Author + information
- Robert P. Giugliano, MD, SMa,∗∗ (, )@JACCJounals@TIMIStudyGroup@rgiugliano,
- Baris Gencer, MDa,∗,
- Stephen D. Wiviott, MDa,
- Jeong-Gun Park, PHDa,
- Charles S. Fuchs, MD, MPHb,
- Wolfram Goessling, MD, PHDc,
- Thomas A. Musliner, MDd,
- Andrew M. Tershakovec, MD, MPHd,
- Michael A. Blazing, MDe,
- Robert Califf, MDf@califf001,
- Christopher P. Cannon, MDa@cpcannon and
- Eugene Braunwald, MDa
- aTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- bSmilow Cancer Hospital at Yale New Haven, New Haven, Connecticut
- cDivision of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
- dMerck, Kenilworth, New Jersey
- eDuke Clinical Research Institute, Durham, North Carolina
- fVerily Life Sciences and Google Health, South San Francisco, California
- ↵∗Address for correspondence:
Dr. Robert P. Giugliano, TIMI Study Group, Brigham and Women’s Hospital, Hale Building, 7th Floor, Suite 7022, 60 Fenwood Road, Boston, Massachusetts 02115.
Background An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial.
Objectives The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Methods Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy.
Results In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68).
Conclusions Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)
↵∗ Drs. Giugliano and Gencer contributed equally to this work.
IMPROVE-IT was supported by research grants from Merck to the Brigham and Women’s Hospital and the Duke Clinical Research Group. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the article, and its final contents. Dr. Giugliano has received a research grant to his institution from Merck for the conduct of the IMPROVE-IT; has received a research grant to his institution from Amgen for other lipid-lowering trials; has received honoraria for continuing medical education activities from Amgen, Daiichi-Sankyo, and Merck; and has received consulting/advisory board fees from Amarin, Bristol-Myers Squibb, CVS Caremark, Daiichi-Sankyo, GlaxoSmithKline, Lexicon, Merck, Portola, Pfizer, and Servier. Dr. Gencer's activities in the TIMI Group, Harvard Medical Schools, are supported by grants from the Geneva University Hospitals, Eugenio Litta, and Athemis Foundations. Dr. Wiviott has received grants from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; has received consulting fees from ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St. Jude Medical, and Xoma; and his spouse is an employee of Merck. Dr. Park is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr. Fuchs has a consulting role for Agios, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, Taiho, and Unum Therapeutics; serves as a Director for CytomX Therapeutics; owns unexercised stock options for CytomX and Entrinsic Health; and is a co-Founder of Evolveimmune Therapeutics and has equity in this private company. Dr. Goessling has received consulting fees from and owns stock in Camp4 Therapeutics; and has received patent royalties from Fate Therapeutics. Drs. Musliner and Tershakovec were employed by Merch at the time IMPROVE-IT was conducted. Dr. Blazing has received research support from Merck for data analysis; and has received consultant/advisory board fees from Merck and Espirion. Dr. Califf is employed by Verily Life Sciences and Google Health; and is on the board of Cytokinetics. Dr. Cannon has received a research grant from Merck to his institution for his role as principal investigator of IMPROVE-IT; and has received consultant or advisory board fees from Merck. Dr. Braunwald has received a research grant to his institution from Merck for his role as Co-Chair of IMPROVE-IT and other support from Merck during the conduct of the study; research grants through his institution from AstraZeneca, Daiichi-Sankyo, and Novartis; and consultancy fees from Amgen, Cardurion, MyoKardia, NovoNordisk, and Verve.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: CardioOncology author instructions page.
- Received June 3, 2020.
- Revision received July 28, 2020.
- Accepted July 29, 2020.
- 2020 The Authors