Use of Oral Anticoagulation for Patients with ESRD on Hemodialysis with Atrial Fibrillation: Verdict 1 : Clinical Journal of the American Society of Nephrology

Journal Logo


Use of Oral Anticoagulation for Patients with ESRD on Hemodialysis with Atrial Fibrillation: Verdict 1

Bansal, Nisha

Author Information
Clinical Journal of the American Society of Nephrology 11(11):p 2093-2094, November 2016. | DOI: 10.2215/CJN.08610816
  • Free

In this issue of the Clinical Journal of the American Society of Nephrology, McCullough et al. (1) and Keskar et al. (2) present compelling perspectives for both the pros and cons of anticoagulation use in patients with ESRD and atrial fibrillation (AF). Patients with ESRD uniquely have increased risk for thromboembolism and a paradoxical increased risk of bleeding, which makes decisions on anticoagulation challenging in this vulnerable population. This is clearly a complex discussion, which has led to confusion and inconsistency among providers. I applaud both groups for providing a comprehensive review of both sides of this important clinical question.

Patients with ESRD and AF are at greater risk for stroke (3,4); however, it remains unclear whether anticoagulation decreases this risk (5–9). There are significant limitations in the available data to effectively guide decision making on appropriate anticoagulation in the fragile ESRD population. Risk prediction scores for stroke and risk of bleeding have not performed well in ESRD populations. Rather than adapt current tools to patients with ESRD, development of dialysis-specific scores are needed, which may better account for the unique considerations in patients on dialysis, such as the high competing risk of death from infections and access-related complications for example. These data would help determine the risk-to-benefit ratio of anticoagulation in the short- and long-term in patients on dialysis with AF.

Review of the observational literature presented by both McCullough et al. (1) and Keskar et al. (2) suggests that risks of warfarin may outweigh the benefits. As both sides point out, the risks of warfarin are significant and include major hemorrhage from out of range International Normalized Ratio values, possibly from vitamin K deficiency from malnutrition, frequent antibiotic exposure, and chronic illness seen in patients with ESRD (10). Warfarin has a narrow therapeutic window and requires frequent monitoring. There are also numerous drug and food interactions, which can commonly occur in a patient population with a heavy pill burden and a myriad of dietary restrictions (10). Furthermore, warfarin use has also been associated with calciphylaxis (11). There is clearly a need for warfarin alternatives in patients with ESRD.

Both sides agree that novel oral anticoagulants (NOACs) are promising warfarin alternatives (12–15). These novel anticoagulants include two direct thrombin inhibitors (ximelagatran and dabigatran) and two factor Xa inhibitors (apixaban and rivaroxaban) and have the benefit of not requiring regular anticoagulation monitoring and frequent dose adjustments. Several NOACs have been approved for clinical use and shown to be noninferior or superior to adjusted dose warfarin for stroke prevention, and in some patients, they reduced risk of major hemorrhagic complications. Keskar et al. (2) raise important points regarding the ability to extrapolate to patients with ESRD from clinical trials that have included a very modest number of patients with CKD (and none with ESRD). However, I do think that the data from subgroup analyses of clinical trial participants of patients with CKD are compelling. In a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (which randomized patients to either apixaban or warfarin), apixaban was more effective than warfarin in preventing stroke and decreasing mortality, independent of level of kidney function (16). Moreover, the apixaban group had fewer bleeding events, and the greatest benefit was seen in patients with moderate kidney disease. In the AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) (which randomized patients to apixaban versus aspirin), a subgroup analysis reported that, among patients with kidney disease, apixaban significantly reduced risk of stroke compared with aspirin without significantly increasing the risk of hemorrhage (17).

In contrast to this clinical trial literature, Keskar et al. (2) cite an observational study that reported that patients on NOACs had significantly higher risk of complications compared with warfarin users (18). However, there are limitations to this study—the number of patients on NOACs was small, and the patients who were prescribed NOACs were more likely to have a history of bleeding compared with warfarin users. Thus, the findings in part may due to bias from confounding by indication.

There are also concerns about possible renal clearance of NOACs. McCullough et al. (1) present interesting pharmacokinetic/pharmacodynamics data. In one study, apixaban exposure was only modestly higher in patients with ESRD compared with healthy subjects (19). Another study showed that, in patients with ESRD, rivaroxaban was not eliminated by dialysis, but there was no accumulation after multiple doses (20). With these data, I would not be quick to dismiss the potential use of these agents in patients on dialysis.

In conclusion, both groups of authors made convincing arguments. Without well conducted clinical trials specifically in patients with ESRD, it is impossible to definitely rule out anticoagulation for patients with ESRD and AF. I agree with Keskar et al. (2) that the risks of warfarin seem to outweigh the benefits on the basis of the current observational data. However, McCullough et al. (1) have provided a strong case for cautious optimism for the potential use of NOACs in patients with ESRD. I await more definitive evidence from clinical trials of NOACs in patients with ESRD to shed light on this important clinical issue.


N.B. is on the steering committee of the RENnal hemodialysis patients ALlocated apixaban versus warfarin in Atrial Fibrillation (RENAL-AF) Trial, which is comparing the safety of apixaban with that of warfarin in patients with ESRD and nonvalvular atrial fibrillation.


This work was supported by National Institutes of Health grants K23 DK088865 and R01 DK103612.

Published online ahead of print. Publication date available at


1. McCullough, Ball T, Cox KM, Assar MD: Use of oral anticoagulation in the management of atrial fibrillation in patients with ESRD: Pro. Clin J Am Soc Nephrol 11: 2079–2084, 2016
2. Keskar, Sood MM: Use of oral anticoagulation in the management of atrial fibrillation in patients with ESRD: Con. Clin J Am Soc Nephrol 11: 2085–2092, 2016
3. Wetmore JB, Ellerbeck EF, Mahnken JD, Phadnis M, Rigler SK, Mukhopadhyay P, Spertus JA, Zhou X, Hou Q, Shireman TI: Atrial fibrillation and risk of stroke in dialysis patients. Ann Epidemiol 23: 112–118, 2013
4. Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW, Robinson BM: Atrial fibrillation in hemodialysis patients: Clinical features and associations with anticoagulant therapy. Kidney Int 77: 1098–1106, 2010
5. Shen JI, Montez-Rath ME, Lenihan CR, Turakhia MP, Chang TI, Winkelmayer WC: Outcomes after warfarin initiation in a cohort of hemodialysis patients with newly diagnosed atrial fibrillation. Am J Kidney Dis 66: 677–688, 2015
6. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Humphries KH, Tu JV, Behlouli H, Guo H, Pilote L: Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 129: 1196–1203, 2014
7. Olesen JB, Lip GY, Kamper AL, Hommel K, Køber L, Lane DA, Lindhardsen J, Gislason GH, Torp-Pedersen C: Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 367: 625–635, 2012
8. Jun M, James MT, Manns BJ, Quinn RR, Ravani P, Tonelli M, Perkovic V, Winkelmayer WC, Ma Z, Hemmelgarn BR; Alberta Kidney Disease Network: The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: Population based observational study. BMJ 350: h246, 2015
9. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK: Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 6: 2662–2668, 2011
10. Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, Acton RT, Allon M: Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 20: 912–921, 2009
11. Eiser AR: Warfarin, calciphylaxis, atrial fibrillation, and patients on dialysis: Outlier subsets and practice guidelines. Am J Med 127: 253–254, 2014
12. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators: Apixaban in patients with atrial fibrillation. N Engl J Med 364: 806–817, 2011
13. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361: 1139–1151, 2009
14. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365: 981–992, 2011
15. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365: 883–891, 2011
16. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L: Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 33: 2821–2830, 2012
17. Eikelboom JW, Connolly SJ, Gao P, Paolasso E, De Caterina R, Husted S, O’Donnell M, Yusuf S, Hart RG: Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis 21: 429–435, 2012
18. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW: Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 131: 972–979, 2015
19. Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, Song Y, Pursley J, Boyd RA, Frost C: Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol 56: 628–636, 2016
20. De Vriese AS, Caluwé R, Bailleul E, De Bacquer D, Borrey D, Van Vlem B, Vandecasteele SJ, Emmerechts J: Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 66: 91–98, 2015

ESRD; cardiovascular disease; dialysis; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Disease Management; Humans; Kidney Failure; Chronic

Copyright © 2016 by the American Society of Nephrology