Direct Oral Anticoagulant for Treatment of Venous Thromboembolism in Obese Patients

Direct Oral Anticoagulant for Treatment of Venous Thromboembolism in Obese Patients
Tyler Stevens, Pharm.D., Centra Care Health 

Background: Direct oral anticoagulants (DOACs) have demonstrated similar safety and efficacy to vitamin K antagonists for the prevention of stroke in atrial fibrillation (AF) and management of venous thromboembolism (VTE). With the advantages of fewer interactions, fixed dosing, and lack of routine monitoring compared to vitamin K antagonists, DOACs have become increasingly popular in the outpatient setting. Due to pharmacodynamic (PD) and pharmacokinetic (PK) differences and limited safety and efficacy data, use has been cautioned in obese patients. Specifically, the 2016 International Society on Thrombosis and Haemostasis (ISTH) discourages the use of DOACs in patients with a body mass index (BMI) >40 kg/m2 or weight >120 kg and recommends peak and trough laboratory monitoring if utilized.

Evidence: A recent review article examined 19 studies including PK studies and clinical trials conducted on DOACs. PK studies in both healthy and VTE patients suggest the effects on the PK and PD properties are variable and may be dependent on which DOAC is used in obesity. Throughout the reviewed clinical trials, there does not appear to be increased risk in the use of DOACs in obese patients, although most data is based on patients with AF. Studies examining safety and efficacy in VTE is lacking; however, three studies following the 2016 ISTH guideline release suggest DOACs may have similar safety and efficacy for VTE in obese patients.

Spyropoulos et al. is a 1:1 propensity matched retrospective cohort study (n = 2890) comparing the use of rivaroxaban and warfarin after a VTE in patients with a diagnosis of “morbid obesity.” The study found no difference in risk of recurrent VTE (0.99 [95% CI 0.85 - 1.14]) or major bleeding (0.75 [95% CI 0.47 - 1.19]). They did observe decreased health care utilization and medical costs in the rivaroxaban group for hospitalizations (0.86 [95% CI 0.77 - 0.96]), outpatient visits (0.23 [95% CI 0.10 - 0.56]), and per patient per year cost ($34,824 vs $37,653).  

Perales et al. examined the use of rivaroxaban (n = 84) compared to warfarin (n=92) retrospectively for initial treatment of either AF or VTE in patients with a BMI >40 kg/m2 or body weight >120 kg. Rivaroxaban treated patients had lower rates of combined VTE recurrence, stroke, or mortality within 12 months of initiation compared to warfarin treated patients although without statistical significance (5% vs 13%, P=0.06). Further, rivaroxaban patients had shorter lengths of stay (two days vs four days, P<0.0001) with a non-statistically significant increase in bleeding complications (8% vs 2%, P=0.06).  

Most recently, a retrospective propensity matched study, Coons et al., examined patients with an acute deep vein thrombosis (DVT) and body weight of 100-300 kg treated with either apixaban, dabigatran. or rivaroxaban (n=632) or warfarin (n=1208). Between the two groups there was no difference in VTE recurrence (6.5% vs 6.5%, P=0.93) or pulmonary embolism (PE) and DVT occurrence (3.7% vs 3.8%, P=0.94 and 3% vs 3.5%, P=0.56, respectively). Likewise, there was no difference in bleeding between the two groups (1.7% vs 1.2%, P=0.31).

Discussion and Clinical Impact: All three studies are retrospective cohort studies. Randomized control trials with similar outcomes would provide stronger evidence that these medications could be used safely in obese patients. Since differences in PK and PD properties have been observed in obese patients taking DOACs, studies demonstrating safe and efficacious drug levels would further support use of these medications. The studies discussed demonstrate that DOACs, specifically rivaroxaban, may have similar outcomes data compared to vitamin K antagonists. Taking into account the trial design and need for further evidence, these studies alone do not provide evidence for the safe use of DOACs in obese patients; however, should be considered as the use of DOACs will continue to change the landscape of anticoagulation. 

Resources: 

  1. Kido K, Lee JC, Hellwig T, Gulseth MP. Use of Direct Oral Anticoagulants in Morbidly Obese Patients. Pharmacotherapy. 2020;40(1):72-83.

  2. Spyropoulos AC, Ashton V, Chen YW, Wu B, Peterson ED. Rivaroxaban Versus Warfarin Treatment Among Morbidly Obese Patients With Venous Thromboembolism: Comparative Effectiveness, Safety, And Costs. Thrombosis Research. 2019;182:159-166.

  3. Perales IJ, San Agustin K, DeAngelo J, Campbell A. Rivaroxaban Versus Warfarin for Stroke Prevention and Venous Thromboembolism Treatment in Extreme Obesity and High Body Weight. Ann Pharmacother. 2020;54(4):344-50.

  4. Coons J, Alber L, Bejjani A, Iasella CJ. Effiectiveness and Safety of Direct Oral Anticoagulants versus Warfarin in Obese Patients with Acute Venous Thromboembolism. Pharmacotherapy. 2020;40(3):204-210.