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 approximately 10% (SVAs and ventricular arrhythmias) to approximately 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).
|投稿者||Salem, Joe-Elie; Manouchehri, Ali; Bretagne, Marie; Lebrun-Vignes, Benedicte; Groarke, John D; Johnson, Douglas B; Yang, Tao; Reddy, Nishitha M; Funck-Brentano, Christian; Brown, Jennifer R; Roden, Dan M; Moslehi, Javid J|
|組織名||Sorbonne Universite, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center,;Pitie-Salpetriere Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of;Pharmacology, Paris, France; Departments of Medicine and Pharmacology,;Cardio-Oncology program, Vanderbilt University Medical Center, Nashville,;Tennessee. Electronic address: email@example.com.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt;University Medical Center, Nashville, Tennessee.;Pharmacology, Paris, France.;Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston,;Massachusetts.;CLL Center, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical;School, Boston, Massachusetts.;University Medical Center, Nashville, Tennessee; Department of Biomedical;Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.;University Medical Center, Nashville, Tennessee. Electronic address:;firstname.lastname@example.org.|