Oral anticoagulant therapy for acute VTE in obese patients

Although direct-acting oral anticoagulants (DOACs) are widely recommended for first-line treatment of venous thromboembolism (VTE), their use in obese patients remains controversial due to the limited representation of such patients in clinical trials. As the prevalence of obesity continues its upward trend, clinicians increasingly have to make treatment decisions for obese patients. MIMS Doctor interviewed Adjunct Assistant Professor Pankaj Kumar Handa, Senior Consultant at Tan Tock Seng Hospital, Singapore, to gain his perspectives on oral anticoagulation in obese patients.

Obesity increases the risk of VTE
Obesity, defined as a BMI of at least 30 kg/m², is increasing worldwide, with rates that have nearly tripled between 1975 and 2016. [https://www.who.int/newsroom/fact-sheets/detail/obesity-and-overweight] In Singapore, the crude prevalence of obesity was 10.5 percent among adult residents in 2020, up from 8.6 percent in 2017. [https://www.moh.gov.sg/resources-statistics/reports/national-survey-2019-20]

VTE is the third most common cause of vascular mortality worldwide and comprises deep-vein thrombosis (DVT) and pulmonary embolism (PE). [Circ Res 2016;118:1340-1347]

“Obesity is a moderate risk factor for VTE. The risk appears to be at least twice that of normal-weight individuals and increases with increasing BMI. Those with a BMI of ≥35 kg/m² may present a sixfold greater risk of VTE than those with normal BMI,” said Handa.

“Various physiological mechanisms link obesity with the development of VTE. First, the physical effects of body fat limit venous return; second, visceral fat releases non-esterified fatty acids which contribute to a chronic pro-inflammatory state; third, increased coagulation factors and impaired fibrinolysis result in a prothrombotic and hypofibrinolytic milieu,” he added. [Med Pharm Rep 2020;93:162-168]

DOAC choice in obese patients: Recommendations vs practice
“The use of DOACs in obese patients is a somewhat contentious issue owing to the paucity of study data on subjects weighing >100 kg. Current guidelines, such as the 2021 CHEST Guideline and Expert Panel Report on antithrombotic therapy for VTE, advise against the use of DOACs in patients with a body weight of >120 kg or BMI >40 kg/m². Warfarin is preferred for morbidly obese patients unless contraindicated, as dose can be adjusted per international normalized ratio (INR), allowing for more accurate individual dosage,” explained Handa. [Chest 2021;160:2247-2259]

However, the 2021 International Society on Thrombosis and Haemostasis (ISTH) guidelines suggest that for the treatment of VTE, standard doses of apixaban or rivaroxaban are among appropriate anticoagulant options regardless of elevated BMI and weight. Vitamin K antagonist (VKA), weight-based low-molecular-weight heparin (LMWH), and fondaparinux are also appropriate options. [J Thromb Haemost 2021;19:1874-1882]

“Practice in Singapore may vary, but many physicians use a DOAC as the drug of choice in obese patients, including those with a BMI of >40 kg/m² or >120 kg, which we see in our clinics occasionally. Some physicians like to monitor anti-factor Xa levels.  In the past, we used to treat patients with LMWH, often monitored with anti-factor Xa levels. For the past couple of years, I have been using only apixaban for the management of VTE in obese patients,” Handa said. “My experience may not be large, but I have not had any issues with apixaban in terms of efficacy and safety. Since DOACs can be given orally, they are currently preferred by patients over LMWH, which is administered via injection,” he added.

Evidence for DOACs in obese patients with VTE
Recently, several retrospective observational cohort studies have investigated the effectiveness and safety of DOACs in obese and morbidly obese patients with VTE.

Study 1
A retrospective matched cohort study evaluated the effectiveness and safety of DOACs (apixaban, dabigatran, or rivaroxaban) compared with warfarin for the treatment of acute VTE in obese patients (weight between 100 and 300 kg). Among 1,840 adults with acute VTE, there was no significant difference in the recurrence of VTE between patients who received a DOAC (n=632) or warfarin (n=1,208). In addition, there were no significant differences in the occurrence of PE and DVT between the DOAC- and warfarin-treated patients respectively. Bleeding rates were also similar (Table 1). [Pharmacotherapy 2020;40:204-210]

“These results showed that DOACs can be a good alternative to warfarin in obese patients,” commented Handa. “The study is the largest to date on the outcomes of DOAC vs warfarin treatment for acute VTE among obese patients.”

Nearly half of the study cohort (45 percent) had a weight of >120 kg and a BMI of >40 kg/m². Unlike prior studies that only included patients who were newly started on anticoagulation, this study also included patients receiving anticoagulation before the index visit, in addition to those who received anticoagulation for acute VTE. There was no significant difference in VTE recurrence between groups regardless of treatment acuity, thus providing insights into differences in patient populations at varying thrombotic risks, added Handa.

“The main limitation of the study is its retrospective design. Anticoagulation treatment decisions were left to the provider’s discretion and clinical factors that could have influenced the choice of therapy, such as concomitant use of medicines, may not have been fully accounted for,” he said.

Study 2
An observational, real-world study pooled five US healthcare claims databases to evaluate the risk of recurrent VTE, major bleeding, and clinically relevant non-major bleeding among patients with VTE who initiated apixaban vs warfarin, stratified by obesity. A total of 112,024 non-obese patients and 43,095 obese patients were included, of whom 19,751 were morbidly obese. In both obese and morbidly obese patients, apixaban was associated with a significantly lower risk of recurrent VTE (obese, HR, 0.73, 95 percent confidence interval [CI], 0.64–0.84; morbidly obese, HR, 0.65, 95 percent CI, 0.53–0.80) and major bleeding (obese, HR, 0.73, 95 percent CI, 0.62–0.85; morbidly obese, HR, 0.68, 95 percent CI, 0.54–0.86) compared with warfarin. [J Clin Med 2021;10:200]

Study 3
A single-center, retrospective study of DOACs was conducted in adult patients with BMI ≥40 kg/m². Of 366 patients prescribed an anticoagulant for VTE, similar incidences of VTE recurrence and major bleeding were observed among patients on apixaban, rivaroxaban, and warfarin (Table 2). [Lancet Haematol 2019;6:e359-e365]