LAUSR

Ibrutinib, a first in class Bruton tyrosine kinase inhibitor, has revolutionized treatment for several B-cell malignancies. However, early data suggested that ibrutinib was associated with supra-ventricular arrhythmias (SVA) and bleeding. Other types of cardiovascular adverse drug reactions (CV-ADR) induced by ibrutinib have been sporadically reported. To determine the full spectrum of CV-ADR associated with ibrutinib and provide data concerning their clinical characteristics. An observational, retrospective, pharmacovigilance study VigiBase, the World Health Organization's pharmacovigilance database. A disproportionality analysis using reporting odds-ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and ADR using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) >0 is considered statistically significant. Exposure to ibrutinib versus entire database. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVA; ROR: 23.1 [21.6–24.7]; IC025:3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7 [3.4–4.1]; IC025:1.63), heart failure (HF; ROR: 3.5 [3.1–3.8]; IC025:1.46), ventricular arrhythmias (VA; ROR: 4.7 [3.7–5.9]; IC025:0.96), conduction disorders (CD; ROR: 3.5 [2.7–4.6]; IC025:0.76), CNS ischemic events (ROR: 2.2 [2.0–2.5]; IC025:0.73) and hypertension (ROR: 1.7 [1.5–1.9]; IC025:0.4). CV-ADR occurred early after ibrutinib administration, as soon as after the first dose, with a shorter median time to onset of 27.5 days (IQR: 1–138.5 days) for CD (p<0.01, Kruskal-Wallis), as compared to CNS ischemic events (51 days; IQR: 17.5–160 days, p: 0.05 vs. CD), CNS hemorrhagic events (53.5 days; IQR: 20.3–183.3 days, p: 0.03 vs. CD), HF (54 days; IQR: 20–142.8 days, p: 0.05 vs. CD), VA (70 days; IQR: 28.5–152.5 days, p: 0.03 vs. CD), SVA (74 days; (IQR: 29.5–196.5 days, p: 0.0004 vs. CD) and hypertension (164 days; IQR: 20–274 days, p: 0.04 vs. CD). CV-ADR were associated with fatalities, with rates ranging from ∼10% (SVA and VA) to ∼20% (CNS events, HF and CD). More deaths occurred when SVA cases were associated with CNS hemorrhagic and/or ischemic events compared to their absence (15/52, 28.8% vs. 88/907, 9.7%, p<0.0001, respectively). Severe and occasionally fatal cardiac events related to cardiac SVA, VA, CD, HF, hypertension, CNS hemorrhagic and ischemic events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs.