Characterization of Atrial Fibrillation and Bleeding Risk Factors in Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Retrospective Cohort Study of Administrative Medical Claims Data in the United States (US)
Authors: Barrientos Jacqueline C. , Meyer Nicole , Song Xue , Rai Kanti R 
Published: October 2019

Abstract
Background:
CLL is the most common form of adult leukemia in the Western World. It primarily affects the elderly with ~70% of patients diagnosed ≥65 years of age. Therapy is reserved until symptoms occur, when most patients have multiple chronic comorbidities including hypertension, arrhythmias, and other conditions that require the use of anticoagulants and/or antiplatelet agents. Understanding the frequency of use of these agents and bleeding events in routine clinical practice could provide additional insights on the real-world burden of the use of these drugs in patients with an underlying predisposition to bleeding due to CLL-related thrombocytopenia and other comorbidities. This is particularly relevant as several chemoimmunotherapy regimens used in CLL may have direct cardiotoxic and antiplatelet effects. Most importantly, emerging evidence suggests that some of the recently approved targeted agents may be associated with risk of cardiac arrhythmias or bleeding events. The mechanisms behind these events and the relations between them are largely unclear but affect the quality of life of CLL patients. The aim of this retrospective database study was to characterize the outcomes of newly diagnosed CLL patients in terms of: [1] incidence of atrial fibrillation (AFIB), [2] incidence of AFIB risk factors, [3] bleeding risk factors as measured by the 5-variable Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score (which quantifies the risk of drug-associated hemorrhage), and [4] anticoagulant/antiplatelet drug usage over the course of their treatment.
Methods:
Based on administrative medical claims from the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases in the US, we identified adults diagnosed with CLL between 1/1/2004 - 4/30/2015. Patients selected for this study were required to have at least two treatment lines where the 2nd line treatment represented a change in initial therapy (index date = start of 1st line treatment). anticoagulant/antiplatelet use, incidence of AFIB (per 10,000 patient days), and ATRIA bleeding risk score were assessed during 1st and 2nd line treatment. Patients were continuously enrolled for ≥ 6 months (baseline) before index date, and followed until disenrollment from the health plan or 4/30/2015, whichever came first.
Results:
Of approximately 67 million adults (per year) in the database, we identified 2,335 adults with newly diagnosed CLL (mean age: 62 years; 66% male; 46% Medicare as primary payer) treated with antineoplastic therapy and followed for a mean of 35.3 months. The mean duration of first line treatment was 3.3 months, and 4.1 months for 2nd line treatment. Anticoagulant/antiplatelet use at baseline was common (25%), and use increased during 1st line (31%) and 2nd line (32%) treatment. During follow-up, the incidence of AFIB during 1st line and 2nd line treatment was 4.57 and 5.70/10,000 person days (95% CI: 3.7-5.5 and 4.8-6.6), respectively. The proportion of patients with ATRIA scores indicating moderate (ATRIA score 4) to high (ATRIA score ≥ 5) risk of bleeding increased from initial therapy (1st line treatment = 18%) to salvage therapy (2nd line treatment = 22%) [see Figure].
Conclusions:
We provide the first real-world estimates of anticoagulant/antiplatelet use, AFIB, AFIB risk, and bleeding risk factors in adult patients newly diagnosed with CLL in the US. In our study, the use of anticoagulant/antiplatelet agents at diagnosis was common (25%) and increased over time from 1st to 2nd line treatment. Similarly, AFIB incidence and the ATRIA bleeding risk score also increased over the course of the natural disease progression. Since ATRIA scores of ≥ 5 correlate with a 5.8% annual risk of major hemorrhage, understanding the characteristics of the CLL patients at diagnosis and relapse will ultimately help optimize treatment selection based on the potential risks and benefits of each individual treatment regimen. These data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CLL.

Disclosures
Barrientos: Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Meyer:Truven Health Analytics: Employment. Song:Truven Health Analytics: Employment. Rai:Leon Levy Foundation: Research Funding; Nash Family Foundation: Research Funding; Nancy Marks Family Foundation: Research Funding; Karches Family Foundation: Research Funding.