Weighing the Risk and Benefits of Direct Oral Anticoagulants in Morbidly Obese Patients: New Data and Guidance

In the United States, over the past two decades, the prevalence of severe obesity (body mass index [BMI] > 40 kg/m²) in adults has almost doubled (from 4.7% to 9.2%).¹  Obesity is a well-recognized risk factor for venous thromboembolism (VTE), and one third of incident idiopathic VTE events can be attributed to obesity.²  Yet there have been concerns about possible loss of efficacy of direct oral anticoagulants (DOACs) in this population. According to drug labeling in the United States for adults with acute VTE, no dose modifications are recommended across the spectrum of body weights (except for edoxaban, which reduces the dose to 30 mg daily for weight ≤ 60 kg). However, due to concerns about inadequate clinical data in patients with severe obesity (> 120 kg or BMI > 40 kg/m²) and concern for reduced drug exposure, the International Society on Thrombosis and Haemostasis Scientific Subcommittee published a guidance document in 2016 suggesting that DOACs be avoided.

Since this guidance in 2016, additional studies and analyses examining this question have been published. Dr. Karlyn Martin and colleagues performed a literature search through August 1, 2020, reviewing the data on DOACs for VTE treatment and provided new, updated recommendations. Authors examined data from several domains: clinical treatment of VTE, dose reduction for extended VTE treatment, VTE prevention, pharmacokinetic/pharmacodynamic (PK/PD) information, and data in relation to bariatric surgeries. Among 12 phase III and IV clinical studies of VTE treatment, none demonstrated increased adverse outcomes with pooled or specific DOAC analyses, but with varying comparators and differing cut-off levels to define the obese populations. Only two studies evaluated reduced-dose apixaban/rivaroxaban for extended VTE treatment, and the analyses of these data were felt to be insufficient to make recommendations regarding severely obese individuals. In the setting of VTE prevention, no studies were identified analyzing betrixaban by weight. Data in this setting for apixaban and rivaroxaban did show similar safety and efficacy in the higher strata of weight, though it was not examined specifically in the severely obese (BMI > 40 kg/m²). For dabigatran, however, a possible signal of lack of efficacy was seen in patients with BMI higher than 40 kg/m², with three (7.1%) of 42 patients treated with dabigatran versus one (2.3%) of 43 patients on enoxaparin having VTE.³ 

The authors conclude with six guidance statements for treatment of VTE with DOACs in obese patients. Recommendations for obese patients with a weight less than 120 kg or a BMI lower than 40 kg/m² remained unchanged from 2016 and deem all DOACs within this population to be appropriate. In a reversal from the initial guidance, both rivaroxaban and apixaban at standard doses were felt to be reasonable choices in patients with severe obesity; however, it was suggested not to use dabigatran, edoxaban, or betrixaban within this population due insufficient clinical and/or PK/PD studies. For primary prevention of VTE, the data suggested that prophylactic doses of rivaroxaban and apixaban for approved indications were reasonable in the severely obese. In the initial guidance it was suggested that DOAC-specific drug levels could be obtained when in question; however, the current guidance suggests not to do this in the severely obese due to a lack of data to influence management decisions (with one caveat below). The final guidance statement specifically addressed patients with prior bariatric surgery and suggested that the oral bioavailability of DOACs might be most limited in the first month after surgery and that VTEs occurring at this time might be better treated with parenteral agents, with subsequent consideration of a DOAC or vitamin K antagonist at a later time. If a DOAC was chosen, it was thought to be reasonable to check drug absorption and bioavailability with a trough drug level.