Background: Patients with end stage renal disease (ESRD) are at significantly increased risk for both thrombosis and bleeding relative to those with normal renal function, which makes anticoagulation particularly challenging. Evidence suggests that rivaroxaban and dabigatran are associated with a higher risk of bleeding in ESRD patients. To date, no large national cohort studies have examined the safety and effectiveness of apixaban relative to warfarin in patients with ESRD who have acute venous thromboembolism (VTE).

Methods: We performed a retrospective cohort study using Medicare claims data linked to the the United States Renal Data System from 2014 through 2018. We included adults with ESRD who were newly initiated on either apixaban or warfarin for an acute VTE during the study period. We required at least six months of continuous enrollment in Medicare Parts A, B, and D and excluded those with diagnoses of atrial fibrillation or recent enrollment in hospice. The primary outcome was major bleeding within six months of anticoagulant initiation, defined as (a) bleeding associated with death, (b) critical site bleed requiring hospitalization, or (c) bleeding requiring hospitalization and transfusion. Specifically, we reported total major bleeding, fatal major bleeding, and non-fatal major bleeding. Secondary bleeding outcomes were clinically relevant non-major bleeding (critical site bleeds not requiring hospitalizations and non-critical site bleeds requiring hospitalizations but not transfusions), intracranial bleeding, and gastrointestinal (GI) bleeding. Co-primary outcomes were all-cause mortality and recurrent VTE within six months of anticoagulant initiation. We employed a new-user, active-comparator cohort design with propensity score adjustment using inverse probability of treatment weighting and adjustment for treatment initiation year to generate hazard ratios. The propensity score adjusted for demographic characteristics and pre-defined medical comorbidities and concurrent medications associated with thrombosis and bleeding. We utilized an intention-to-treat analysis, defined by the first prescription given after VTE diagnosis.

Results: The apixaban and warfarin cohorts included 3,179 and 11,735 patients, respectively. The two groups were similar prior to propensity adjustment and very well-matched afterwards in terms of demographic characteristics, comorbidities, and concurrent medications. Before weighting, the mean age in the apixaban and warfarin cohorts were 60.2 (standard deviation (SD) – 14.8 years) and 58.6 (SD 14.9). The apixaban and warfarin cohorts were 51.2% and 48.6% white, and both were 51.8% female (Table 1).Apixaban was associated with a lower risk of major bleeding (hazard ratio 0.75, 95% confidence interval (CI): 0.65-0.86), intracranial bleeding (hazard ratio 0.64, 95% CI 0.47-0.89), and GI bleeding (hazard ratio 0.77, 95% CI 0.66-0.90) (Table 2). All-cause mortality and recurrent VTE were not significantly different between the cohorts.

Conclusions: Apixaban was associated with lower bleeding risk and similar effectiveness relative to warfarin when used to treat acute VTE in ESRD. Using apixaban is also likely to reduce hospital length of stay due to avoidance of heparin bridging. Ongoing work will seek to clarify the frequency of a 2.5mg (off-label) versus 5mg strategy and to quantify the use of healthcare resources associated with an apixaban versus warfarin strategy.

IMAGE 1: Table 1. Patient Demographics

IMAGE 2: Table 2. Bleeding and Thrombotic Outcomes at 6 months