Author + information
- Received October 18, 2019
- Revision received November 21, 2019
- Accepted November 26, 2019
- Published online February 10, 2020.
- Janice M. Bonsu, MPHa,
- Avirup Guha, MDa,b,∗,
- Lawrence Charles, MDa,∗,
- Vedat O. Yildiz, MSa,c,
- Lai Wei, PhDa,c,
- Brandee Baker, BSa,d,
- Jonathan E. Brammer, MDe,
- Farrukh Awan, MD, MSe,f,
- Maryam Lustberg, MD, MPHa,g,
- Raquel Reinbolt, MDg,
- Eric D. Miller, MD, PhDh,
- Hani Jneid, MDi,
- Patrick Ruz, BSa,
- Rebecca R. Carter, PhDa,j,
- Michael W. Milks, MDa,
- Electra D. Paskett, PhD, MPHd and
- Daniel Addison, MDa,d,∗ (, )@DanielA41995293@md_addison
- aCardio-Oncology Program, Division of Cardiology, The Ohio State University Medical Center, Columbus, Ohio
- bHarrington Heart and Vascular Institute, Case Western Reserve University, Cleveland, Ohio
- cCenter for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio
- dDivision of Cancer Prevention and Control, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio
- eDivision of Hematology, James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, Ohio
- fDivision of Hematology, University of Texas-Southwestern Cancer Center, Dallas, Texas
- gDivision of Medical Oncology, James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, Ohio
- hDepartment of Radiation Oncology, James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, Ohio
- iDivision of Cardiology, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas
- jCenter for the Advancement of Team Science, Analytics, and Systems Thinking (CATALYST), Ohio State University College of Medicine, Columbus, Ohio
- ↵∗Address for correspondence:
Dr. Daniel Addison, Division of Cardiovascular Medicine, Davis Heart & Lung Research Institute, 473 West 12th Avenue, Suite 200, Columbus, Ohio 43210.
Background Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.
Objectives The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
Methods From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Results Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Conclusions Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.
- cancer clinical trials
- cardiovascular disease
- U.S. Food and Drug Administration
- reporting of adverse events
↵∗ Drs. Guha and Charles are joint second authors.
The manuscript’s content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Preliminary results were presented in-part at the 2019 American College of Cardiology annual meeting. This work was supported in part by National Institutes of Health (NIH) grant P30 CA016058, and by NIH grants KL2-TR002734 (Dr. Brammer), R01-CA238946 (Dr. Lustberg), and K12-CA133250 (Dr. Addison). Ms. Baker was supported by the Ohio State University Comprehensive Cancer Center’s Pelotonia grant funds. Dr. Carter is supported in part by charitable contributions from the Mary H. and J. Churchill Hodges Clinical Prevention Program Fund at the Ohio State University Wexner Medical Center. Dr. Awan has received research funding from Innate Pharma, and Pharmacyclics; has provided consulting services to Gilead Sciences, Pharmacyclics, Janssen, Abbvie, Sunesis, AstraZeneca, Genentech, and Novartis Oncology; and has served on the Speakers Bureau of Abbvie and AstraZeneca. Dr. Paskett has received research funding from Merck, Foxconn, Pfizer, and The American Cancer Society; and has been a stockholder in Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 18, 2019.
- Revision received November 21, 2019.
- Accepted November 26, 2019.
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.