Ibrutinib linked to cardiovascular toxicities

Although ibrutinib has revolutionized treatment for several B-cell malignancies, patients exposed to this drug are more likely to experience severe and occasionally fatal cardiac events, according to a study.

“[A] recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy,” the investigators said. “Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.”

Overall, 303 ibrutinib-related cardiovascular deaths were identified. Ibrutinib was associated with increased incidence of supraventricular arrhythmias (SVAs; reporting odds ratio [ROR], 23.1, 95 percent CI, 21.6–24.7; p<0.0001; information component (IC)₀₂₅, 3.97), central nervous system (CNS) haemorrhagic events (ROR, 3.7, 3.4–4.1; p<0.0001; IC₀₂₅, 1.63), heart failure (ROR, 3.5, 3.1–3.8; p<0.0001; IC₀₂₅, 1.46), ventricular arrhythmias (ROR, 4.7, 3.7–5.9; p<0.0001; IC₀₂₅, 0.96), conduction disorders (ROR, 3.5, 2.7–4.6; p<0.0001; IC₀₂₅, 0.76), CNS ischaemic events (ROR, 2.2, 2.0–2.5; p<0.0001; IC₀₂₅, 0.73) and hypertension (ROR, 1.7, 1.5–1.9; p<0.0001; IC₀₂₅, 0.4).

Cardiovascular adverse drug reactions (CV-ADR) usually occurred early following ibrutinib administration and were associated with fatalities, ranging from ∼10 percent (SVAs and ventricular arrhythmias) to ∼20 percent (CNS events, heart failure and conduction disorders). Ibrutinib-related SVA correlated with poor prognosis when CNS events occurred concomitantly, with 15 of 52 (28.8 percent) patients dying.

“These events should be considered in patient care and in clinical trial designs,” the investigators said.

VigiBase (International pharmacovigilance database) was used in this study, and a disproportionality analysis was performed using ROR and IC to determine whether CV-ADR and CV-ADR deaths correlated with ibrutinib. IC compared observed and expected values to assess relationships between drugs and ADRs using disproportionate Bayesian-reporting; IC₀₂₅ >0 is significant.