the potentially eligible population. The LDL levels at baseline were lower in the REDUCE-IT trial compared with the two pivotal PCSK9 inhibitor outcome studies; however, the prioritization of further triglycer- ide- or LDL-lowering therapy after high-intensity statin/ezetimibe therapy remains to be determined in a population with mild to moderately elevated triglycerides and an LDL level between 50 and 100 mg/dL. In the search for reducing the residual risk of ath- erosclerotic cardiovascular disease, the compelling data from REDUCE-IT must broaden the focus of lipid therapy from only LDL to include triglycerides as well. Reference 1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018 Nov 10. doi: 10.1056/NEJMoa1812792. [Epub ahead of print.] www.practiceupdate.com/c/77103

anti-thrombotic effect, going back to the original observations of Sinclair in the mid-twentieth century. Regardless of the mechanisms, we now possess firm evidence from a superbly conducted and well-powered clinical trial that, on top of contemporary standard of care, the administration of a high dose (4 g/day) of a pharmaceutical-grade EPA can offer many cardiovascular benefits. These results have the potential of advancing the clinical care of individuals with or at high risk of coronary artery disease with hypertriglyceridemia, the population studied in REDUCE-IT. The results of REDUCE-IT offer consid- erable promise to patients in an era when conditions linked to hypertriglyceridemia such as obesity, insulin resistance, and dia- betes have become epidemic and drive considerable remaining risk for cardiovascular disease. References 1. Ewin J. Fine wines and fish oil: the life of Hugh Macdonald Sinclair. J R Soc Med 2002;95(5):263-264. 2. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354(9177):447-455. 3. Yokoyama M, Origasa H, Matsuzaki 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(9567):1090-1098. 4. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018;3(3):225-234. 5. Group ASC, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-1550. 6. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2018 Nov 10. doi: 10.1056/ NEJMoa1811403. [Epub ahead of print.] 7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018 Nov 10. doi: 10.1056/ NEJMoa1812792. [Epub ahead of print.] 8. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-776. 9. Nissen S, Lincoff AM, Nicholls S. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). 2017;2017. www.practiceupdate.com/c/76801

VOL. 4 • NO. 1 • 2019