Cardiovascular Toxicities Associated With Ibrutinib

Study Questions:

What are the characteristics of cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib?

Methods:

The study authors utilized VigiBase, the World Health Organization’s global database of individual case safety reports (an international pharmacovigilance database), to perform 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 ADRs using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant. Characteristics of cases were described in terms of mean ± standard deviation or median (interquartile range) for quantitative variables, and in terms of effective and proportion for qualitative ones.

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 [CI], 21.6-24.7; p < 0.0001; IC025, 3.97), central nervous system hemorrhagic events (ROR, 3.7; 95% CI, 3.4-4.1; p < 0.0001; IC025, 1.63), heart failure (HF) (ROR, 3.5; 95% CI, 3.1-3.8; p < 0.0001; IC025, 1.46), VAs (ROR, 4.7; 95% CI, 3.7-5.9; p < 0.0001; IC025, 0.96), conduction disorders (ROR, 3.5; 95% CI, 2.7-4.6; p < 0.0001; IC025, 0.76), central nervous system ischemic events (ROR, 2.2; 95% CI, 2.0-2.5; p < 0.0001; IC025, 0.73), and hypertension (ROR, 1.7; 95% CI, 1.5-1.9; p < 0.0001; IC025, 0.4).

CV-ADR often occurred early after ibrutinib administration. CV-ADR were associated with fatalities that ranged from ~10% (SVAs and VAs) to ~20% (central nervous system events, HF, and conduction disorders). SVAs were associated with HF in 11.9% of SVA cases (114 of 959), with central nervous system ischemic events in 4.2% (40 of 959) and with central nervous system hemorrhagic events in 3.4% (33 of 959). There were more deaths when SVA cases were associated with central nervous system hemorrhagic and/or ischemic events compared with their absence (15 of 52, 28.8% vs. 88 of 907, 9.7%; p < 0.0001, respectively). HF cases were frequently associated with concurrent contributing conditions such as SVAs (114 of 363, 31.4%) and, more rarely, hypertension (18 of 363, 5%). Conduction disorders were often associated with SVAs (11 of 50, 22%). The median time from initiation of treatment with ibrutinib to onset for SVA was about 2-3 months and for hypertension was about 4-5 months. Whereas conduction disorders occurred mainly within the first month of ibrutinib start, contrasting with central nervous system events, HF and VA occurred around 2-3 months.

Conclusions:

The authors concluded that severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib and that these events should be considered in patient care and in clinical trial designs.

Perspective:

Ibrutinib has been living saving in several hematological malignancies. This is a very important study because it highlights the fact that the burden of ibrutinib (and possibly other tyrosine-kinase inhibitors) associated cardiovascular toxicity has been underestimated in prospective randomized clinical trials. These authors have identified important cardiovascular complications not reported earlier. The need for prospective after-market surveillance of this class of drugs for cardiovascular toxicity is urgent to better serve cancer patients and cancer survivors. The authors of this paper need to be congratulated for shining a light on this emerging field of cardiovascular toxicity of cancer therapeutics and this paper is a MUST READ for all those prescribing ibrutinib and tyrosine kinase inhibitors.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension

Keywords: Arrhythmias, Cardiac, Cardiotoxicity, Central Nervous System Neoplasms, Drug-Related Side Effects and Adverse Reactions, Heart Failure, Hypertension, Myocardial Ischemia, Neoplasms, Secondary Prevention, Tachycardia, Supraventricular, Tachycardia, Ventricular, Vascular Diseases


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