The study received approval from the University of Utah Institutional Review Board and used individual patient-level historical administrative, cancer registry, and electronic health care record data. Patients diagnosed and treated for CLL at the VHA from 2010 to 2014 were identified through the VACRS and CDW; patients with a prior malignancy were excluded. Patients who received ibrutinib or BR based on pharmacy dispensation information were selected. Patients were followed until December 31, 2016 or death; patients with documentation of another cancer or lack of utilization of the VHA hematology or oncology services (defined as absence of any hematology and/or oncology clinic visits for ≥ 18 months) were omitted from the final analysis (Figure).
Previous and concomitant utilization of antiplatelet (aspirin, clopidogrel) or anticoagulant (dalteparin, enoxaparin, fondaparinux, heparin, rivaroxaban, and warfarin) medications was extracted 6 months before and after the first dispensation of ibrutinib or BR using pharmacy dispensation records.
Study Definitions
Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.13 Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.14 The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.15 Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.16
A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.17 Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.
