Clarification-safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis.

Abstract

Dear Editor, I would like to bring to your attention an error observed in the above-mentioned manuscript. The manuscript states that “At the present, apixaban is the only non-vitamin K oral anticoagulant (NOAC) approved by the FDA for use with patients with creatinine clearance <15 mL/min or end-stage renal disease (ESRD).” This is incorrect; both the apixaban and rivaroxaban labels have similar recommendations for patients diagnosed with ESRD and atrial fibrillation. These recommendations can be found in Section 8.6 of the respective labels. Regarding the rivaroxaban and apixaban labels, both sponsors performed a similarly designed trial which consisted of an open-label, parallel group design: they enrolled 16 adult subjects (eight with ESRD and eight with normal renal function); administered a single dose of medication (apixaban 5 mg/rivaroxaban 15 mg), once for those with normal renal function and twice for those with ESRD (once prior to dialysis and once after dialysis, separated by a washout period); collected serial pharmacokinetic and pharmacodynamic blood samples prior to dose and up to 72 hours postdose; and each trial was conducted at a single research center in the United States. The only significant deviation in design between the two studies was the use of saline or unfractionated heparin (UFH) during dialysis to keep the lines patent. Apixaban utilized saline, while rivaroxaban utilized a low dose of UFH.1, 2 While direct comparisons cannot be made as they were two separate studies, the pattern of results was similar for both compounds. That is, the overall increase in systemic exposure postdialysis (as measured by the area under the curve [AUC]) was 36% for apixaban and 56% for rivaroxaban, which is representative of the decrease in overall clearance expected with complete loss of kidney function for these compounds, respectively.1, 2 We also see a similar pattern of increasing exposure when assessing the progressive decline of renal function. For example, apixaban displays an approximate 16%, 29%, 38%, and 36% increase in AUC for those subjects with mild, moderate, and severe renal impairment, and ESRD, respectively.3 Similarly, rivaroxaban displays a 44%, 52%, 64%, and 56% increase in AUC for those subjects with mild, moderate, severe renal impairment, and ESRD, respectively.4 With both compounds, subjects with either severe renal impairment or ESRD, have a similar increase in systemic exposure (AUC) suggesting a limit may be reached by the time a subject has severe renal impairment. Considering the similarity in study designs and the data obtained, the FDA went through a process of harmonization across the labels. The end result is that both the apixaban and rivaroxaban labels have similar recommendations for patients diagnosed with ESRD and AF. Neither compound has a specific “Indication” for ESRD; however, a recommendation is provided.