Comparing direct oral anticoagulants and vitamin K antagonist use in morbidly obese patients with venous thromboembolism: A single center retrospective cohort study

Abstract Introduction: Limited data exists on the safety and efficacy of direct‐acting oral anticoagulants (DOAC) use in morbidly obese patients with venous thromboembolism (VTE). Given the benefits of DOAC use over vitamin K antagonists (VKAs), in terms of monitoring requirements, and dietary and drug interactions, it is important to evaluate whether this is consistent in the higher risk for VTE recurrence morbidly obese group body mass index (BMI ≥ 40 kg/m2). Materials and methods: This retrospective, single‐center cohort study included patients with a BMI of at least 40 kg/m2 who were admitted to Emory University Hospital from 1st January 2012 to 31st May 2020 with acute VTE, and subsequently initiated on anticoagulation treatment with either DOAC or VKA (warfarin). Univariate and bivariate analyses were used to evaluate differences in demographics by treatment type and BMI. Multivariate Cox proportional hazard regression was used to assess the risk of VTE recurrence by type of treatment among morbidly obese patient subgroup. Results: There were 247 (11.8%) morbidly obese (≥ 40 kg/m2) patients who were more likely than non‐obese patients to be younger, female, and of non‐white race. Thirty percent of the study population (n=74) had a BMI >50 kg/m2. T ime‐to‐event analysis confirmed that the hazard of experiencing a recurrent thrombosis was not statistically significantly different among morbidly obese patients treated with a DOAC compared with VKA (hazard ratio [HR]: 0.28, confidence interval [CI] 0.07‐1.11, p = 0.07). Conclusions: This study aligns with previous literature and confirms that morbidly obese patients receiving DOAC or VKA have similar risks of recurrent VTE.


INTRODUCTION
Direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism (VTE) has replaced vitamin K antagonists (VKAs) as the standard of care. Compared with VKAs which have a narrow therapeutic window, need for monitoring, and have many food and drug interactions, DOACs offer many advantages including their ease of administration, fixed dosing, fast onset and offset of action, fewer drug and food interactions, lower bleeding risk, and the lack of need for routine monitoring [1][2][3][4]. DOACs include dabigatran, rivaroxaban, apixaban, and edoxaban. Compared to VKAs, DOACs were equally effective in preventing recurrence, and are associated with less bleeding [4].
Obesity is associated with a greater risk of VTE and is a substantial public health problem in the United States with a prevalence of 42.4% in 2017-2018 among adults [5][6][7]. Unfortunately, the safety and efficacy of DOACs in obese patients is unclear as patients with weights > 120 kg were not included in the phase 3 licensing trials of these products [8]. Given that DOACs are associated with less bleeding and similar efficacy as VKA and that obesity increases the risk of VTE, it is important to evaluate the effectiveness of treatments within this group [4][5][6]. Observational data evaluating the efficacy and safety of DOACs in obese patients has been evolving through reports of real-world and observational studies. A large study analyzing data from two US claims databases found that morbidly obese patients with VTE receiving rivaroxaban had similar risks of recurrent VTE and major bleeding compared with patients treated with warfarin [9].

Recent guidelines from the International Society of Hemostasis and
Thrombosis suggested the DOACs can be safely used in those with a BMI > 40 kg/m 2 ; however, as the body mass index (BMI) approaches or exceeds 50 kg/m 2 the data supporting the use of DOAC thins [10]. The objective of this study is to quantify the difference in the risk of VTE recurrence in morbidly obese patients at 6 months, 1 year, and 5 years after acute VTE by type of treatment, hypothesizing that there will not be a statistically significant difference in risk of recurrent VTE in morbidly obese patients treated with DOAC or VKA.

Outcome
A recurrent VTE was defined as readmission with a new VTE confirmed by ultrasound for DVT or CTA for PE and determined through individual review of clinical medical record. We confirmed a recurrent DVT and PE based on reading radiologist's report that interpreted the clots as new and true clots.

Statistical analysis
Descriptive statistics and tests for group differences were employed.

RESULTS
Our entire cohort consisted of 2175 VTE patients, with 247 morbidly obese patients (Figure 1 year, and 5 years, respectively ( Table 3). The risk of recurrent VTE was not statistically significantly different between DOAC and VKA treatment among morbidly obese patients, p = 0.07 ( Figure 2). In patients with super obesity, there were no recurrences among those treated with DOACs (n = 40) and 2 recurrences occurred among those treated with VKA (n = 36).

DISCUSSION
The present study found that patients with morbid obesity (average the findings were not statistically significant [14]. In clinical trials of DOACs for extended anticoagulation, recurrence rates at 12 months were 1.2%-1.7% on VKA 0.7% [15,16]. Recurrence rates in this study population were lower than expected for those on DOACs and higher for those on VKA, though within the CIs of this study population.