Given the widespread use of ibrutinib, patients and clinicians must be aware of the cardiotoxicity of the medication. Atrial fibrillation is the most commonly encountered cardiac arrhythmia and contributes to myriad complications. Our single-institution study examined the incidence of new-onset atrial arrhythmia in patients with and without pre-existing CVD treated with ibrutinib for various hematologic malignancies, most commonly CLL. Hypertension, diabetes, hyperlipidemia, and COPD were the most significant comorbidities in our cohort of patients with prior CVD and remain amongst the most common causes of major modifiable risk factors for CVD across the general population (Table 1). While the association between ibrutinib use and the development of atrial fibrillation has been previously cited in the literature as high as 6–16% (13, 14, 15), our data demonstrated that patients with pre-existing CVD prior to initiation of ibrutinib were nearly three-times more likely to develop atrial fibrillation than those without prior CVD. A previous study demonstrated that an elevated Framingham Heart Study-AF score was associated with increased incidence of atrial fibrillation in those receiving ibrutinib therapy (16). Survival probability estimates also differed significantly for those patients with a history of CVD versus those without CVD, with an absolute difference of 11% in those patients with prior CVD vs. those without CVD within our follow-up. Previous studies have demonstrated the time-to-onset of atrial fibrillation after ibrutinib initiation to occur within the first year of ibrutinib initiation (17, 18), making our mean follow-up time of 1.1 years to be adequate.
The pathophysiology of atrial fibrillation is multifactorial, and various etiologies have shown association with the development of atrial fibrillation. In particular, cardiac conditions associated with persistent inflammation and ischemia have been implicated in the development of atrial fibrillation. Valvular heart disease, congestive heart failure, and coronary artery disease also increase the likelihood of atrial fibrillation. Elevated filling pressures within the atria, either due to hemodynamically significant valvular disease or diminished cardiac function, leads to eventual chamber dilation and resultant fibrosis. This cardiac remodeling provides the foundation for the electrical disturbances, primarily through ion channel dysfunction and myocyte uncoupling associated with atrial fibrillation (19). On a molecular level, profibrotic growth factors, such as transforming growth factor-beta1 (TGF-B1) and platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF), are upregulated as a result of various cardiac injury (20).
Disruptions in molecular signaling also provide insights into the association of ibrutinib and atrial fibrillation. Through the binding to cysteine 481 residue of BTK, ibrutinib inhibits the dysregulated B-cell receptor signaling responsible for proliferation and survival in B-cell malignancies (21, 22). BTK is expressed in human cardiac tissue and appears to be expressed greater in patients with atrial fibrillation compared to those in normal sinus rhythm (23, 24), which could explain the pro-arrhythmogenic effects of ibrutinib in atrial dysrhythmias. Similar sequela of atrial dysfunction has been seen in those with genetic mutations of tyrosine kinase pathways, such as the KCNA5 mutation which encodes the ultrarapid delayed rectifier potassium channel that then in turn modulates tyrosine kinase signaling (25). Other in vivo animal studies have suggested that ibrutinib induces atrial fibrillation through structural remodeling and dysregulated calcium handling within atrial myocytes (26).
Our study demonstrates the increased rate of atrial fibrillation and decreased survival in patients with pre-existing CVD initiated on ibrutinib for hematological malignancies. No formal guidelines exist for how to monitor and treat this population, although some strategies have been proposed through the assessment of hemodynamic stability, ECG and echocardiograph findings, and careful assessment of drug-drug interactions in rate/rhythm control pharmacotherapy (26). While most studies on the management of atrial fibrillation are in patients without malignancy, cancer patients with atrial fibrillation are at an increased risk of both heart failure and thromboembolism (27). In addition to anticoagulation medications, rate and rhythm control medications also interact with ibrutinib through the CYP450 CYP3A metabolic pathway, making management of atrial fibrillation difficult (28). Surveillance electrocardiography in order to identify left atrial abnormalities has been identified as a simple clinical tool, especially in the early stages of treatment (29). Routine blood pressure monitoring should also be part of regular surveillance metrics as worsening hypertension has also been associated with ibrutinib use (30, 31). More studies are warranted to help create sound clinical guidelines for the management of atrial fibrillation in patients being treated with ibrutinib with careful consideration to stroke risk and other cardiac complications.
Our study was limited due to a relatively small sample size and inherent nature of retrospective studies. Additionally, our search for patients on ibrutinib was limited to our institutional EMR only. From the chart review, it was difficult to locate exact dates or timing of atrial fibrillation, and “time-to-event” was not possible. Our decision to include patients with various cardiac conditions was based on our referral patterns, but future studies should focus on the impact of specific cardiovascular conditions on ibrutinib patients. Many echocardiographic variables, such as atrial size, are not available since the majority of patients did not undergo routine echocardiography before and while on ibrutinib. Therefore, we couldn’t adjust for these variables.
Our study highlights important implications for management of patients on Ibrutinib. While our study did not reveal statistically significant differences in bleeding events between the two cohorts, predisposition to bleeding is a well-known side effect of ibrutinib (32, 33). This must be taken into consideration when either initiating, continuing, or terminating anticoagulation therapy for stroke and thromboembolic prevention in patients receiving ibrutinib therapy, as certain groups of patients may already be receiving antiplatelet therapy. This also presents a clinical conundrum in the decision of whether to discontinue ibrutinib at the expense of progressive oncologic disease or to continue ibrutinib treatment with the risk of cardiovascular compromise. Our study did not reveal a difference in the rate of ibrutinib discontinuation in our two cohorts; however, atrial fibrillation remains the most common cause of ibrutinib discontinuation in treated patients (34, 35).