Apixaban, is it a One-Size-Fits-All Anticoagulant? Using Apixaban to Treat VTE in Individuals of Higher Body Weight

Apixaban, is it a One-Size-Fits-All Anticoagulant? Using Apixaban to Treat VTE in Individuals of Higher Body Weight
Yesenia Lopez-Mendoza, PharmD, Community-University Health Care Center

Background: Historically, guidelines from the American Heart Association advised using caution when selecting direct oral anticoagulants (DOACs) in populations with low or high body weight due to lack of evidence. New evidence from a multi-center retrospective study comparing apixaban versus warfarin supports the safety and efficacy of apixaban for treatment of venous thromboembolism (VTE) in patients with severe obesity. 

Purpose: The comparison trial of apixaban versus warfarin aimed to evaluate the efficacy and safety of the two agents to treat VTE in individuals with a BMI >40 kg/m2 or weight >120 kg. The primary efficacy and safety outcomes were time to recurrence of VTE and time to major bleeding at 12 months, respectively. 

Study Design: This retrospective, cohort, multi-center trial involved 26 hospitals across six different states. Data was pulled from inpatient admissions between January 1, 2012 and December 31, 2019 as a subset from a larger multi-study research group. The information obtained from a patient’s first admission was used to determine trial enrollment for patients with multiple admissions linked with a VTE diagnosis code. Inclusion criteria consisted of patients ≥18 years of age, have a BMI >40 kg/m2, actual body weight >120 kg, have at least one dose of apixaban or warfarin during hospitalization, and anticoagulation treatment was continued at discharge. Exclusion criteria included any history of mechanical valve replacement, severe liver disease (hepatic encephalopathy or esophageal varices), pregnancy, or taking a medication contraindicated for concurrent use with DOAC or warfarin therapy (i.e. itraconazole, ketoconazole, ritonavir, rifampin, carbamazepine, phenytoin, and St. John’s wort).

Results: Of 1099 patients enrolled in the study, there were 314 patients in the apixaban group and 785 patients in the warfarin cohort. The baseline characteristics were similar between the two cohorts and included an average age of 58 years, average BMI of 44-47 kg/m2, and 60-70% White and 24-30% Black patients. Through manual chart review, common clot risk factors of the enrolled patients included diabetes mellitus (DM), history of VTE, active smoker, and chronic kidney disease. The results were adjusted for these confounding variables and noted the warfarin cohort having a greater percentage of patients with DM and/or history of VTE than the apixaban cohort. The study observed better outcomes for the apixaban cohort before and after adjusting for confounding variables. 

Without adjustment, apixaban demonstrated better results compared to warfarin at 12 months for time to recurrent VTE (P= 0.018), incidence of recurrent VTE (4.5% versus 8.7%, P= 0.02) and had significantly fewer hospital encounters (2.92 + 4.3 versus 6.5 + 9.2, P< 0.01). With adjustment, apixaban still showed a reduced incidence of recurrent VTE compared to warfarin (HR 0.54, 95% CI 0.29-0.97, P= 0.04). In terms of safety, there was no significant difference between the apixaban and warfarin groups in time to major bleeding (P= 0.665) or major bleeding events in 12 months (3.8% versus 3.3% , P= 0.715). 

To further eliminate the influence of confounding variables, the study completed a propensity match analysis of baseline characteristics and paired 297 patients of each arm. They found no significant differences in recurrent VTE (HR 0.515, 95% CI 0.26-1.04, P=0.057) or major bleeding in 12 months (HR 1.25, 95% CI 0.5-3.18, P=0.632). There was also a reduced risk of clinically relevant non-major bleeding (CRNMB) (HR 0.27, 95% CI 0.08-0.98, P= 0.031) and lower total number of hospital encounters within 12 months in the apixaban group compared to warfarin (2.9 + 4.4 apixaban versus 6.7 + 9.1 warfarin, P< 0.01).

Lastly, a subgroup analysis included 428 patients with BMI >50 kg/m2 and/or weight >140 kg. This included 93 patients on apixaban and 335 patients on warfarin. There was no significant difference in VTE recurrence (3.2% versus 9.9%, P= 0.06), major bleeding (4.3% versus 3.0%, P= 0.52), CRNMB (1.1% versus 2.7%, P= 0.7) and all-cause mortality (4.3% versus 2.4%, P= 0.30) between apixaban and warfarin respectively.  

Conclusions: Historically, warfarin has been preferred in situations where there was insufficient evidence to support the use of DOACs, including patients with increased body weight. This study found that apixaban is safe and effective at treating and preventing recurrence of VTE while not increasing risk of major bleeding for patients with a BMI >40 kg/m2 and/or actual body weight >120 kg. The subgroup analysis suggests that apixaban may even be effective for treatment of VTE of BMI >50 kg/m2 and/or weight >140 kg. Limitations of this study include the warfarin cohort had an overall greater BMI and higher frequency of VTE history, both of which are underlying risk factors for clots. As a retrospective study, it did not assess for adherence, duration of anticoagulation therapy or events that occured in the outpatient setting after discharge. Nonetheless, the study acknowledges that including these limitations would still display apixaban as a non-inferior alternative to warfarin in patients with increased body weight.  

Key Point: Growing evidence supports the use of DOACs, like apixaban, in a larger range of patients due to their demonstration of unfaltered efficacy and safety in patients with higher BMI and actual body weight. 

Reference:

  1. Crouch A, Ng TH, Kelley D, et al. Multi‐center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity. Pharmacotherapy : official journal of the American College of Clinical Pharmacy. 2022;42(2):119-133. doi:10.1002/phar.2655