Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH

Abstract

Four direct-acting oral anticoagulants (DOACs) – the thrombin inhibitor dabigatran, and the activated factor X (FXa) inhibitors apixaban, edoxaban, and rivaroxaban –are approved in many countries for the treatment of venous thromboembolism (VTE), the prevention of VTE after hip and knee arthroplasty, and ischemic stroke prevention in patients with non-valvular atrial fibrillation (AF). Because of their fixed dosing – without the need for routine monitoring – and limited dietary interactions, they are used as a convenient anticoagulant alternative to vitamin K antagonists (VKAs). In the product labeling (package inserts) of the approved DOACs, none has a dose adjustment for high weight or body mass index (BMI) in obese categories. However, there is uncertainty about their efficacy and safety in the obese population, with ‘obese’ defined by the National Institutes of Health as a BMI between 30 kg m−2 and 40 kg m−2, and ‘extreme obesity’ as a BMI of > 40 kg m−2. Although a recent publication has suggested recommendations for use of DOACs in the obese population [1], data from clinical outcomes studies and pharmacokinetic (PK)/pharmacodynamic (PD) studies regarding the efficacy and safety of DOACs in obese patients are limited. We reviewed the available data on the use of DOACs in obese patients through a PubMed search of key terms, including each DOAC in combination with the terms ‘pharmacokinetic’, ‘pharmacodynamic’, ‘drug level’, ‘VTE’, ‘VTE prophylaxis’, and ‘atrial fibrillation’. Data on obese patients in phase III clinical trials were pooled by anticoagulation indication to obtain risk ratios for DOACs versus VKAs. Guidance statements were then developed to provide practical guidance for clinicians regarding the use of DOACs in obese patients.