Reduce-It

The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) has established a new standard of care in addressing residual risk in patients with elevated triglycerides already treated with statins.1,2 The study found that icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid (EPA), reduced the risk of major adverse cardiovascular events (MACE) by 25%. This included a statistically significant 20% reduction in death from cardiovascular causes, as well as statistically significant reductions in a variety of other prespecified endpoints, including a 31% reduction in myocardial infarction (MI), a 28% reduction in stroke, a 32% reduction in hospitalization for unstable angina, and a 35% reduction in urgent or emergent coronary revascularization. REDUCE-IT randomized 8179 patients with established atherosclerosis or diabetes mellitus plus at least one additional risk factor, who had fasting triglyceride levels of 1.52 to 5.63 mmol/L (135–499 mg/dL) while on statin therapy, to either icosapent ethyl or placebo. A high proportion (43%) of patients screened were randomized, suggesting good generalizability of the trial findings. The median follow-up was 4.9 years. The primary endpoint of 5-point MACE (cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina) was reduced from 22.0% to 17.2% [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68–0.83; P = 0.00000001]. This translates into a number needed to treat of only 21. The key secondary endpoint of cardiovascular death, MI, or stroke was reduced from 14.8% to 11.2% (HR 0.74, 95% CI 0.65–0.83; P = 0.0000006), which translates to a number needed to treat of only 28. A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation/flutter with icosapent ethyl, although the rates were low. In addition, there was a statistically significant 28% reduction in stroke observed, the most feared complication of atrial fibrillation. There was a trend towards an increase in serious bleeding with icosapent ethyl, though not for serious intracranial or gastrointestinal bleeding, or for haemorrhagic stroke endpoints, and there were no bleeding-associated deaths assessed by investigators as related to either icosapent ethyl or placebo. The large relative and absolute risk reductions noted in REDUCE-IT would be expected to make icosapent ethyl highly cost effective. In fact, in prespecified analyses, when examining not only first events, but also recurrent and total ischaemic events, a 30% reduction was seen using the negative binomial method (P = 0.00000000036), and a 32% reduction was seen using the Andersen-Gill method (P = 0.0000000000000000000003), which likely has significant implications with respect to formal evaluations of cost effectiveness.3 Cardiovascular death was significantly reduced in the trial. There was a trend towards lower all-cause mortality (P = 0.091), with no offsetting increase in non-cardiovascular mortality. Thus, with longer treatment and follow-up duration, a significant decrease in total mortality would be expected. Interestingly, there were significant reductions in sudden cardiac death (31% reduction; P = 0.026) and cardiac arrest (48% reduction; P = 0.011). Potentially, the cell membrane stabilizing properties of EPA that have been demonstrated in vitro are in part responsible for these important benefits. The fact that other adjudicated endpoints, including elective coronary revascularization, were reduced in this blinded trial strongly suggests multiple mechanisms of action of icosapent ethyl. Several prespecified subgroups were examined and revealed consistent benefit in the primary and key secondary endpoints. Of note, 10.3% of REDUCE-IT patients had baseline triglycerides less than 1.69 mmol/L (150 mg/dL), and this subgroup showed a similar degree of benefit as those with higher baseline triglyceride levels. Much as the definition of ‘normal’ LDL-cholesterol has been dropping, in the future the same is likely going to happen for triglyceride levels. Even when current cardiovascular risk-reducing strategies are optimally utilized, residual risk remains. Advances in statin therapy, ezetimibe, and PCSK9 inhibition have been important, but each target the LDL-cholesterol axis of risk. Elevated triglycerides identify patients at increased cardiovascular risk and additionally appear to be part of the causal pathway of atherosclerosis. Icosapent ethyl is known to lower triglycerides as well as inflammatory markers, and through these and other pleiotropic effects, substantially reduces a variety of ischaemic endpoints. As such, this drug is an important addition to the armamentarium of preventive medicine. Furthermore, REDUCE-IT has opened up an entirely novel EPA-based pathway to cardiovascular risk reduction, akin to the advent of statin therapy decades ago. The results, applied to patients worldwide, would be expected to produce a significant reduction in atherosclerotic events. Future studies will likely expand the boundaries of efficacy to include patients with even lower levels of triglycerides and even lower levels of cardiovascular risk. Conflict of interest: Please refer to online Supplementary material. References are available as supplementary material at European Heart Journal online.