Icosapent ethyl (IPE) significantly reduced ischemic events in patients with prior myocardial infarction (MI) in the Phase IIIb REDUCE-IT trial, including cardiovascular deaths. The subgroup analysis was published Monday online ahead of the May 3 issue of the Journal of the American College of Cardiology, led by Harvard Medical School’s Prakriti Gaba, MD. A history of MI is strongly associated with recurrent ischemic events, particularly in those with higher low-density lipoprotein cholesterol (LDL-C) and/or triglyceride levels. American Heart Association/American College of Cardiology guidance recommends intensified cholesterol medicines for those with elevated LDL-C – targeting 70 mg/dL – but recommendations on goal triglyceride levels have been “limited,” said the authors. Still, a “myriad” of therapeutics have been developed with the goal of lowering both LDL-C and triglyceride levels, including HMG-CoA reductase inhibitors, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors. REDUCE-IT Recently, the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) ethyl ester known as IPE has emerged as an “important additive agent,” said the researchers, noting that even with the aforementioned therapies, residual cardiovascular risk has remained an issue. REDUCE-IT was a multinational double-blinded clinical trial sponsored by IPE manufacturer Amarin Pharma, which randomized 8,179 patients already on statins – with controlled LDL-C and moderately elevated triglyceride levels – to receive either IPE or placebo. It found that IPE lowered the composite primary endpoint of cardiovascular death, nonfatal MI and nonfatal stroke. The current post hoc subgroup analysis assessed the specific effect of IPE among the 3,693 patients within the study (45.2% of the total cohort) who also had prior MI, which was previously unknown, said the researchers. The median time to follow-up was 4.8 years, and the maximum follow-up time was 6.2 years. Fresh analysis At baseline, the treatment and placebo groups were of similar age (IPE mean 62.6 years old vs. placebo mean 62.5 years), and the majority were male (81.1% vs. 80.4%, respectively), white (92% vs. 92.6%), not diabetic (60.2% vs. 59.5%) and on moderate-intensity statins (59.3% vs. 59.4%). Body mass index was a mean of 30.7 kg/m2 in the IPE group compared to 30.9 kg/m2 in the placebo. Triglyceride levels at baseline were a median 219.5 mg/dL (interquartile ratio: 179.5-277 mg/dL) in IPE patients and 220 mg/dL (IQR: 178.5-278 mg/dL) for the placebo group. The primary endpoint – cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina – was reduced from 26.1% to 20.2% with IPE vs. placebo (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.65-0.85; P = 0.00001). The key secondary endpoint of cardiovascular death, MI or stroke dropped from 18% to 13.3% (HR: 0.71; 95% CI: 0.61-0.84; P = 0.00006). Total ischemic events also saw a significant relative risk reduction by 35% (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% drop in CV death (P = 0.01) and 20% lower all-cause mortality (P = 0.054). There was also a 40% relative risk reduction in sudden cardiac deaths (P = 0.02) and a 56% relative risk reduction in cardiac arrests (P = 0.02). However, atrial fibrillation was higher in IPE patients than placebo patients with prior MI (3.6% vs. 2.2%; log-rank P = 0.01), as were bleeding rates (10.6% vs. 8.7%; Fisher exact P = 0.05). Safety – including increased atrial fibrillation and bleeding – and tolerability in those with prior MI were “consistent with the main study findings in the entire population,” said the researchers, stressing that there was “no significant increase in major bleeding despite a very high rate of use of antithrombotic therapy, including dual antiplatelet therapy and anticoagulation”. As for “slightly higher” atrial fibrillation rates, the researchers noted that similar arrhythmogenic associations have been seen with other omega-3 fatty acid compounds in the VITAL and STRENGTH trials. Nevertheless, “the mechanistic basis remains unclear.” “IPE led to significant reductions in both first and total ischemic events,” in the post-MI patients, the researchers concluded, adding that future trials should examine whether initiating IPE treatment at the time of an MI can prevent early ischemic events. ‘Highly clinically relevant to contemporary practice’ In an accompanying editorial, Boston University School of Medicine colleagues William E. Boden, MD, and Charlotte Andersson, MD, PhD, said the results add to mounting evidence for IPE as a highly effective adjunct to current pharmacotherapy for residual cardiovascular risk reduction in high-risk patients such as those with elevated triglyceride levels and prior MI. “Because it is well-recognized that prior MI is a driver of worse overall long-term outcomes and represents a coronary artery disease subgroup for whom additional treatment strategies are needed to mitigate cardiovascular residual risk (as reflected by the high cumulative event rates), these observations are highly clinically relevant to contemporary practice.” Sources: Gaba P, Bhatt DL, Steg PG, et al. Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction. J Am Coll Cardiol 2022;79:1660-1671. Boden WE, Andersson C. Optimizing Dyslipidemic Cardiovascular Residual Risk Reduction With Icosapent Ethyl in Post-MI Patients. J Am Coll Cardiol 2022;79:1672-1674. Image Credit: Taina Sohlman – stock.adobe.com