The prevalence of atrial fibrillation (AF) in patients with impaired kidney function or on dialysis is considerably higher than in the general population with estimates that about one in six patients on hemodialysis has AF.^1,2 The risk of ischemic stroke has also been reported to be higher in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD).^2-4 Impaired renal function was recently shown to be an independent risk factor for stroke in a sub-study of ROCKET-AF.⁵

Oral anticoagulation therapy (OAT) in atrial fibrillation has been demonstrated to be very effective in reducing ischemic strokes with the use of adjusted-dose warfarin⁶ and now with comparable evidence on novel oral anticoagulants (NOACs) in treating non-valvular atrial fibrillation.^7-10 The applicability of this information to patients with CKD, and especially to patients on dialysis, has not been as straightforward. CKD is not only a risk factor for ischemic stroke but also an independent risk factor for bleeding.^11,12 Concern with the use of vitamin K antagonists (VKAs) is based on multiple issues such as initial overdosing due to frequent vitamin K deficiency in renal patients, heparin use during dialysis, impaired platelet and coagulation function, and the possibility warfarin may increase calcification formation in ESRD patients.¹³

There is evidence suggesting the use of anticoagulation therapy in patients with mild to moderate CKD provides similar to potentially greater benefit with OAT compared to the general population in certain AF studies. Warfarin was found in a post hoc analysis of patients with CKD stage III in the Stroke Prevention in Atrial Fibrillation III trial to markedly lower ischemic stroke and/or systemic venous thromboembolism (VTE) by 76% (95% confidence interval [CI], 42-90; P < 0.001) compared to aspirin plus low, fixed doses of warfarin.¹⁴ Subgroup analyses of RE-LY, ARISTOTLE, ROCKET-AF, and ENGAGE AF-TIMI 48 also demonstrated that all four NOACs that recently completed phase III warfarin-controlled trials in patients with AF produced at least comparable results to the primary outcomes of the study when just the patients with mild to moderate renal disease were evaluated.^12,15,16

Unfortunately, patients with severe renal impairment or on dialysis have been excluded from large randomized clinic trials evaluating antithrombotic therapy in AF.^17,18 Therefore, the optimal approach to anticoagulation in patients with non-valvular AF who have severe renal disease or are on dialysis is controversial. In the last decade, several observational studies have raised concerns about the use of warfarin in dialysis patients with non-valvular AF.^2,19,20 The paucity and limited data is reflected in the heterogeneity of recommendations from various guideline documents.^11,17,18 The Kidney Disease: Improving Global Outcomes guidelines in 2011 changed the recommendation to advise against the use of warfarin for stroke prevention in ESRD patients. Likewise the Canadian Cardiovascular Society AF guidelines in 2012 made a conditional recommendation against routine use of anticoagulation treatment for the primary prevention of stroke in this population.^13,17 However, the recently published 2014 ACC/AHA/HRS guideline gives a IIa (Level of Evidence: B) recommendation for the prescription of warfarin (INR 2.0-3.0) in non-valvular AF patients with a CHA2DS2-VASc score of 2 or greater and who have end stage CKD (CrCl <15 mL/min) or are on hemodialysis.²¹ The ESC guidelines chose not to make any definitive recommendations due to the lack of data for these patients and encouraged assessing individual risk of stroke and bleeding risks.²²

Two recent publications this year in Circulation by Shah and his colleagues and in JAMA by Carrero and coauthors highlight the unclear risk-benefit profile for the routine use of warfarin in patients on hemodialysis with non-valvular AF.^13,23 Shah et al. studied a retrospective cohort of 1626 patients on dialysis with a diagnosis of AF at two large medical centers in Canada with approximately half of the patients being prescribed warfarin. No reduction in stroke risk was found with warfarin even after adjusting for multiple factors (hazard ratio [HR], 1.14; 95% CI, 0.78–1.67). However, a significantly higher risk of bleeding was seen for patients on warfarin as compared to patients not prescribed warfarin (HR, 1.44; 95% CI, 1.13–1.85).¹³ 

The results are concordant with a study done by Winkelmayer et al., which compared 237 patients on hemodialysis with incident AF versus 949 propensity-matched patients not receiving anticoagulation using Medicare claims and prescription program.¹⁹ There were 7.7 ischemic strokes per 100 person-years of follow-up with no difference among warfarin users and nonusers (HR 0.92; CI, 0.61 to 1.37). Warfarin recipients experienced more than twice the event rate for hemorrhagic stroke compared with patients who did not receive warfarin (HR, 2.38; 95% CI, 1.15 to 4.96), but no overall difference in mortality rates was found.¹⁹ Two other large retrospective cohort analyses both found an increase in the composite outcome of stroke/death associated with the use of warfarin.^2,20 In the Dialysis Outcomes and Practice Patterns Study (DOPPS), Wizemann et al. demonstrated that warfarin use in AF patients >75 years of age (n=1107) was associated with a 2.2-fold higher risk for the composite stroke/death outcome, however in the two groups analyzed under age 75 no difference with warfarin use was observed.²

In contrast, Olesen et al demonstrated a favorable analysis for the use of warfarin in 901 patients with ESRD in a large observational study from the National Danish Registry from 1997-2008 evaluating patients with AF at hospital discharge.³ The study showed a 56% reduction in the risk for the composite stroke/death outcome compared to no antithrombotic therapy (HR 0.44; 95% CI, 0.26-0.74).³ Although of note, patients in this registry receiving renal replacement were overall younger and healthier with less comorbidities and HAS-BLED scores than the other cohorts of ESRD.^13,18 Carrero and coauthors showed that warfarin was associated with lower risk of the composite endpoint including death, repeat myocardial infarction (MI), or ischemic stroke in patients with both CKD and AF one year after discharge for an acute MI in the SWEDEHEART registry, a large prospective registry of consecutive patients admitted with MI to a Swedish Hospital.²³ There were 2444 patients included with an eGFR <30, and 438 of those patients received a prescription for warfarin. The lower event rate for the primary outcome was seen across all strata of eGFR and primarily driven by mortality events. The event rate per 100 person-years for eGFR 15-30 was 84.3 for warfarin vs 110.1 for no warfarin (HR 0.84; 95% CI, 0.70-1.02) and for eGFR ≤15: 83.2 for warfarin vs 128.3 for no warfarin (HR 0.57; 95% CI, 0.37-0.86). Additionally, the risk of bleeding was not significantly higher in patients treated with warfarin in any CKD stratum.²³ The study has the advantages of being based on a large prospective cohort with reliable ascertainment of outcomes using a national registry database, but the study is limited in generalizability and subject to confounding due to the nature of these post MI patients.²⁴ One important note the authors point out was the high percentage of time in therapeutic range (TTR) for goal INR in Scandinavian countries (75%),which, as Winkelmayer points out in his accompanying editorial, is similar to Sweden’s high performance in the  RE-LY trial (77% TTR) vs the United States population in RE-LY (66%).²³

The role of other OAT in patients with CKD and atrial fibrillation has not been studied in much detail. Dabigatran, rivaroxaban, and apixaban received a Class IIb (LOE C) recommendation for use in patients with moderate renal impairment in the 2014 ACC/AHA/HRS AF guidelines.^12,15,21 Each of the recently approved NOACs, as well as a 4th NOAC edoxaban, has some degree of renal clearance, especially dabigatran, and in the stroke prophylaxis trials patients with  eGFR <30 were excluded.^22,25 Dabigatran and rivaroxaban were both received a class III recommendation (no benefit) for patients with ESRD.²² Apixaban was not mentioned in this category and the prescribing information was updated by the FDA in January 2014 to include an indication to use 5 mg of apixaban twice-daily (dose reduced to 2.5 mg twice daily age 80 or greater or in patients weighing ≤60 kg) in patients with ESRD maintained on hemodialysis.^22,26 This recommendation was based upon pharmacokinetic and pharmacodynamic modeling. However, there are limited clinical data regarding the efficacy and safety of apixaban in patients on hemodialysis.¹⁶

There remains a lack of clarity on the best strategy for antithrombotic prophylaxis in patients with advanced CKD or ESRD based on conflicting results and the inherent limitations of observational data with confounding and selection bias despite adjustment and propensity matching. Hopefully the call by many investigators for a randomized trial will be answered,¹⁷ but until then a prudent strategy should involve evaluating and discussing with patients on an individual basis to assess for other reasons for anticoagulation and assessment for stroke and bleeding risk factors before making a decision. In patients for whom anticoagulation is recommended, the outcomes appear more favorable if they are able to achieve higher TTR with adjustment for goal INR of 2-3.^23,24

References

1. Winkelmayer WC, Liu J, Patrick AR, et al. Prevalence of atrial fibrillation and warfarin use in older patients receiving hemodialysis. J Nephrol 2012;25:341–353.
2. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010;77:1098–1106.
3. Wiesholzer M, Harm F, Tomasec G, et al. Incidence of stroke among chronic hemodialysis patients with nonrheumatic atrial fibrillation. Am J Nephrol 2001;21:35–39.
4. Olesen JB, Lip GY, Kamper AL, Hommel K,et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625–635.
5. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral,direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and EmbolismTrial in Atrial Fibrillation) and ATRIA(Anticoagulation and Risk Factors In Atrial Fibrillation). Circulation 2013;127:224–232.
6. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146(12):857-67.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-891.
9. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981-992.
10. Connolly SJ,  Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
11. Ricarda Marinigh R, Lane DA ,and Lip GY  Severe Renal Impairment and Stroke Prevention in Atrial Fibrillation Implications for Thromboprophylaxis and Bleeding Risk. J Am Coll Cardiol 2011;57:1339–48
12. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights form the ARISTOTLE trial. Eur Heart J 2012;33:2821-30.
13. Shah M, Tsadok MA, Jackevicius CA et al Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014;129:1196–1203.
14. Hart RG, Pearce LA, Asinger RW, et al. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J AmSoc Nephrol 2011;6(11):2599-2604.
15. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;32:2387-94.
16. Hart RG, Eikelboom JW, Brimble KS et al. Stroke Prevention in Atrial Fibrillation Patients with Chronic Kidney Disease. Can J Cardiol 2013; 29:S71-S78.
17. Christopher B. Granger and Glenn M. Chertow. A Pint of Sweat Will Save a Gallon of Blood: A Call for Randomized Trials of Anticoagulation in End-Stage Renal Disease. Circulation 2014;129:1190-1192.
18. Kruger, Brandenburg V, Schlieper G et al. Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients. Nephrol Dial Transplant 2013;28(3):534-41.
19. Winkelmayer WC, Liu J, Setoguchi S, et al. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011;6:2662–2668.
20. Chan KE, Lazarus JM, Thadhani R, et al. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009;20:2223–2233.
21. January CT, Wann L, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014; [Epub Ahead of Print].
22. Camm AJ1, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.
23. Carrero JJ, Evans M, Szummer K, et al. Warfarin,kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014;311:919-928.
24. Wolfgang C. Winkelmayer and Mintu P. Turakhia. Warfarin Treatment in PatientsWith Atrial Fibrillation and Advanced Chronic Kidney Disease Sins of Omission or Commission? JAMA 2014;311:913-914.
25. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
26. Eliquis[package insert]. Princeton, New Jersey:Bristol-Meyers Squibb; 2012

Keywords: Anticoagulants, Atrial Fibrillation, Blood Coagulation, Blood Platelets, Hemorrhage, Heparin, Kidney Failure, Chronic, Prevalence, Renal Dialysis, Renal Insufficiency, Risk Factors, Stroke, Vitamin K, Vitamin K Deficiency, Warfarin

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