Atrial Fibrillation and Bleeding in Patients With Chronic Lymphocytic Leukemia Treated with Ibrutinib in the Veterans Health Administration
Background: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. The introduction of novel oral agents, starting with ibrutinib in 2013, has revolutionized the therapeutic landscape; however, clinical trials have suggested an association between ibrutinib and the risk of bleeding-related adverse events and atrial fibrillation (Afib) in patients with CLL.
Methods: Patients diagnosed and treated for CLL at the Veterans Health Administration (VHA) from 2010 to 2014 were followed until December 31, 2016, death, or lack of utilization of hematology/oncology services for ≥ 18 months; or until incidence of another cancer. Treatments dispensed, evidence of VHA system use, bleeding events, and Afib were determined from the administrative records, laboratory records, pharmacy dispensation records, and clinical notes in the electronic healthcare record.
Results: From 2010 to 2014, 2,796 patients were diagnosed and received care for CLL within the VHA, of whom 172 patients received ibrutinib and 291 received bendamustine + rituximab (BR). The use of anticoagulants following induction therapy did not differ between BR and ibrutinib patients (9% vs 8%, respectively), nor did the use of antiplatelets agents (6% vs 2%, respectively). Of the 291 patients that received BR, 12 (4%) developed a bleeding event compared with 20 (12%) who received ibrutinib. Additionally, 13 (8%) ibrutinib patients developed Afib compared with 9 (3%) BR patients.
Conclusions: Real-world evidence from a nationwide cohort of patients with CLL suggests that while ibrutinib is associated with increased bleeding-related adverse events and Afib, the risk is comparable to those reported in previous clinical trials. These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at an increased risk for bleeding events and Afib.
A single-site observational study of patients treated with ibrutinib reported a high utilization rate of antiplatelet medications (70%), anticoagulant medications (17%), or both (13%) with a concomitant major bleeding rate of 18% of patients.11 Prevalence of bleeding events seemed to be highly affected by the presence of concomitant medications: 78% of patients treated with ibrutinib while concurrently receiving both antiplatelet and anticoagulant medications developed a major bleeding event, while none of the patients who were not receiving antiplatelets, anticoagulants, or medications that interact with cytochrome P450 (an enzyme that metabolized chemotherapeutic agents used to treat cancer) experienced a major bleeding event.11
The prevalence of major bleeding events, comorbidities, and utilization of medications that could increase the risk of major bleeding in patients with CLL on ibrutinib in the Veterans Health Administration (VHA) is not known. The VHA is the largest integrated health care system in the US. To address these knowledge gaps, a retrospective observational study was conducted using data on demographics, comorbidities that could affect bleeding, use of anticoagulant and antiplatelet medications, and bleeding events in patients with CLL who were treated in the first year of ibrutinib availability from the VHA.
The first year of ibrutinib availability was chosen for this study since we anticipated that many health care providers would be unfamiliar with ibrutinib during that time given its novelty, and therefore more likely to codispense ibrutinib with medications that could increase the risk of a bleeding event. Since Afib is both an AE associated with ibrutinib treatment and a condition that often is treated with anticoagulants, the prevalence of Afib in this population was also included. For context, the incidence of bleeding and Afib and use of anticoagulant and antiplatelet medications during treatment in a cohort of patients with CLL treated with bendamustine + rituximab (BR) also was reported.
Methods
The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.
Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.12 Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.
