Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment

Majed S Al Yami,1,2 Sawsan Kurdi,2,3 Ivo Abraham2,4,5 1Department of Pharmacy Practice, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 2Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ, USA; 3Department of Pharmacy Practice, University of Dammam, Dammam, Saudi Arabia; 4Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA; 5Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA Background: Standard-duration (7–10 days) thromboprophylaxis with low molecular weight heparin, low dose unfractionated heparin, or fondaparinux in hospitalized medically ill patients is associated with ~50% reduction in venous thromboembolism (VTE) risk. However, these patients remain at high risk for VTE post-discharge. The direct oral anticoagulants (DOACs) apixaban, rivaroxaban and betrixaban have been evaluated for extended-duration (30–42 days) thromboprophylaxis in this population. Methods: We review the efficacy and safety results from the 3 pivotal trials of extended-duration DOAC thromboprophylaxis in medically ill patients. We performed a meta-analysis of these pivotal trials focusing on 6 VTE (efficacy) and three bleeding outcomes (safety). These results were integrated into a quantitative risk/benefit assessment. Results: The trials evaluating extended-duration DOAC thromboprophylaxis in medically ill patients failed to establish clear efficacy and/or safety signals for each agent. Our meta-analysis shows that, as a class, DOACs have selective and partial extended-duration prophylactic activity in preventing VTE events. However, this is associated with a marked increase in the risk of various bleeding events. The risk/benefit analyses fail to show a consistent net clinical benefit of extended-duration DOAC prophylaxis in medically ill patients. Conclusion: At this time, the evidence of safe and effective extended-duration thromboprophylaxis with DOACs in this population is inconclusive. Keywords: venous thromboembolism, direct oral anticoagulants, enoxaparin, thromboprophylaxis, medically ill patients