Icosapent ethyl reduces coronary revascularization in patients with high CV risk and elevated TG

Reduction in Revascularization with Icosapent Ethyl: Insights from REDUCE-IT REVASC.

Literature - Peterson BE, Bhatt DL, Steg PG, et al. - Circulation 2020 Nov 5. doi: 10.1161/CIRCULATIONAHA.120.050276.

Introduction and methods

Patients with hypertriglyceridemia while receiving statin treatment, have an increased risks of ischemic events, including coronary revascularization. Plus, elevated triglycerides (TG) levels are thought to play a role in the development and progression of coronary plaque and vessel inflammation contributing to residual coronary atherosclerosis [1-7]. However, previous clinical trials with TG-lowering agents, including omega-3 fatty acids, fibrates and niacin, have not demonstrated a consistent reduction in coronary revascularization events [8-12].

Previous analyses of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) have shown that icosapent ethyl reduced the occurrence of major cardiovascular events [13,14]. This study further assessed the effect of icosapent ethyl, compared to placebo, on coronary revascularization in participants of the REDUCE-IT, by evaluating all first coronary revascularization events, which included preoperative conditions and surgical procedure types.

The REDUCE-IT trial was a multicenter, double-blind, placebo-controlled, randomized trial with statin treated patients (≥50 years) with CVD, or diabetes with at least one additional CV risk factor, all with persistent elevated triglyceride levels (≥135 mg/dL and ≤500 mg/dL) and well-controlled LDL-c levels between 41 mg/dL and 100 mg/dL. Patients were randomized (1:1) to 4 gram icosapent ethyl daily or matching placebo. For this analysis, the primary endpoint was first coronary revascularization events, including the preoperative revascularization conditions (elective, urgent, emergent, or salvage) as well as categories of surgical procedures (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]). These revascularization endpoints were reviewed by blinded adjudicators. Median follow-up was 4.9 years.

Main results

  • Icosapent ethyl significantly reduced the risk of first coronary revascularization compared to placebo (HR 0.66, 95% CI: 058-076, P<0.0001). There was a significant and sustained difference in treatment outcome for time to first coronary revascularization, already observed after 11 months. The NNT was 24.
  • Patients treated with icosapent ethyl had a lower risk for first occurrence of emergent (HR 0.62, 95% CI: 0.42-0.92, P=0.016), urgent (HR 0.66, 95% CI: 0.54-0.79, P<0.0001), or elective revascularization (HR 0.68, 95% CI: 0.57-0.82, P<0.0001) compared to patients treated with placebo.
  • There was a significant reduction in the number of patients in the icosapent ethyl group vs. placebo group that underwent PCI (7.7% vs. 10.9%; HR 0.68, 95% CI: 0.59-0.79, P<0.0001). Similar results were obtained for CABG (1.9% vs. 3.0%; HR 0.61, 95% CI: 0.45-0.81, P=0.0005).
  • The number of total revascularization events (first and subsequent events) in the icosapent ethyl group was reduced by 36% compared to the placebo group, using a negative binomial model (RR 0.64, 95% CI: 0.56-0.74, P<0.0001). Other models produced similar results. When analyzing the distribution of reduction of first and subsequent revascularization, patients in the icosapent ethyl group had a 33% reduction in first revascularization events (P<0.0001), 51% in second (P<0.0001) and 50% in third or more events (P=0.04) compared to placebo.

Conclusion

In this subanalysis of the REDUCE-IT trial, icosapent ethyl additionally given to statins in high risk CV patients with persistent elevated TG levels reduced the risk for first and subsequent revascularization. This effect was consistent among different preoperative revascularization conditions, and PCI and CABG procedures.

References

1. Boden WE, Bhatt DL, Toth PP, et al. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics. Eur Heart J. 2020;41:2304-12.

2. Rosinger A, Carroll MD, Lacher D, Ogden C. Trends in Total Cholesterol, Triglycerides, and Low-Density Lipoprotein in US Adults, 1999-2014. JAMA Cardiol. 2017;2:339-41.

3. 12. Gitt AK, Lautsch D, Ferrières J, et al. Cholesterol target value attainment and lipid-lowering therapy in patients with stable or acute coronary heart disease: Results from the Dyslipidemia International Study II. Atherosclerosis. 2017;266:158-66.

4. Fan W, Philip S, Granowitz C, et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. 2019;13:100-8.

5. 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;369:1090-98.

6. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200:135-40.

7. Bhatt DL. REDUCE-IT: Residual Cardiovascular Risk in Statin-Treated Patients with Elevated Triglycerides: Now We Can REDUCE-IT! Eur Heart J. 2019;40:1174-75.

8. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.

9. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018;379:1540-1550.

10. ORIGIN Trial Investigators, Bosch J, Gerstein HC, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309-318.

11. 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 77 917 Individuals. JAMA Cardiol. 2018;3:225-234.

12. Manson JE, Cook NR, Lee IM, et al. VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019;380:23-32. doi:10.1056/NEJMoa1811403.

13. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, et al. REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.

14. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, et al. REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. 2019;73:2791-2802.

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