Prakriti Gaba1, Deepak L Bhatt2, Robert P Giugliano1, Ph Gabriel Steg3, Michael Miller4, Eliot A Brinton5, Terry A Jacobson6, Steven B Ketchum7, Rebecca A Juliano7, Lixia Jiao7, Ralph T Doyle7, Craig Granowitz7, Jean-Claude Tardif8, Christie M Ballantyne9, Duane S Pinto10, Matthew J Budoff11, C Michael Gibson10. 1. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: DLBhattMD@post.Harvard.edu. 3. Université de Paris, FACT (French Alliance for Cardiovascular Trials), Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, INSERM Unité 1148, Paris, France. 4. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. 5. Utah Lipid Center, Salt Lake City, Utah, USA. 6. Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. 7. Amarin Pharma, Inc, Bridgewater, New Jersey, USA. 8. Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada. 9. Department of Medicine, Baylor College of Medicine, and the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA. 10. Department of Cardiovascular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 11. Division of Cardiology, Harbor UCLA Medical Center, Torrance, California, USA.
Abstract
BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. OBJECTIVES: The purpose of this study was to determine the effects of IPE on investigator-reported events. METHODS: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. RESULTS: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. CONCLUSIONS: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. OBJECTIVES: The purpose of this study was to determine the effects of IPE on investigator-reported events. METHODS: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. RESULTS: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. CONCLUSIONS: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
Authors: Catherine G Derington; Adam P Bress; Jennifer S Herrick; Wenjun Fan; Nathan D Wong; Katherine E Andrade; Jonathan Johnson; Sephy Philip; David Abrahamson; Lixia Jiao; Deepak L Bhatt; William S Weintraub Journal: Am J Prev Cardiol Date: 2022-04-28
Authors: William S Weintraub; Deepak L Bhatt; Zugui Zhang; Sarahfaye Dolman; William E Boden; Adam P Bress; Jordan B King; Brandon K Bellows; Gabriel S Tajeu; Catherine G Derington; Jonathan Johnson; Katherine Andrade; P Gabriel Steg; Michael Miller; Eliot A Brinton; Terry A Jacobson; Jean-Claude Tardif; Christie M Ballantyne; Paul Kolm Journal: JAMA Netw Open Date: 2022-02-01
Authors: Anna Meta Dyrvig Kristensen; Manan Pareek; Kristian Hay Kragholm; Thomas Steen Gyldenstierne Sehested; Michael Hecht Olsen; Eva Bossano Prescott Journal: Cardiology Date: 2022-05-10 Impact factor: 2.342
Authors: Lars Jakobsen; Evald H Christiansen; Phillip Freeman; Johnny Kahlert; Karsten Veien; Michael Maeng; Bent Raungaard; Julia Ellert; Steen D Kristensen; Martin K Christensen; Christian J Terkelsen; Troels Thim; Ashkan Eftekhari; Rebekka V Jensen; Nicolaj B Støttrup; Anders Junker; Henrik S Hansen; Lisette O Jensen Journal: Catheter Cardiovasc Interv Date: 2022-04-06 Impact factor: 2.585