AN EVALUATION OF THE EFFECTIVENESS AND SAFETY OF DIRECT ORAL ANTICOAGULANTS VERSUS WARFARIN IN CHRONIC LIVER DISEASE, AND AFTER ANTICOAGULANT-RELATED MAJOR BLEEDING

Abstract

The introduction of direct oral anticoagulants (DOACs) in the last decade have greatly expanded available treatment options for the management of thromboembolic diseases. Based on their non-inferiority in efficacy and safety, and more convenient dose monitoring and adjustment compared to warfarin, DOACs are now considered the first-line treatment option in the management and prevention of venous thromboembolism (VTE) and nonvalvular atrial fibrillation (NVAF). While the use of DOACs continues to increase in the general population, limited evidence exists to support its use in chronic liver disease (CLD). Of note, individuals with elevated liver enzymes, liver cirrhosis or CLD were excluded from the pivotal randomized clinical trials (RCTs) for DOACs. There is also a paucity of large, population-based comparative effectiveness and safety studies of DOACs and warfarin in individuals with indication for oral anticoagulation (NVAF or VTE) and CLD. To this end, we conducted two studies to assess the comparative effectiveness and safety of DOACs (individually and as a class) and warfarin in patients with CLD and NVAF (Aim 1) or VTE (Aim 2). Oral anticoagulants interfere with the normal hemostatic process, inadvertently increasing the risk of bleeding. Consequently, among individuals with NVAF on oral anticoagulants, bleeding is the most prevalent major treatment-related adverse events, with gastrointestinal bleeding (GIB) the most common. Individuals who survive a major bleeding event while on oral anticoagulant treatment face the competing risks of stroke (if oral anticoagulation is discontinued), recurrent bleeding (if oral anticoagulation is restarted), and mortality. The general consensus in review articles and contemporary guidelines is to restart oral anticoagulation (often within a month) after hospitalization for major GIB. However, there is limited comparative effectiveness and safety data to guide the selection of DOACs versus warfarin after major GIB. To address this evidence gap, in Aim 3, we evaluated the effectiveness and safety for DOACs versus warfarin in individuals with NVAF who restarted oral anticoagulant treatment after surviving a major GIB event. These three aims are presented in a manuscript format, with three distinct manuscripts each containing an abstract, introduction, methods, results, discussion and conclusion section. All three aims were conducted using 2010 – _2017 data submitted to the Optum Clinformatics database - a deidentified claims data of beneficiaries of commercial and Medicare Advantage health insurance plans throughout the US. Manuscript 1. In this retrospective cohort study, 10,209 subjects with NVAF and CLD initiated oral anticoagulation with DOACs (apixaban, dabigatran, edoxaban or rivaroxaban)