Author + information
- Received May 10, 2019
- Revision received July 5, 2019
- Accepted July 7, 2019
- Published online September 23, 2019.
- Joe-Elie Salem, MD, PhDa,b,∗∗ (, )@DrJESalem,
- Ali Manouchehri, MDb,
- Marie Bretagne, MDa,
- Bénédicte Lebrun-Vignes, MDa,
- John D. Groarke, MBBCh, MPHc,
- Douglas B. Johnson, MDb,
- Tao Yang, MD, PhDb,
- Nishitha M. Reddy, MDb,
- Christian Funck-Brentano, MD, PhDa,
- Jennifer R. Brown, MD, PhDd,
- Dan M. Roden, MDb,e and
- Javid J. Moslehi, MDb,∗ (, )@CardioOncology
- aSorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center, Pitié-Salpêtrière Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of Pharmacology, Paris, France
- bDepartments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee
- cDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- dCLL Center, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston, Massachusetts
- eDepartment of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
- ↵∗Address for correspondence:
Dr. Javid Moslehi, Cardio-Oncology Program, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, Tennessee 37232.
- ↵∗∗Dr. Joe-Elie Salem, Centre d'Investigation Clinique Paris-Est, Hôpital Pitié-Salpêtrière, Bâtiment Antonin Gosset, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
Background Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.
Objectives The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.
Methods This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant.
Results This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).
Conclusions Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215)
Funding for this work was provided by the Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): “Plan Cancer 2014-2019” (to Dr. Salem). The funding sources had no role in study design, collection, analysis, or interpretation of the data, neither in the writing of the manuscript nor the decision to submit it for publication. The supplied data from VigiBase come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the UMC or the World Health Organization. Dr. Groarke has received research grant support from Amgen. Dr. Johnson has served on the Advisory Boards for Array Biopharma, Bristol-Myers Squibb, Genoptix, Incyte, Merck, and Novartis; has received research funding from Bristol-Myers Squibb and Incyte; and has received travel support from Genentech. Dr. Reddy has served as a consultant for Bristol-Myers Squibb, Abbvie, KiTe, Genentech, Bayer, and TG Therapeutics; and has received research funding from Bristol-Myers Squibb and Celgene. Dr. Brown has served as a consultant for Abbvie, Acerta, Astellas, AstraZeneca, Beigene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Sun, Sunesis, TG Therapeutics, and Verastem; has received honoraria from Janssen and Teva; has received research funding from Gilead, Loxo, Sun, and Verastem; and has served on Data Safety Monitoring Committees for Morphosys and Invectys. Dr. Moslehi has served on Advisory Boards for Pharmacyclics, Bristol-Myers Squibb, Pfizer, Novartis, Regeneron, Takeda, Deciphera, and Myokardia; and has received research funding from Pfizer and Bristol-Myers Squibb. 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 May 10, 2019.
- Revision received July 5, 2019.
- Accepted July 7, 2019.
- 2019 American College of Cardiology Foundation
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