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Featured Clinical Topic - Cardiology/Anticoagulation: Direct oral anticoagulants for atrial fibrillation in hemodialysis

20 Sep 2017 3:57 PM | MSHP Office (Administrator)


Emily Shor, PharmD Candidate 2018: St. Louis College of Pharmacy
Jerrica Shuster, PharmD, BCPS, AQ-Cardiology: Barnes-Jewish Hospital
Eli Deal, PharmD, FCCP, BCPS: Barnes-Jewish Hospital

End-stage renal disease (ESRD), venous thromboembolism (VTE), and atrial fibrillation (AF) are continuously growing disease states worldwide. AF greatly impacts over 20% of ESRD patients, and AF patients on hemodialysis (HD) have 1.72 times higher one-year mortality rates than those not on HD.1,2 Additionally, HD patients are at a six-fold increased predisposed risk of ischemic or hemorrhagic stroke compared with the general population.2 Warfarin has served as the main oral anticoagulant for the general AF population.  However, it lacks randomized, controlled trials comparing it to placebo in patients on HD.2 Results from cohort studies have been inconsistent and limit warfarin’s utility in the HD population.2 Recently developed direct oral anticoagulants (DOACs) offer several advantages in comparison to warfarin while remaining as or more safe and effective. Similar data is still needed in the HD population to establish efficacy and safety. This review will evaluate the available literature in regards to DOACs in non-valvular atrial fibrillation (NVAF) patients requiring HD.

Dabigatran, a direct thrombin inhibitor, was FDA-approved in October 2010 for the prevention of stroke and systemic embolism in patients with NVAF. Dabigatran 75 mg twice daily, a 50% dose reduction, is recommended in patients with NVAF and severe renal impairment (CrCl 15-29 mL/min).3 The landmark NVAF trial, RE-LY, excluded patients with severe renal impairment (CrCl < 30 mL/min).4 A pharmacokinetic (PK) study determined the appropriate dose adjustment in patients with severe renal impairment, but did not explore dosing recommendations in patients undergoing HD.5 However, Stangier, et al. found a two-fold increase in drug exposure in six patients undergoing HD and receiving a single 50 mg dose in comparison to healthy subjects. In addition, HD removed 62-68% of the dose in contrast to excretion of 80% of a dose in the urine with normal renal function.6 The use of dabigatran in HD should be avoided until steady-state PK studies or prospective clinical trials provide more insight due to the two-fold increase in drug exposure, and decreased removal with HD, identified by the single-dose PK study.6

Rivaroxaban, a direct factor Xa inhibitor, was FDA-approved in November 2011 for the reduction of stroke and systemic embolism in patients with NVAF. Per manufacturer labeling, NVAF patients with CrCl 15 to 50 mL/min or on HD, a dose reduction to rivaroxaban 15 mg is recommended.7 However, the landmark trial, ROCKET-AF, excluded patients with CrCl less than 30 mL/min.8 The dose adjustment recommendation in HD for NVAF is based on a single-dose PK study consisting of eight patients that found a 56% increase in drug exposure following post-dialysis administration of rivaroxaban 15 mg when compared to healthy patients. In addition, drug clearance decreased by approximately 35% in ESRD patients.9 However, a multiple-dose PK study found that a 10 mg daily dose of rivaroxaban in HD patients without NVAF or VTE resulted in similar drug exposure when compared to a 20 mg daily dose in healthy patients with normal renal function. This dose contrasts the currently recommended dose reduction to rivaroxaban 15 mg in patients with NVAF and ESRD.10 A dose reduction to rivaroxaban 10 mg daily should be considered in HD patients with NVAF due to the renal accumulation indicated with the recommended 15 mg dose in PK studies.

Apixaban, a direct factor Xa inhibitor, was FDA-approved in December 2012 for the reduction of stroke and systemic embolism in patients with NVAF. Currently, manufacturer labeling recommends in NVAF a dose reduction to apixaban 2.5 mg twice daily in ESRD patients (SCr > 1.5 g/dL) if they are also either > 80 years old or have a body weight < 60 kg. However, patients with ESRD requiring HD, but not meeting the dose reduction criteria, are recommended to receive the unadjusted dose of 5 mg twice daily.11 Both landmark trials, ARISTOTLE and AVERROES, excluded patients with CrCl < 25 mL/min or SCr > 2.5 mg/dL.12,13 A single-dose PK study including eight patients determined that the administration of apixaban 5 mg to HD patients resulted in 36% increase in drug exposure compared to patients with normal renal function. Additionally, this study revealed that dialysis removed only 14% of apixaban, indicating that HD would not be an effective method to remove apixaban in the event of an overdose or bleed.14 However, the results of these studies cannot be confidently extrapolated to patients receiving multiple doses. Recently, Mavrakanas, et al. assessed apixaban PK at steady state in HD patients and found that HD patients receiving apixaban 2.5 mg twice daily had comparable drug exposure when compared to patients with preserved renal function receiving the standard dose (5 mg twice daily). This study did not discuss whether age or weight impacted the results. In HD patients, apixaban 5 mg twice daily, the recommended dose for HD patients not meeting dose reduction requirements, led to supratherapeutic drug exposure, which may be associated with adverse events, such as bleeding.2 Based on these findings, an apixaban dose reduction to 2.5 mg twice daily may be cautiously considered in HD patients with NVAF while monitoring for potential adverse events, as opposed to the labeled recommendations.

Edoxaban, a direct factor Xa inhibitor, was FDA-approved in January 2015 for the prevention of stroke and systemic embolism in patients with NVAF. Per manufacturer labeling for NVAF patients with CrCl 15 to 50 mL/min, a dose reduction to edoxaban 30 mg daily is recommended.15 However, the ENGAGE AF-TIMI 48 Trial excluded patients with CrCl < 30 mL/min.16 No recommendations are currently available in HD. The use of edoxaban is contraindicated in patients with CrCl greater than 95 mL/min.15 A single-dose PK study assessed a 15 mg dose in patients in ESRD without NVAF, and found that HD resulted in a slight decrease in total exposure when compared to patients off dialysis (AUC0–›∞ 676.2 v. 691.7 ng·h/mL), and HD only accounted for one-fourth of the total clearance in healthy patients, indicating that edoxaban was not effectively cleared by HD.17 Further studies providing additional, reliable guidance including steady state dosing in HD are needed prior to utilizing edoxaban in this population.

Most recently, betrixaban, a direct factor Xa inhibitor, was FDA-approved in June 2017 for prophylaxis of VTE in hospitalized adults. The landmark APEX trial excluded patients with CrCl < 15 mL/min or requiring HD.18 The comparison of betrixaban and warfarin in the setting of atrial fibrillation is still being explored. Therefore, without safety and efficacy data, betrixaban should not be utilized in HD patients with NVAF.

Overall, consistent pharmacokinetic and pharmacodynamic evidence supporting the use of DOACs in HD is lacking. While single-dose studies exist for the majority of DOACs, they do not describe the potential impact of administering the medications as long-term anticoagulation. These single-dose studies also describe that HD does not affect the clearance of most DOACs, which indicates the potential for drug accumulation. Of the available DOACs, reduced doses of apixaban 2.5 mg twice daily and rivaroxaban 10 mg daily can be considered as alternatives in NVAF patients undergoing HD based on multiple-dose studies rather than the manufacturer labeling recommendations, which were based on single dose studies. Until large, prospective, clinical trials evaluate the efficacy and safety of these drugs in HD, DOACs should be used with extreme caution due to the limited evidence available.


  1. United States Renal Data System. 2016 USRDS annual report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 2016.
  2. Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017;28(7):2241-48.
  3. Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim; November 2015.
  4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.
  5. Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol. 2012;52(1 Suppl):119S-25S.
  6. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-68.
  7. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; August 2016. 
  8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
  9. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis. Am J Nephrol. 2016;43(4):229-36.
  10. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66(1):91-8.
  11. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; July 2016.
  12. Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.
  13. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17.
  14. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-36.
  15. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc.; September 2016.
  16. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-104.
  17. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015;113(4):719-27.
  18. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016;375(6):534-44.

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