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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; IC 025 (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; IC 025 : 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC 025 : 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC 025 : 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC 025 : 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC 025 : 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC 025 : 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC 025 : 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)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized., Objectives: The authors sought to understand the presentation and clinical course of ICI-associated myocarditis., Methods: After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block., Results: The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates., Conclusions: Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hodgkin lymphoma (HL) survivors treated with thoracic radiation therapy (RT) have impaired exercise tolerance and increased cardiovascular mortality., Objectives: The purpose of this study was to evaluate the prevalence of autonomic dysfunction and its implications on exercise capacity and mortality in long-term survivors of HL., Methods: Exercise parameters in 263 HL survivors referred for exercise treadmill testing at a median interval of 19 years after RT were compared with 526 age-, sex-, and cardiovascular risk score-matched control subjects. Within the RT cohort, the presence of autonomic dysfunction, defined by an elevated resting heart rate (HR) (≥80 beats/min) and abnormal heart rate recovery (HRR) at 1 min (≤12 beats/min if active cool-down, or ≤18 beats/min if passive recovery), was correlated with exercise capacity and all-cause mortality over a median follow-up of 3 years., Results: RT was associated with elevated resting HR and abnormal HRR after adjusting for age, sex, cardiovascular risk factors, medications, and indication for exercise treadmill testing: odds ratio: 3.96 (95% confidence interval [CI]: 2.52 to 6.23) and odds ratio: 5.32 (95% CI: 2.94 to 9.65), respectively. Prevalence of autonomic dysfunction increased with radiation dose and time from RT. Both elevated resting HR and abnormal HRR were associated with reduced exercise capacity in RT patients. Abnormal HRR was also associated with increased all-cause mortality (age-adjusted hazard ratio: 4.60 [95% CI: 1.62 to 13.02])., Conclusions: Thoracic RT is associated with autonomic dysfunction, as measured by elevated resting HR and abnormal HRR. These abnormalities are associated with impaired exercise tolerance, and abnormal HRR predicts increased all-cause mortality in RT patients., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)