Association Between the Renin–Angiotensin System and Ibrutinib-Related Cardiovascular Adverse Events: A Translational Cohort Study

Background: Ibrutinib has been associated with an increased risk of cardiovascular adverse events (CVAEs), including atrial fibrillation (AF), hypertension (HTN), heart failure (HF), and ventricular arrhythmias (VAs). However, baseline predictors of CVAEs remain poorly characterized. In this study, we sought to identify baseline patient characteristics associated with the occurrence of ibrutinib-related CVAEs, with particular emphasis on parameters linked to the renin–angiotensin system. Methods: We conducted a prospective, single-center cohort study of consecutive patients treated with ibrutinib for B-cell malignancy, with systematic assessment of a predefined panel of potential predictors of CVAEs at baseline (NCT03678337). These predictors included demographic and clinical variables, 16 circulating biomarkers related to inflammation, fibrosis, and neurohormonal activation, as well as nine echocardiographic parameters. The primary objective was to evaluate the association between baseline patient characteristics and the occurrence of CVAEs from ibrutinib initiation through the end of follow-up. The CVAE endpoint was defined as a composite of atrial fibrillation, new or worsening hypertension, new or worsening heart failure, and ventricular arrhythmias. Statistical analyses were performed using the Wilcoxon–Mann–Whitney test or Fisher’s exact test, with a p-value < 0.05 considered statistically significant. Results: Among the 25 patients included, 7 experienced a total of 9 CVAEs over a median follow-up of 672 days. Elevated baseline plasma renin levels (>1336.10 pg/mL) were significantly associated with CVAEs occurrence (57% vs. 11%, p = 0.032). Higher baseline plasma aldosterone levels (>488.95 pg/mL) were also observed in patients who developed CVAEs, although this association did not reach statistical significance (p = 0.058). Conclusions: Baseline plasma renin level was univariably associated with CVAEs occurrence, while plasma aldosterone levels were higher among patients with CVAEs but did not reach statistical significance. These findings provide preliminary insights into the mechanisms underlying ibrutinib-related cardiovascular toxicity, suggesting a potential role for the renin–angiotensin–aldosterone system. Confirmation of this hypothesis, however, will require larger, dedicated studies.