By: Joanna Callier, Pharm. D. Candidate Class of 2023; University of Health Sciences and Pharmacy in St. Louis
Mentor: Emily Reinke, Pharm. D., CVS Pharmacy
Chronic kidney disease (CKD) affects more than 14% of the general population with over 660,000 of those individuals having kidney failure, 468,000 having end-stage renal disease (ESRD) requiring dialysis, and 193,000 currently living with a functioning kidney transplant. The incidence of ESRD is steadily rising with approximately 21,000 new cases each year with limited treatment options and increasing morbidity and mortality. 1 Most landmark clinical trials evaluating the use of direct oral anticoagulants (DOACs)—including apixaban, rivaroxaban, edoxaban, and dabigatran—exclude patients on hemodialysis (HD) and those with severe CKD. The majority of the available clinical trials exclude CKD when the creatinine clearance is below 25 mL per minute or requiring dialysis, resulting in a lack of safety and efficacy data for DOAC use in patients with ESRD.2 Patients who suffer from CKD and ESRD are at an increased risk of experiencing a thromboembolic or major bleeding event.2 Renal impairment decreases platelet adhesion and aggregation increasing the risk of bleeding events in these individuals.3 Due to DOACs renal clearance, patients with CKD are more prone to serious complications such as anemia, cardiovascular disease, hypertension, fluid retention, and electrolyte disorders.4
The Food and Drug Administration (FDA) approved DOACs for several indications including non-valvular atrial fibrillation (NVAF) and the prevention and treatment of venous thromboembolism (VTE) after their development in 2010.5,6,7,8 Prior to DOACs FDA approval, warfarin, enoxaparin, heparin, and fondaparinux were the standard of care.9 Many clinical trials show apixaban to be the superior DOAC in reducing thromboembolic events and bleeding risks in the general population suggesting clinical trials including patients with CKD will manifest similar risk reduction in this patient population.9 In 2014, the FDA approved apixaban for anticoagulation in patients with ESRD, despite a lack of this patient population in the landmark ARISTOTLE trial.5 Studies like RENAL-AF and the retrospective study “Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal Impairment” used the results of ARISTOTLE to support their trials with ESRD patients. The data on anticoagulation in ESRD is limited due to the insufficient number of clinical trials that include this patient population, making a true assessment of bleeding risks difficult.
ARISTOTLE:The ARISTOTLE trial is a randomized, double blind, controlled trial, which enrolled patients with NVAF to receive dose-adjusted warfarin or apixaban 5mg twice daily to evaluate these agents’ safety and efficacy in stroke prevention.10 The primary outcome was ischemic or hemorrhagic stroke or systemic embolism and the secondary outcome was with the rate of major bleeding events as defined by the International Society on Thrombosis and Hemostasis (ISTH). The study included some of the following criteria: patients with NVAF or atrial flutter, having a previous stroke, transient ischemic attack, or systemic embolism, and being older than 75 years.10 The primary outcome occurred at a rate of 1.27% per year in patients receiving apixaban and 1.6% in patients receiving warfarin (HR with apixaban, 0.79; 95% CI, 0.66 to 0.95; P< 0.001 for non-inferiority). Major bleeding events occurred at a rate of 2.13% per year for apixaban and 3.09% for warfarin (HR, 0.69; 95% CI, 0.60 to 0.80; P < 0.001).10 The results of ARISTOTLE show that apixaban was superior to warfarin in preventing stroke or systemic embolism while causing fewer major bleeding events. This results in lower mortality in the apixaban group than the warfarin group thus making it the more favorable treatment option. These results were applied to patients with ESRD, despite their exclusion from the trial.
RENAL-AF:The RENAL-AF trial enrolled patients with NVAF and ESRD requiring HD to receive apixaban 5mg twice daily or 2.5mg for adjusted renal dosing— having two of the following: ≥ 80 years of age, weight ≤ 60kg, or a serum creatine ≥1.5mg/dL—to dose-adjusted warfarin.11 This randomized, open-label, blinded end-point evaluation trial assessed the safety and efficacy of apixaban. Inclusion criteria included, NVAF, a CHA2DS2-VASc score ≥ 2, ESRD with HD ≥ 3 months, and require anticoagulation considered by the treating physician.11 The primary outcome assessed relevant non-major bleeding and major bleeding events as defined by the ISTH of apixaban versus warfarin. There were similar rates of clinically relevant non-major bleeding events between apixaban and warfarin (31.5% vs. 25.5%, P > 0.05).11 The findings of this trial show similar rates of bleeding and stroke between apixaban and warfarin in patients with ESRD on HD. A major limitation of this trial was that it ended early due to a lack of funding that led to the study not meeting power.
Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal ImpairmentThis single-centered retrospective matched-cohort trial compared renally adjusted dosing of apixaban 2.5mg to dose-adjusted warfarin.12 Inclusion criteria included a CrCl < 25mL/min, a SCR > 2.5mg/dL, or were receiving peritoneal dialysis (PD) or HD. The primary outcome was major bleeding and the secondary outcomes included major bleeding events defined by the ISTH, relevant nonmajor bleeding events, and minor bleeding events in patients with ischemic stroke, NVAF, and VTE determined by a physician.12 This trial did not result in a statistical significance difference between the two drug groups in patients with ESRD in occurrence of bleeding, stroke, and VTE —resulted in a 33% power when 80% was needed.12 This trial however did find that less bleeding was present in the apixaban group, making this drug a potentially safer option in ESRD with close monitoring—this suggestion mirrors that of the ARISTOTLE trial.12 It is also important to note that bleeding occurred more often in this patient population than in the general population, most likely due to the increased risks of bleeding already present in ESRD mentioned previously.
Recommendations:Patients with ESRD are at higher risks of NVAF, stroke, and bleeding which can make this patient population more difficult to treat.13 The results of the analyzed trials show apixaban being superior to warfarin in treating NVAF and ESRD with higher risks of stroke.10,11,12 Although apixaban has shown to be a superior anticoagulation option for ESRD, the pharmacokinetics need further evaluation to ensure safety and efficacy in this patient population. The few studies that have focused on the pharmacokinetics of apixaban have results that suggest 2.5mg is appropriate whereas 5mg becomes supratherapeutic and may expose these patients to higher risks of bleeding.14 Apixaban is the only thoroughly studied DOAC in patients with ESRD, which suggests development of more clinical trials are necessary to determine the safety and efficacy of the remaining DOACs on market—edoxaban, rivaroxaban, and dabigatran. As patients are getting older and more people are requiring hemodialysis, it is important to have trials focused on ESRD to avoid gaps in care.