Background: Although rivaroxaban has demonstrated consistent drug levels in normal weight and obese patients, sufficient confirmation of equal clinical effectiveness and safety is currently lacking. Purpose: To evaluate the effectiveness and safety of rivaroxaban versus warfarin for prevention of stroke and systemic embolism (SSE) in obese nonvalvular atrial fibrillation (NVAF) patients. Methods: Using Optum de-identified Electronic Health Record (EHR) data from November 2011 to September 2018,we evaluated NVAF patients with a body mass index (BMI)!30 kg/m 2 newly initiated on rivaroxaban or warfarin (index date), with !12-months of EHR activity and !1 encounter before the index date. We excluded patients with valvular disease or evidence of oral anticoagulant (OAC) use at baseline. Patients who were prescribed rivaroxaban were 1:1 propensity-score matched to patients who were prescribed warfarin (standard differences <0.10 achieved for all covariates). Outcomes included SSE and major bleeding using an intent-to-treat approach. Subanalyses stratified by BMI (30.0-34.9, 35.0-39.9 and !40 kg/m 2) were performed. Cox regression was performed and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We included 35,613 rivaroxaban and 35,613 warfarin users with NVAF. Patients were followed for a median of 2.6 years (25%-75% range ¼ 1.2-4.1). Rivaroxaban was associated with a reduced risk of SSE (HR ¼ 0.83, 95%CI ¼ 0.73-0.94) and major bleeding (HR ¼ 0.82, 95%CI ¼ 0.75-0.89) compared to warfarin. Subanalysis did not show a statistically significant interaction across BMI categories for SSE (p-interaction ¼ .58) or major bleeding (p-interaction ¼ .44) outcomes. Conclusions: Among obese NVAF patients, prescription of rivaroxaban was associated with a reduced risk of SSE and major bleeding compared to warfarin, which remained consistent across BMI classes.
Background
Andexanet alfa is approved (FDA “accelerated approval”; EMA “conditional approval”) as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).
Methods
This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.
Results
The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16–6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13–0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.
Conclusions
In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC.
Trial registration NCT02329327; registration date: December 31, 2014.
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