Letter to the Editor: Rivaroxaban Use in Patients With Atrial Fibrillation on Hemodialysis

Dear Dr. Moll,

I read your analysis [November/December 2017, Volume 14, Issue 6] of the study conducted by Dr. Thomas Mavrakanas and colleagues.¹  I would like to point out a few discrepancies regarding the use of rivaroxaban in those with severe renal impairment (SRI) or end-stage renal disease (ESRD). You state that rivaroxaban should be avoided in those patients with either SRI or ESRD. While this is the label guidance for the deep venous thromboembolism/pulmonary embolism treatment population, the current label allows for the reduced dose of 15 mg in the atrial fibrillation population. In fact, the current labeling for both the apixaban and rivaroxaban are essentially identical for atrial fibrillation. Neither has an “indication” for use, but a recommendation is provided. This is supported by the fact that both sponsors performed a similar designed clinical pharmacology trial.^2,3 

Your review nicely identified some of the findings (i.e., significant accumulation and supratherapeutic exposures of apixaban after multiple doses). I would like to bring to your attention an independent study conducted by De Vriese et al⁴  that assessed multiple doses of rivaroxaban in dialysis patients and did not show significant accumulation. While I agree with your overall recommendation regarding the use of direct oral anticoagulants in this population, I wanted to provide an accurate update of current data.

— Kenneth Todd Moore, MS, Scientific Director, Cardiovascular Disease, Cardiovascular and Metabolism Medical Affairs, Janssen Pharmaceuticals, Raritan, NJ

1. Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban pharmacokinetics at steady-state in hemodialysis patients. J Am Soc Nephrol. 2017;28:2241-2248.

2. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43:229-236.

3. Wang X, Tirucherai G, Marbury T, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56:628-636.

4. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66:91-98.

Reply: Since the Diffusion article “Use of Direct Oral Anticoagulants in Patients on Hemodialysis”¹  was submitted in October 2017 and published in the November/December 2017 issue of The Hematologist, there have been revisions to the prescribing information (package insert) for rivaroxaban (revised October 2017) and apixaban (revised February 2018).^2,3  In his letter, Mr. Moore correctly points out that the current package insert discusses dosing in patients with ESRD on hemodialysis. The rivaroxaban insert states that 15 mg of rivaroxaban once daily will result in similar plasma drug activity as 15 mg once daily in patients with a creatinine clearance of 15 to 50 mL/min (in the previous phase III atrial fibrillation study); the apixaban insert reads that apixaban at the usual recommended dose of 5 mg twice daily or, if two of three dose-reducing criteria are met (age ≥ 80 years, body weight ≤ 60 kg, and creatinine ≥ 1.5 mg/dL), 2.5 mg twice daily, leads to plasma drug activity similar to the dosing in the phase III atrial fibrillation trial. These sentences open the door for clinicians to consider apixaban or rivaroxaban in patients with ESRD. However, the dosing conclusions are based on very limited data — a single-dose pharmacokinetic/pharmacodynamic (PK/PD) study in eight patients with ESRD for rivaroxaban,⁴ and a single-dose PK/PE study in eight patients for apixaban.⁵ 

Moore’s comment that a previously published study⁶  did not show significant accumulation of rivaroxaban in dialysis patients has to be taken with a grain of salt. The study quoted investigated the PK/PD of 10 mg rivaroxaban taken once daily for seven days.6 While the authors of that study concluded that there was no drug accumulation in patients on HD, it is noteworthy that the PK/PD data of the six patients studied show a trend toward accumulation, as evidenced by a higher mean area under the curve, higher mean peak plasma concentration, and a longer mean drug half-life.⁶  Unfortunately, no detailed data or statistical analysis are provided in the publication to back up the authors’ conclusion that the data show an absence of drug accumulation. In addition, I wonder whether the numerically higher plasma drug levels observed with the 10 mg dose studied may be more pronounced if higher doses of rivaroxaban (15 mg or 20 mg once daily) were used. Therefore, my conclusion is that the data in the literature do not allow me to deduce that there is no drug accumulation in patients with ESRD on HD who take daily rivaroxaban, particularly the higher dose of 15 mg once daily that the package insert mentions for patients with ESRD on HD. To expand on existing data, I would like to see a study of 15 mg rivaroxaban once daily in patients with ESRD on HD, comparing day 1 and day 8 PK data.

At present, in view of the sparsity of PK/PD and clinical data on the use of direct oral anticoagulants in patients with ESRD on HD, I prefer to treat these patients with warfarin if anticoagulation is needed.

— Stephan Moll, MD, Professor of Medicine, Division of Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, NC