Cardiovascular safety profiles of proteasome inhibitors: an eudravigilance based disproportionality analysis
A Draghici, Y Shhab, A Tariq, A Altaleb, I Tarabasanu-Mihaila, S Stoleru, A ZugravuAbstract
Background/Introduction
Proteasome inhibitors are cornerstone therapies for multiple myeloma and other hematologic malignancies. The proteasome inhibitor class is heterogeneous, including reversible and irreversible proteasome inhibiting agents and both oral and intravenous formulations. Carfilzomib, bortezomib, ixazomib share emerging concerns regarding cardiotoxicity, particularly heart failure, which may lead to treatment interruption. However, comparative European pharmacovigilance data on cardiovascular adverse events across these agents remain limited.
Purpose
To evaluate reporting patterns of heart failure and related cardiovascular adverse events associated with bortezomib, carfilzomib, and ixazomib using disproportionality analysis of the EudraVigilance database, with the aim of identifying agent-specific cardiotoxicity patterns.
Methods
A retrospective disproportionality analysis was conducted using EudraVigilance. Adverse event reports for carfilzomib, bortezomib, and ixazomib were extracted using MedDRA terminology and categorized into five predefined cardiovascular clusters: heart failure, arrhythmic events, ischemic events, myocardial/pericardial adverse effects, and hypertension. Reporting disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals and corresponding p values. Each proteasome inhibitor was compared with a pooled comparator consisting of the other two agents. A subgroup analysis was performed in elderly patients (>65 years). All statistical analyses and figure generation were performed using R software version 4.5.2.
Results
Carfilzomib demonstrated a clear reporting disproportionality signal for heart failure (784 reports; ROR 3.42, 95% CI 3.10–3.76), which was more pronounced in the elderly subpopulation (419 reports; ROR 3.63, 3.16–3.76). Elevated disproportionality for carfilzomib extended across all cardiovascular clusters, including arrhythmic events (378 reports; ROR 1.85, 1.64–2.09), ischemic events (235 reports; ROR 2.96, 2.51–3.50), myocardial/pericardial adverse effects (184 reports; ROR 2.22, 1.85–2.65), and hypertension, which showed the strongest signal (342 reports; ROR 9.41, 7.80–11.35). In contrast, the reversible proteasome inhibitors ixazomib and bortezomib demonstrated similarly low reporting across heart failure and all other cardiovascular adverse event clusters.
Conclusion(s)
This EudraVigilance disproportionality analysis confirms the cardiovascular safety concerns with carfilzomib, particularly hypertension and heart failure, and demonstrates consistently stronger cardiovascular reporting signals across all event clusters compared with other proteasome inhibitors. These findings highlight clinically relevant differences between irreversible and reversible proteasome inhibitors and support the need for dedicated cardio-oncology surveillance, with particular attention to heart failure in patients receiving carfilzomib.Heart Failure RORsFor image description, please refer to the figure legend and surrounding text.RORs across adverse event clustersFor image description, please refer to the figure legend and surrounding text.