Atrial Fibrillation (AF) and Ibrutinib, a Monocentric Experience: Should Cardiological Evaluation be a Guide in Clinical Practice?

Introduction

Reported prevalence of AF in patients with chronic lymphocytic leukemia (CLL) on ibrutinib is approximately 5-10%. Management of AF in ibrutinib treated patients represents a multidisciplinary and challenging clinical need. Despite therapeutic advances, substantial morbidity and mortality still remain, and preventive or therapeutic strategies need to be implemented. Older age, male gender, arterial hypertension (AH) and valvular heart disease have recently been recognized as strong predictors of AF on ibrutinib. A clear relationship exists between an enlarged left atrium (LA), assessed by transthoracic echocardiography (TTE), and incidence of AF. LA dysfunction at ibrutinib start has been suggested as a predictor of AF: it helps identifying a selected cohort of patients who may benefit from strict follow-up and preventive strategies to reduce incidence of AF and associated complications. To date no prospective clinical trials have been conducted.

Aim

To analyse cardiovascular predictors and incidence of AF in a monocentric population of CLL patients on ibrutinib and in regular cardio-oncologic follow-up.

Methods

From June 2014 to June 2017 we prospectively evaluated CLL patients requiring ibrutinib treatment at our Institution. Before starting therapy a full cardiovascular evaluation including accurate history, clinical examination and assessment of concomitant cardiovascular risk factors and cardioactive therapy were performed by an expert cardio-oncologist. All patients underwent non-invasive instrumental investigations performed by the same clinician: baseline electrocardiography (ECG) was used for rhythm documentation and TTE was focused on studying LA size and function. In a selected group of patients a 24 hours ECG monitoring was performed.

Results

Fourty-three patients on ibrutinib were evaluated for a median of 12 months (range 1-37). Male/female ratio was 2.07 (M/F 29/14) and median age was 71 years (range 54-86). AF occurred in 7 patients (16.3%) after a median period of 6 months from the beginning of ibrutinib. Before starting therapy 30 patients (69.8%) had at least one cardiovascular risk factor, with 23 (53.5%) suffering from AH and 27 (62.8%) having more than one cardiovascular comorbidity. Twenty-three patients (53.5%) were regularly taking at least one cardioactive drug. We observed male gender and AH (p=0.009) to be significantly related to incidence of AF (p=0.04). One or more pre-existent cardiovascular comorbidity was found to be a strong predictive factor for AF (p=0.03). Concomitant cardioactive therapy and incidence of AF failed to show a significant correlation. Analysing TTE data, a strong predictive value of increased LA linear dimensions (p 0.02) and area (p 0.03) clearly emerged. Sixteen patients (37.2%) were evaluated through prolonged ECG-monitoring. We observed a trend to significance (p=0.07) of a higher maximal heart rate (HR) (109,5±0,7) reached in AF patients compared to those in stable sinus rhythm (73,35±30,6): higher HR, uncovering an increased sympathetic tone, is known to be a risk factor for AF. No significant correlation emerged between occurrence of AF and atrial conduction abnormalities recorded by baseline ECG.

Conclusions

Due to the widespread use of ibrutinib in CLL population prompt recognition of AF high risk patients represents an emerging issue.As reported in literature, male sex and AH significantly correlate with AF development. LA enlargement represents a strong predictive factor for AF and TTE can reliably be used as a non-invasive exam to detect early signs of atrial dysfunction. In our cohort AF has occurred in a slightly higher percentage of patients treated with Ibrutinib than in literature. This finding, especially if validated in a larger CLL cohort, can suggest that silent, undetected AF is a common and a often underdiagnosed event in older patients with multiple risk factors. These initial results support a systematic cardiologic monitoring and AF screening program. Proper cardiological evaluation aims to identify patients at higher risk of AF. Educating patients to early recognize adverse events and behave accordingly to clinician's instructions allow to avoid unnecessary drug suspension. Comorbidity control and implementation of cardioactive therapy by an expert cardio-oncologist, preventing LA dilation and dysfunction, could be pursued as a means of reducing AF on ibrutinib.