Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End-Stage Renal Disease Requiring Chronic Hemodialysis.

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single-dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62-year-old 156-kg African-American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.

Kufel WD ，Zayac AS ，Lehmann DF ，Miller CD ... -  《-》

Reprint of: Efficacy and safety of apixaban compared to warfarin for nonvalvular atrial fibrillation in end-stage renal disease on hemodialysis.

This study compared the efficacy and safety of apixaban and warfarin in patients with nonvalvular atrial fibrillation (NVAF) and end-stage renal disease (ESRD) on hemodialysis (HD). Apixaban decreased incidence of stroke and bleeding compared with warfarin in major clinical trials that excluded patients with severe renal dysfunction. Apixaban is no longer contraindicated in patients with ESRD on HD with NVAF based on pharmacokinetic studies. Limited clinical data exist for patients with ESRD on HD on apixaban. A retrospective chart review was performed on patients with a diagnosis of NVAF and ESRD on HD who were prescribed apixaban or warfarin for stroke prevention in the years 2018 through 2019. Patients' charts were reviewed for up to a 2-year period. Patients on renal replacement therapy other than HD, those using anticoagulation for reasons other than NVAF, patients with Child-Pugh Class C cirrhosis, and those with severe mitral valve stenosis were excluded. The primary outcome was emergency department visits or hospital admissions for ischemic stroke or transient ischemic attack. Secondary outcomes included major or minor bleeding and adverse effects. A total of 181 patients were screened; 110 patients met eligibility criteria and were included in the analysis. Four patients (7.5%) in the apixaban group and 6 patients (10.5%) in the warfarin group met the primary outcome of hospitalization or emergency department visit for stroke (P = 0.742). Symptomatic bleeding occurred in 39.6% of patients in the apixaban group and 36.8% in the warfarin group (P = 0.918). A trend in major bleeding occurred more often in the warfarin group, 52.4% versus 49.2% (P = 0.758). There were no statistically significant differences in efficacy and safety outcomes between apixaban and warfarin in patients with NVAF and ESRD on HD in the intention-to-treat analysis of our study. Larger trials are needed to further analyze this patient population.

Moore M ，Vizcaino K ，Ewing JA ，St Ville M ... -  《-》

Influence of apixaban on antifactor Xa levels in a patient with acute kidney injury.

The case of a patient requiring conversion from apixaban to heparin in the setting of acute kidney injury is reported. A 70-year-old man was initiated on apixaban 5 mg twice daily for new-onset, nonvalvular atrial fibrillation with a CHA2DS2-VASc score of 4, indicating a high risk of stroke. Soon after starting apixaban, he experienced pulmonary edema with pneumonia requiring hospitalization. During the course of hospitalization, the patient developed acute kidney injury requiring hemodialysis, and apixaban was stopped due to concerns about altered pharmacokinetics and impaired drug elimination in this setting. A heparin infusion was started 36 hours after the last dose of apixaban was administered. Antifactor Xa levels were monitored consistent with the hospital's standard practice protocols. The initial and repeat antifactor Xa concentrations were elevated (1.8-4.4 IU/mL) for up 72 hours after stopping the heparin infusion. Given the suspected interference of apixaban with standard antifactor Xa level monitoring, the heparin protocol was modified to reflect drip-rate adjustments based on activated partial thromboplastin times (aPTTs). The hospital protocol for heparin infusions was reinstituted on hospital day 7, with dosage adjustments based on antifactor Xa levels. The patient remained on a continuous heparin infusion for atrial fibrillation for the remainder of his hospitalization without complications or bleeding events. A 70-year-old man with new-onset nonvalvular atrial fibrillation and receiving apixaban discontinued this therapy and was given heparin instead due to acute kidney injury. His heparin dosage was successfully adjusted based on antifactor Xa levels and aPPTs.

Wendte J ，Voss G ，VanOverschelde B 《-》

The Successful Use of Apixaban in Dialysis Patients with Calciphylaxis Who Require Anticoagulation: A Retrospective Analysis.

Calciphylaxis is a disease of dermal arteriolar calcification that results in necrosis. It commonly occurs in individuals with end-stage renal disease (ESRD) on hemodialysis and is associated with a high morbidity and mortality. Warfarin use is an identified risk factor. Twenty patients with ESRD on dialysis with calciphylaxis who were treated with apixaban for indications of deep vein thrombosis or atrial fibrillation were identified. There were no reports of thrombosis. Three individuals experienced bleeding requiring a transfusion, and anticoagulation was resumed without further event. Findings suggest that apixaban may be a safe and effective alternative to warfarin in patients with ESRD on dialysis with calciphylaxis.

Garza-Mayers AC ，Shah R ，Sykes DB ，Nigwekar SU ，Kroshinsky D ... -  《-》

Safety of apixaban compared to warfarin in hemodialysis patients: Do antiplatelets make a difference?

Data on the safety of apixaban compared to warfarin in hemodialysis (HD) patients are accumulating, but the impact of concomitant antiplatelet use is unknown. Compare hemorrhagic risk and impact of antiplatelets in HD patients receiving oral anticoagulants (OAC). Retrospective, multi-center study of HD patients started on OAC inpatient over 5 years. 707 patients were included: 563 received warfarin, and 144 received apixaban. 197 had bleeding, most in the warfarin group (173 [30.1%] vs 24 [16.7%] in the apixaban group), P-value < .01). However, with concomitant antiplatelet use, frequencies were similar (31.4% vs 25.0%; P-value = .292). Cumulative incidence using bleeding as event of interest and death as competing risk showed higher rates of bleeding with warfarin. In a multivariate model, apixaban was associated with a lower hemorrhagic risk (hazard ratio [HR] 0.55 [95% confidence interval {CI} 0.35-0.86}). Apixaban showed lower hemorrhagic risk alone (HR 0.24, 95% CI 0.10-0.55) and similar risk when administered with antiplatelets (HR 0.93, 95% CI 0.55-1.56). Apixaban is associated with less bleeding in HD patients compared to warfarin, but concomitant antiplatelet use may negate the safety advantage. Prospective trials are warranted to determine the impact of antiplatelets on apixaban safety.

Ionescu F ，Cooper C ，Petrescu I ，George J ，Mansuri S ... -  《-》