Author + information
- Received November 30, 2018
- Revision received March 10, 2019
- Accepted March 19, 2019
- Published online June 10, 2019.
- David M. Charytan, MD MSca,b,∗ (, )@Dcharytan,
- Marc S. Sabatine, MD, MPHb,c,
- Terje R. Pedersen, MDd,
- KyungAh Im, PhDb,c,
- Jeong-Gun Park, PhDb,c,
- Armando Lira Pineda, MDe,
- Scott M. Wasserman, MDe,
- Prakash Deedwania, MDf,
- Anders G. Olsson, MD, PhDg,
- Peter S. Sever, MDh,
- Anthony C. Keech, MDi,j,
- Robert P. Giugliano, MD, SMb,c@rgiugliano,
- on behalf of the FOURIER Steering Committee and Investigators
- aDepartment of Medicine, NYU Langone Medical Center, New York, New York
- bDepartment of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- cTIMI Study Group, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- dDepartment of Medicine, Oslo University Hospital, Ullevål, Oslo, Norway
- eAmgen, Thousand Oaks, California
- fCardiology Division, Veteran Affairs Central California Healthcare System, Fresno, California
- gUniversity of California San Francisco School of Medicine, Fresno, California
- hDepartment of Medicine and Health Sciences, Linkӧping University, Linkӧping, Sweden
- iDepartment of Medicine, Imperial College London, London, United Kingdom
- jNHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
- ↵∗Address for correspondence:
Dr. David M. Charytan, NYU Langone Medical Center, 462 1st Avenue, New York, New York 10010.
Background Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited.
Objectives The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function.
Methods The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non–high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate.
Results There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); pint = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (pint = 0.75)—preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were −2.5% (95% CI: −0.4% to −4.7%) for stage ≥3 CKD compared with −1.7% (95% CI: 0.5% to −2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage.
Conclusions LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633)
The FOURIER trial was funded by Amgen, Inc., who also participated in the design, conduct, collection, management, and analysis of the data. Statistical analyses were primarily performed by the Thrombolysis In Myocardial Infarction (TIMI) Group. The sponsor’s participation in this analysis was under the direction of the FOURIER Executive Committee. Dr. Charytan has received research support from Janssen Pharmaceuticals as a member of the CREDENCE trial steering committee; has served as a consultant for Amgen, Fresenius, Daichi-Sankyo, and Medtronic/Covidien; and has received fees related to service on trial committees for PLC Medical, AstraZeneca, and Allena Pharmaceuticals. Dr. Sabatine has received grants from Abbott Laboratories, Clinical Diagnostics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Roche Diagnostics, Takeda, Novartis, Poxel, Eisai, Genzyme, and Pfizer; and has received grants and personal fees from Amgen and AstraZeneca. Dr. Pedersen has received grants and personal fees from Amgen during the conduct of the study; and has received personal fees from Amgen, Sanofi, Merck, Boehringer Ingelheim, and The Medicines Company outside of the submitted work. Dr. Pineda is an employee of and holds stock in Amgen. Dr. Wasserman is an employee of Amgen; and is an inventor on a number of patent applications related to evolocumab licensed and assigned to Amgen. Dr. Deedwania has a consulting agreement with Amgen; and has served as a consultant/on the advisory board of and received honoraria from Amgen and Sanofi. Dr. Olsson has received personal fees from Amgen and Sanofi during the conduct of the FOURIER and ODYSSEY studies; and has received personal fees from The Medicines Company outside of the submitted work. Dr. Severs has received grants and personal fees from Amgen during the conduct of the study; has received grants and personal fees from Pfizer outside of the submitted work; is the recipient of a National Institute for Health Research Senior Investigator Award; has received support from the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust, Intarcia, Merck, Janssen Research Development, The Medicines Company, and MedImmune; and has received personal fees from Alnylam, CVS Caremark, Lonis, Cubist, Esperion, and MyoKardia, outside of the submitted work. Dr. Keech has received grants and personal fees from Abbott and Mylan; and has received personal fees from Amgen, AstraZeneca, and Pfizer, outside the submitted work. Dr. Giugliano has received grants and personal fees from Amgen during the conduct of the study; has received grants and personal fees from Amgen, Daiichi-Sankyo, and Merck; and has received personal fees from Akcea, Amarin, American College of Cardiology, Angel Med, Boehringer Ingelheim, Bristol-Myers Squibb, CVS Caremark, GlaxoSmithKline, Janssen, Lexicon, Portola, Pfizer St. Jude, and Stealth Peptides outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received November 30, 2018.
- Revision received March 10, 2019.
- Accepted March 19, 2019.
- 2019 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.