By Jason Chau, PharmD; Holly Flynn, PharmD; Sarah Greiner, PharmD; Stephanie Hendricks, PharmD
According to the Centers for Disease Control and Prevention (CDC), over 40% of the US population is classified as obese.(1) Obesity is a major public health concern that serves as a risk factor for the development of venous thromboembolism (VTE). As the prevalence of obesity rises, providers are often challenged to make therapeutic plans using anticoagulants for the prevention and treatment of VTE in this special population. For the treatment of VTE, direct-acting oral anticoagulants (DOACs) have become first-line agents for most patients.(2) Since dabigatran was introduced as the first DOAC in 2010, four additional DOAC agents have been approved by the Food and Drug Administration (FDA) for the treatment and prevention of VTE, including rivaroxaban, apixaban, betrixaban, and edoxaban. In 2016, the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH SSC) Subcommittee on Control of Anticoagulation provided guidance that recommended not using DOACs in patients with extreme obesity (body mass index [BMI] >40 kg/m2 or weight >120 kg).(3) They recommended obtaining peak and trough drug levels if DOACs were still used in this patient population. The purpose of this blog post is to summarize the 2021 updated guidance recommendations from the ISTH SSC on the use of DOACs for treatment and prevention of VTE in patients with obesity.
The recent update from the ISTH SSC on Control of Anticoagulation endorses standard dosing of rivaroxaban and apixaban for treatment of VTE, regardless of high BMI or weight.(4) Rivaroxaban has the most robust evidence supporting its use in obesity. Firstly, there is phase III trial data from a post-hoc analysis of the EINSTEIN randomized controlled trial that compared rivaroxaban to warfarin in patients with a BMI ≥35 kg/m2.(5) In this analysis, the authors found no difference in VTE recurrence at both 21 days and 12 months. Additionally, there was no difference in major bleeding between the two groups. The results of this study are summarized in Table 1. Another single-center retrospective study compared rivaroxaban and warfarin in patients with a BMI ≥40 kg/m2 and found similar rates of both recurrent VTE and major bleeding.(6) This same study also reported outcomes specifically in patients with a BMI ≥50 kg/m2 and still found similar rates of VTE at this elevated BMI (0/30 vs. 2/52, respectively; p = 0.50). The results of this study are summarized in Table 2.
Table 1. Key efficacy and safety endpoints of treatment of VTE with rivaroxaban in relation to body weight by Di Nisio, et al.
Table 2. Key efficacy and safety endpoints of rivaroxaban versus warfarin for VTE treatment in patients with morbid obesity by Kusnir, et al.
In addition to data for VTE treatment, evidence also exists for the use of rivaroxaban for VTE prevention in patients with obesity. Pooled data from four studies compared rivaroxaban 10 mg once daily to enoxaparin 40 mg once daily or 30 mg twice daily for post-operative prevention of VTE following knee and hip arthroplasty in patients weighing ≥90 kg.(7) A similar rate of VTE and all-cause mortality was seen in the two groups (0.6% vs. 1.3%, respectively; HR 0.49; CI 0.2–1.1), although patients receiving rivaroxaban did have a significant increase in major and non-major bleeding compared to enoxaparin (4.4% vs. 2.7%; HR 1.6; CI 1.1–2.4). Based on the results of these and other studies, the ISTH now endorses the use of rivaroxaban in patients with a BMI >40 kg/m2 or weight >120 kg for VTE treatment and VTE prevention following orthopedic procedures.
While the strongest evidence for DOAC use in obesity lies with rivaroxaban, enough evidence has recently emerged to also support the use of apixaban in obesity. First, there was a small, single-center, retrospective study designed to evaluate the safety and efficacy of DOACs versus warfarin for VTE or atrial fibrillation in patients with a BMI ≥40 kg/m2.(6) Within the entire patient population of 366 patients, 47 patients received apixaban. The study found similar incidences of VTE recurrence and major bleeding between patients receiving apixaban and warfarin, respectively. This same study did a subset analysis for patients with a BMI ≥50 kg/m2 and found that the rates of VTE recurrence (0/10 vs. 2/52; p = 0.53) and major bleeding (0/10 vs. 2/52) remained similar between apixaban and warfarin, even with this increased BMI. The results of this study are summarized in Table 3. Additionally, another observational study of combined data from US insurance claim databases compared safety and efficacy data for apixaban and warfarin in morbidly obese patients, which was defined as a BMI of ≥40 kg/m2.(8) This study found that apixaban, compared to warfarin, was associated with a lower risk of recurrent VTE and major bleeding. The results of this study are summarized in Table 4.
Table 3. Key efficacy and safety endpoints of apixaban versus warfarin for VTE treatment in patients with morbid obesity by Kusnir, et al.
Table 4. Key efficacy and safety endpoint of apixaban versus warfarin for VTE patients with obesity and morbid obesity by Cohen, et al.
In addition to data for VTE treatment, apixaban has emerging data for use in VTE prevention for patients with obesity. A study analyzed pooled data from the ADVANCE-2 and ADVANCE-3 trials, which compared apixaban 2.5 mg twice daily to enoxaparin 40 mg daily for post-operative prevention of VTE in knee and hip arthroplasty in patients with a BMI ≥30 kg/m2.(9) A similar rate of the primary VTE outcome (proximal deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death) was seen in patients who received apixaban compared to enoxaparin (0.96% vs. 1.9%, respectively; RR 0.52; CI 0.25–1.07). Similar rates of major bleeding were also seen in this study (0.5% vs. 0.7%; ARR 0.24; CI 0.79–0.30). Based on the results of these and other studies, the ISTH now endorses the use of apixaban in patients with a BMI >40 kg/m2 or weight >120 kg for VTE treatment and VTE prevention following orthopedic procedures.
The ISTH update did not identify any studies that provided individual analysis of dabigatran, betrixaban, or edoxaban for the treatment of VTE, and as such, recommends against use of these agents in obesity.(4) In general, the available evidence for VTE treatment using DOACs comes from pooled data. When analyzing dabigatran for VTE prevention following orthopedic surgeries, post hoc analysis of pooled data comparing dabigatran to enoxaparin 40 mg daily found similar rates of VTE (3.5% vs. 2.8%, respectively, OR 1.25; 0.33–4.75) and major bleeding (1.0% vs. 1.1%, respectively; OR 0.95; CI 0.13–6.80) in patients with BMIs ≥35 kg/m2.(10) However, there is an overall lack of available clinical data for using betrixaban or edoxaban for VTE prevention in patients with BMIs >40 kg/m2 or weight >120 kg. When considering pharmacokinetic or pharmacodynamic (PK/PD) data, a single study found that peak plasma concentrations for dabigatran were 20% below the usual treatment range in 10 patients weighing >120 kg.(11) No studies were identified that contained PK/PD data for betrixaban use in patients with obesity. Additionally, these updated guidance recommendations noted that there was little evidence to support the use of peak or trough levels in DOAC management for patients with obesity. Therefore, in contrast to the 2016 recommendations, the 2021 updated guidance recommendations suggest not to regularly follow peak or trough DOAC drug levels.
In conclusion, for patients with a BMI >40 kg/m2 or a weight >120 kg, recent data has strengthened the evidence supporting the use of standard dose rivaroxaban and apixaban for VTE treatment and VTE prevention. More supportive data exists for rivaroxaban than apixaban. Due to limited evidence, the ISTH updated guidance recommendations suggest against use of dabigatran, edoxaban, or betrixaban for VTE treatment or prevention in patients with a BMI >40 kg/m2 or a weight >120 kg. These updated recommendations summarize evidence from the primary literature that support the use of DOACs over warfarin in this unique patient population. Ultimately, these updated recommendations allow clinicians to feel more confident in safely recommending the use of direct acting oral anticoagulants for their patients with obesity who require VTE treatment or VTE prophylaxis.
1. Centers for Disease Control and Prevention. Adult Obesity Facts. CDC: Overweight & Obesity page. https://www.cdc.gov/obesity/data/adult.html. Accessed November 15, 2021.
2. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
3. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313.
4. Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882.
5. Di Nisio M, Vedovati MC, Riera-Mestre A, Prins MH, Mueller K, Cohen AT, et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost. 2016;116(4):739-46.
6. Kushnir M, Choi Y, Eisenberg R, Rao D, Tolu S, Gao J, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6(7):e359-e365.
7. Turpie AGG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Misselwitz F, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies. Thromb Kaemost. 2011;105(3):444-453.
8. Cohen A, Sah J, Lee T, Rosenblatt L, Hlavacek P, Emir B, et al. Effectiveness and safety of apixaban vs. warfarin in venous thromboembolism patients with obesity and morbid obesity. J Clin Med. 2021;10(2):200.
9. Pineo GF, Gallus AS, Raskob GE, Chen D, Ramirez LM, Ramacciotti E, et al. Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups. J Thromb Haemost. 2013;11(3):444-451.
10. Eriksson BI, Dahl OE, Feuring M, Clemens A, Noack H, Hantel S, et al. Dabigatran is effective with a favorable safety profile in normal and overweight patients undergoing major orthopedic surgery: a pooled analysis. Thromb Res. 2012;130(5):818-820.
11. Wasan SM, Feland N, Grant R, Aston CE. Validation of apixaban anti-factor XA Nassau and impact of body weight. Thromb Res. 2019;182:51-55.
Jason Chau, PharmD, PGY2 Ambulatory Care Resident (left)
Holly Flynn, PharmD, PGY2 Ambulatory Care Resident (right)
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