Skip to main content

Advertisement

SpringerLink
Log in

Systematic DOACs oral anticoagulation in patients with atrial fibrillation and chronic kidney disease: the nephrologist’s perspective

  • Review
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Atrial fibrillation (AF) is highly prevalent among patients with chronic kidney disease (CKD), and also associated with unfavorable outcome. Anticoagulant therapy is the mainstep of management in such patients, aimed at reducing the high risk of systemic thromboembolism and especially of ischemic stroke, which is reportedly associated with increased mortality in CKD patients. Even though new direct oral anticoagulant agents (DOACs) proved to be effective in patients with non valvular chronic AF, and are therefore recommended by recent guidelines for their treatment, warfarin is currently used in more than one-half of subjects needing oral anticoagulation, and only 30% of them are converted from a vitamin K antagonist- to a DOAC-based regimen. The main reason for not prescribing DOACs is often a reduction in renal function, even if mild. Aim of this review was therefore to evaluate the impact of DOAC therapy in the setting of CKD, from a nephrological perspective, by comparing available evidence on the role of DOACs in patients with CKD and AF with that emerging from traditional warfarin-based therapy. Both the pathogenesis of AF in CKD, and available findings of renal, cardiovascular and bone effects of DOACs in CKD are discussed, leading to the conclusion that DOAC therapy should be considered as the first line therapy for non valvular AF in patients with mild and moderate reduction of renal function, and could also be adopted for patients with severe CKD not on hemodialysis treatment, whereas there is insufficient evidence for ESRD patients on dialysis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, Levin A (2013) Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 382(9887):158–169

    PubMed  Google Scholar 

  2. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE et al (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375(9731):2073–2081

    PubMed  PubMed Central  Google Scholar 

  3. Fox SC, Matsushita K, Woodward M, Bilo HJG, Chalmers J, Lambers Heerspink HJ, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti JA, Yamagishi K, Coresh J, de Jong PE, Wen CP, Nelson RG (2012) Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 380(9854):1662–1673

    PubMed  PubMed Central  Google Scholar 

  4. Tancredi M, Rosengren A, Svensson AM, Kosiborod M, Pivodic A, Gudbjörnsdottir S, Wedel H, Clements M, Dahlqvist S, Lind M (2015) Excess mortality among persons with type 2 diabetes. N Engl J Med 373:1720–1732

    CAS  PubMed  Google Scholar 

  5. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci SL (2014) Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 6:213–220

    PubMed  PubMed Central  Google Scholar 

  6. Turakhia MP, Blankestijn PJ, Carrero JJ, Clase CM, Deo R, Herzog CA, Kasner SE, Passman RS, Pecoits-Filho R, Reinecke H, Shroff GR, Zareba W, Cheung M, Wheeler DC, Winkelmayer WC, Wanner C (2018) Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J. 39(24):2314–2325. https://doi.org/10.1093/eurheartj/ehy060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baber U, Howard VJ, Halperin JL, Soliman EZ, Zhang X, McClellan W, Warnock DG, Muntner P (2011) Association of chronic kidney disease with atrial fibrillation among adults in the United States: Reasons for geographic and racial differences in stroke (REGARDS) study. Circ Arrhythm Electrophysiol 4(1):26–32

    PubMed  Google Scholar 

  8. McManus DD, Corteville DC, Shlipak MG, Whooley MA, Ix JH (2009) Relation of kidney function and albuminuria with atrial fibrillation (from the Heart and Soul Study). Am J Cardiol 104(11):1551–1555

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M, Ojo A, Teal VL, Jensvold NG, Robinson NL, Dries DL, Bazzano L, Mohler ER, Wright JT, Feldman HI, Chronic Renal Insufficiency Cohort Study G (2010) Chronic kidney disease and prevalent atrial fibrillation: the chronic renal insufficiency cohort (CRIC). Am Heart J 159(6):1102–1107

    PubMed  PubMed Central  Google Scholar 

  10. Ananthapanyasut W, Napan S, Rudolph EH, Harindhanavudhi T, Ayash H, Guglielmi KE, Lerma EV (2010) Prevalence of atrial fibrillation and its predictors in nondialysis patients with chronic kidney disease. Clin J Am Soc Nephrol 5(2):173–181

    PubMed  PubMed Central  Google Scholar 

  11. Zimmerman D, Sood MM, Rigatto C, Holden RM, Hiremath S, Clase CM (2012) Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant 27(10):3816–3822

    CAS  PubMed  Google Scholar 

  12. Wetmore JB, Mahnken JD, Rigler SK, Ellerbeck EF, Mukhopadhyay P, Spertus JA, Hou Q, Shireman TI (2012) The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients. Kidney Int 81(5):469–476

    PubMed  Google Scholar 

  13. Konigsbrugge O, Posch F, Antlanger M, Kovarik J, Klauser-Braun R, Kletzmayr J, Schmaldienst S, Auinger M, Zuntner G, Lorenz M, Grilz E, Stampfel G, Steiner S, Pabinger I, Saemann M, Ay C (2017) Prevalence of atrial fibrillation and antithrombotic therapy in hemodialysis patients: cross-sectional results of the vienna investigation of atrial fibrillation and thromboembolism in patients on hemodIalysis (VIVALDI). PLoS One 12(1):e0169400

    PubMed  PubMed Central  Google Scholar 

  14. Camm J, Lip GY, Caterina R, ESC Committee for Practice Guidelines (CPG) et al (2012) focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012(33):2719–2747

    Google Scholar 

  15. Camm J, Kirchhof P, Lip GY et al (2010) Guidelines for the management of atrial fibrillation. Eur Heart J 31:2369–2429

    PubMed  Google Scholar 

  16. Olesen JB, Lip GY, Kamper AL, Hommel K, Køber L, Lane DA, Lindhardsen J, Gislason GH, Torp-Pedersen C (2012) Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 367(7):625–635

    CAS  PubMed  Google Scholar 

  17. Hart RG, Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ (2013) Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol 29(7 Suppl):S71–S78

    PubMed  Google Scholar 

  18. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbüchel H (2018) The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 39:1330–1393

    CAS  PubMed  Google Scholar 

  19. Bansal N, Zelnick LR, Alonso A, Benjamin EJ, de Boer IH, Deo R, Katz R, Kestenbaum B, Mathew J, Robinson-Cohen C, Sarnak MJ, Shlipak MG, Sotoodehnia N, Young B, Heckbert SR (2017) eGFR and albuminuria in relation to risk of incident atrial fibrillation: a meta-analysis of the jackson heart study, the multi-ethnic study of atherosclerosis, and the cardiovascular health study. Clin J Am Soc Nephrol 12(9):1386–1398

    PubMed  PubMed Central  Google Scholar 

  20. Watanabe H, Watanabe T, Sasaki S, Nagai K, Roden DM, Aizawa Y (2009) Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. Am Heart J 158(4):629–636

    PubMed  Google Scholar 

  21. Martin FL, McKie PM, Cataliotti A, Sangaralingham SJ, Korinek J, Huntley BK, Oehler EA, Harders GE, Ichiki T, Mangiafico S, Nath KA, Redfield MM, Chen HH, Burnett JC Jr (2012) Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection. Am J Physiol Regul Integr Comp Physiol 302:R292–R299

    CAS  PubMed  Google Scholar 

  22. Huang SY, Chen YC, Kao YH, Hsieh MH, Chen YA, Chen WP, Lin YK, Chen SA, Chen YJ (2016) Renal failure induces atrial arrhythmogenesis from discrepant electrophysiological remodeling and calcium regulation in pulmonary veins, sinoatrial node, and atria. Int J Cardiol 202:846–857

    PubMed  Google Scholar 

  23. Lopez FL, Agarwal SK, Grams ME, Loehr LR, Soliman EZ, Lutsey PL, Chen LY, Huxley RR, Alonso A (2013) Relation of serum phosphorus levels to the incidence of atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] study). Am J Cardiol 111:857–862

    CAS  PubMed  Google Scholar 

  24. Mathew JS, SachsMC Katz R, Patton KK, Heckbert SR, Hoofnagle AN, AlonsoA Choncho LM, Deo R, Ix JH, Siscovick DS, Kestenbaum B, de Boer IH (2014) Fibroblast growth factor-23 and incident atrial fibrillation: the multi-ethnic study of atherosclerosis (MESA) and the cardiovascular health study (CHS). Circulation 130:298–307

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cerasola G, Nardi E, Palermo A, Mulè G, Cottone S (2011) Epidemiology and pathophysiology of left ventricular abnormalities in chronic kidney disease: a review. J Nephrol. 24:1–10

    PubMed  Google Scholar 

  26. Lamprea-Montealegre JA, Zelnick LR, Shlipak MG, Floyd JS, Anderson AH, He J, Christenson R, Seliger SL, Soliman EZ, Deo R, Ky B, Feldman HI, Kusek JW, deFilippi CR, Wolf MS, Shafi T, Go AS, Bansal N (2019) Cardiac biomarkers and risk of atrial fibrillation in chronic kidney disease: the CRIC study. J Am Heart Assoc. 8(15):e012200. https://doi.org/10.1161/jaha.119.012200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shih CJ, Ou SM, Chao PW, Kuo SC, Lee YJ, Yang CY, Tarng DC, Lin CC, Huang PH, Li SY, Chen YT (2016) Risks of death and stroke in patients undergoing hemodialysis with new-onset atrial fibrillation: a competing-risk analysis of a nationwide cohort. Circulation 133(3):265–272

    CAS  PubMed  Google Scholar 

  28. Bansal N, Fan D, Hsu CY, Ordonez JD, Go AS (2014) Incident atrial fibrillation and risk of death in adults with chronic kidney disease. J Am Heart Assoc 3(5):e001303

    PubMed  PubMed Central  Google Scholar 

  29. Wetmore JB, Ellerbeck EF, Mahnken JD, Phadnis M, Rigler SK, Mukhopadhyay P, Spertus JA, Zhou X, Hou Q, Shireman TI (2013) Atrial fibrillation and risk of stroke in dialysis patients. Ann Epidemiol 23(3):112–118

    PubMed  PubMed Central  Google Scholar 

  30. Bansal N, Xie D, Tao K, Chen J, Deo R, Horwitz E, Hsu CY, Kallem RK, Keane MG, Lora CM, Raj D, Soliman EZ, Strauss L, Wolf M, Go AS (2016) Atrial fibrillation and risk of ESRD in adults with CKD. Clin J Am Soc Nephrol 11(7):1189–1196

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bansal N, Fan D, Hsu CY, Ordonez JD, Marcus GM, Go AS (2013) Incident atrial fibrillation and risk of end-stage renal disease in adults with chronic kidney disease. Circulation 127(5):569–574

    PubMed  Google Scholar 

  32. O’Neal WT, Tanner RM, Efird JT, Baber U, Alonso A, Howard VJ, Howard G, Muntner P, Soliman EZ (2015) Atrial fibrillation and incident end-stage renal disease: the reasons for geographic and racial differences in stroke (REGARDS) study. Int J Cardiol 185:219–223

    PubMed  PubMed Central  Google Scholar 

  33. Hijazi Z, Hohnloser SH, Andersson U, Alexander JH, Hanna M, Keltai M, Parkhomenko A, López-Sendón JL, Lopes RD, Siegbahn A, Granger CB, Wallentin L (2016) Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial. JAMA Cardiol. 1(4):451–460

    PubMed  Google Scholar 

  34. Fordyce CB, Hellkamp AS, Lokhnygina Y, Lindner SM, Piccini JP, Becker RC, Berkowitz SD, Breithardt G, Fox KA, Mahaffey KW, Nessel CC, Singer DE, Patel MR, ROCKET AF Steering Committee and Investigators (2016) On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF. Circulation. 134(1):37–47

    CAS  PubMed  Google Scholar 

  35. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ (2010) Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 137:263–272

    PubMed  Google Scholar 

  36. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138:1093–1100

    PubMed  Google Scholar 

  37. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001) Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285:2864–2870

    CAS  PubMed  Google Scholar 

  38. Apostolakis S, Guo Y, Lane DA, Buller H, Lip GY (2013) Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial. Eur Heart J 34:3572–3579

    CAS  PubMed  Google Scholar 

  39. Singer DE, Chang Y, Borowsky LH et al (2013) A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc. 2:e000250

    PubMed  PubMed Central  Google Scholar 

  40. Fang MC, Go AS, Chang Y et al (2011) A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 58:395–401

    PubMed  PubMed Central  Google Scholar 

  41. O’Brien EC, Simon DN (2015) The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 36(46):3258–3264

    PubMed  PubMed Central  Google Scholar 

  42. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, Radford MJ (2006) Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 151(3):713–719

    PubMed  Google Scholar 

  43. McAlister FA, Wiebe N, Jun M, Sandhu R, James MT, McMurtry MS, Hemmelgarn BR, Tonelli M (2017) are existing risk scores for nonvalvular atrial fibrillation useful for prediction or risk adjustment in patients with chronic kidney disease? Can J Cardiol 33:243–252

    PubMed  Google Scholar 

  44. Lin WY, Lin YJ, Chung FP, Chao TF, Liao JN, Chang SL, Lo LW, Hu YF, Chiang CE, Cheng SM, Lin WS, Chen SA (2014) Impact of renal dysfunction on clinical outcome in patients with low risk of atrial fibrillation. Circ J 78(4):853–858

    PubMed  Google Scholar 

  45. Chao TF, Tsao HM, Ambrose K, Lin YJ, Lin WS, Chang SL, Lo LW, Hu YF, Tuan TC, Suenari K, Li CH, Hartono B, Chang HY, Chung FP, Hanafy DA, Lin WY, Chen SA (2012) Renal dysfunction and the risk of thromboembolic events in patients with atrial fibrillation after catheter ablation—the potential role beyond the CHA2DS2-VASc score. Heart Rhythm. 9:1755–1760

    PubMed  Google Scholar 

  46. Ravera M, Bussalino E, Paoletti E, Bellasi A, Di Lullo L, Fusaro M (2019) Haemorragic and thromboembolic risk in CKD patients with non valvular atrial fibrillation: do we need a novel risk score calculator? Int J Cardiol 274:179–185

    PubMed  Google Scholar 

  47. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron. 16:31–41

    CAS  PubMed  Google Scholar 

  48. Fu S, Zhou S, Luo L, Ye P (2017) R2(GFR)CHADS2 and R2(GFR)CHA2DS2VASc schemes improved the performance of CHADS2 and CHA2DS2VASc scores in death risk stratification of Chinese older patients with atrial fibrillation. Clin Interv Aging 12:1233–1238

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K (2012) Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med 156:785–795

    PubMed  Google Scholar 

  50. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, RE-LY Steering Committee and Investigators et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 361(12):1139–1151

    CAS  PubMed  Google Scholar 

  51. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, ARISTOTLE Committee and Investigators et al (2011) ARISTOTLE Committee and Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 365(11):981–992

    CAS  PubMed  Google Scholar 

  52. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, ROCKET AF Investigators et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 365(10):883–891

    CAS  PubMed  Google Scholar 

  53. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104

    CAS  PubMed  Google Scholar 

  54. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA (2017) Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 69(23):2779–2790

    CAS  PubMed  Google Scholar 

  55. Connors JM (2018) Testing and monitoring direct oral anticoagulants. Blood 132(19):2009–2015

    CAS  PubMed  Google Scholar 

  56. Lip G, Freedman B, De Caterina R, Potpara TS (2017) Stroke prevention in atrial fibrillation: past, present and future: comparing the guidelines and practical decision-making. Thromb Haemost. 117(7):1230–1239

    PubMed  Google Scholar 

  57. Hart RG, Pearce LA, Asinger RW, Herzog CA (2011) Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol 6(11):2599–2604

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Dahal K, Kunwar S, Rijal J, Schulman P, Lee J (2016) Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: a meta-analysis of observational studies. Chest 149(4):951–959

    PubMed  Google Scholar 

  59. Brancaccio D, Neri L, Bellocchio F, Barbieri C, Amato C, Mari F, Canaud B, Stuard S (2016) Patients’ characteristics affect the survival benefit of warfarin treatment for hemodialysis patients with atrial fibrillation: a historical cohort study. Am J Nephrol. 44(4):258–267

    CAS  PubMed  Google Scholar 

  60. Kai B, Bogorad Y, Nguyen LN, Yang SJ, Chen W, Spencer HT, Shen AY, Lee MS (2017) Warfarin use and the risk of mortality, stroke, and bleeding in hemodialysis patients with atrial fibrillation. Heart Rhythm. 14:645–651

    PubMed  Google Scholar 

  61. Genovesi S, Rebora P, Gallieni M, Stella A, Badiali F, Conte F, Pasquali S, Bertoli S, Ondei P, Bonforte G, Pozzi C, Rossi E, Valsecchi MG, Santoro A (2017) Effect of oral anticoagulant therapy on mortality in end-stage renal disease patients with atrial fibrillation: a prospective study. J Nephrol. 30:573–581

    CAS  PubMed  Google Scholar 

  62. Jun M, James MT, Ma Z, Zhang J, Tonelli M, McAlister FA, Manns BJ, Ravani P, Quinn RR, Wiebe N, Perkovic V, Wilton SB, Winkelmayer WC, Hemmelgarn BR, Alberta Kidney Disease Network (2017) Warfarin initiation, atrial fibrillation, and kidney function: comparative effectiveness and safety of warfarin in older adults with newly diagnosed atrial fibrillation. Am J Kidney Dis. 69(6):734–743

    CAS  PubMed  Google Scholar 

  63. Tan J, Liu S, Segal JB, Alexander GC, McAdams-DeMarco M (2016) Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and meta-analysis. BMC Nephrol 17:157

    PubMed  PubMed Central  Google Scholar 

  64. Voskamp PWM, Rookmaaker MB, Verhaar MC, Dekker FW, Ocak G (2018) Vitamin K antagonist use and mortality in dialysis patients. Nephrol Dial Transplant 33:170–176

    CAS  PubMed  Google Scholar 

  65. Hussain S, Siddiqui AN, Baxi H, Habib A, Hussain MS, Najmi AK (2019) Warfarin use increases bleeding risk in hemodialysis patients with atrial fibrillation: a meta-analysis of cohort studies. J Gastroenterol Hepatol 34(6):975–984

    CAS  PubMed  Google Scholar 

  66. Feldberg J, Patel P, Farrell A, Sivarajahkumar S, Cameron K, Ma J, Battistella M (2019) A systematic review of direct oral anticoagulant use in chronic kidney disease and dialysis patients with atrial fibrillation. Nephrol Dial Transplant 34:265–277

    CAS  PubMed  Google Scholar 

  67. Writing Group Members, January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW (2019) 2019 AHA/ACC/HRS focused update of the 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 Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 16(8):e66–e93

  68. Königsbrügge O, Ay C (2019) Atrial fibrillation in patients with end-stage renal disease on hemodialysis: magnitude of the problem and new approach to oral anticoagulation. Res Pract Thromb Haemost 3:578–588

    PubMed  PubMed Central  Google Scholar 

  69. Di Lullo L, Tripepi G, Ronco C, De Pascalis A, Barbera V, Granata A, Russo D, Di Iorio BR, Paoletti E, Ravera M, Fusaro M, Bellasi A (2018) Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: real world data. J Nephrol 31(5):751–756

    PubMed  Google Scholar 

  70. Shin JI, Secora A, Alexander GC, Inker LA, Coresh J, Chang AR, Grams ME (2018) Risks and benefits of direct oral anticoagulants across the spectrum of GFR among incident and prevalent patients with atrial fibrillation. Clin J Am Soc Nephrol 13:1144–1152

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Siontis KC, Zhang X, Eckard A, Bhave N, Schaubel DE, He K, Tilea A, Stack AG, Balkrishnan R, Yao X, Noseworthy PA, Shah ND, Saran R, Nallamothu BK (2018) Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 138:1519–1529

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Coleman CI, Kreutz R, Sood NA, Bunz TJ, Eriksson D, Meinecke AK, Baker WL (2019) Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney disease or undergoing hemodialysis. Am J Med 132(9):1078–1083. https://doi.org/10.1016/j.amjmed.2019.04.013

    Article  CAS  PubMed  Google Scholar 

  73. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW (2015) Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 131(11):972–979

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Glassock RJ (2019) Anticoagulant-related nephropathy. it’s the real McCoy CJASN 2019, CJN.02470319. https://doi.org/10.2215/CJN.02470319

  75. Brodsky SV, Nadasdy T, Rovin BH, Satoskar AA, Nadasdy GM, Wu HM, Bhatt UY, Hebert LA (2011) Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 80(2):181–189

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Brodsky SV, Satoskar A, Chen J, Nadasdy G, Eagen JW, Hamirani M, Hebert L, Calomeni E, Nadasdy T (2009) Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis 54(6):1121–1126

    PubMed  Google Scholar 

  77. Brodsky SV, Collins M, Park E, Rovin BH, Satoskar AA, Nadasdy G, Wu H, Bhatt U, Nadasdy T, Hebert LA (2010) Warfarin therapy that results in an International Normalization Ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract 115(2):c142–c146

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Price PA, Faus SA, Williamson MK (1998) Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 18(9):1400–1407

    CAS  PubMed  Google Scholar 

  79. Schurgers LJ, Spronk HM, Soute BA et al (2007) Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 109:2823–2831

    CAS  PubMed  Google Scholar 

  80. Price PA, Fraser JD, Metz-Virca G (1987) Molecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase. Proc Natl Acad Sci USA 84(23):8335–8339

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Parker BD, Ix JH, Cranenburg EC, Vermeer C, Whooley MA, Schurgers LJ (2009) Association of kidney function and uncarboxylated matrix Gla protein: data from the Heart and Soul Study. Nephrol Dial Transplant 24(7):2095–2101

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Moeckel GW, Luciano RL, Brewster UC (2013) Warfarin-related nephropathy in a patient with mild IgA nephropathy on dabigatran and aspirin. Clin Kidney J. 6:507–509

    PubMed  PubMed Central  Google Scholar 

  83. Escoli R, Santos P, Andrade S, Carvalho F (2015) Dabigatran-related nephropathy in a patient with undiagnosed IgA nephropathy. Case Rep Nephrol. 2015:298261

    PubMed  PubMed Central  Google Scholar 

  84. Gois M, Azevedo A, Carvalho F, Nolasco F (2017) Anticoagulant-related nephropathy in a patient with IgA nephropathy. BMJ Case Rep

  85. Kalaitzidis RG, Duni A, Liapis G et al (2017) Anticoagulant-related nephropathy: a case report and review of the literature of an increasingly recognized entity. Int Urol Nephrol 49:1401–1407. https://doi.org/10.1007/s11255-017-1527-9

    Article  PubMed  Google Scholar 

  86. Awesat J, Sagy I, Haviv YS et al (2018) Dabigatran-induced nephropathy and its successful treatment with Idarucizumab—case report and literature review. Thromb Res 169:120–122

    CAS  PubMed  Google Scholar 

  87. Böhm M, Ezekowitz MD, Connolly SJ, Eikelboom JW, Hohnloser SH, Reilly PA, Schumacher H, Brueckmann M, Schirmer SH, Kratz MT, Yusuf S, Diener HC, Hijazi Z, Wallentin L (2015) Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol 65(23):2481–2493

    PubMed  Google Scholar 

  88. Zhang C, Gu ZC, Ding Z, Shen L, Pan MM, Zheng YL, Lin HW, Pu J (2019) Decreased risk of renal impairment in atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants: a pooled analysis of randomized controlled trials and real-world studies. Thromb Res 174:16–23

    CAS  PubMed  Google Scholar 

  89. Sparkenbaugh EM, Chantrathammachart P, Mickelson J, van Ryn J, Hebbel RP, Monroe DM, Mackman N, Key NS, Pawlinski R (2014) Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood 123(11):1747–1756

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lee IO, Kratz MT, Schirmer SH, Baumhäkel M, Böhm M (2012) The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther 343(2):253–257

    CAS  PubMed  Google Scholar 

  91. Horinouchi Y, Ikeda Y, Fukushima K, Imanishi M, Hamano H, Izawa-Ishizawa Y, Zamami Y, Takechi K, Miyamoto L, Fujino H, Ishizawa K, Tsuchiya K, Tamaki T (2018) Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis. Sci Rep 8(1):10858

    PubMed  PubMed Central  Google Scholar 

  92. Schurgers LJ, Cranenburg EC, Vermeer C (2008) Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100(4):593–603

    CAS  PubMed  Google Scholar 

  93. Clemens TL, Karsenty G (2011) The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 26:677–680

    CAS  PubMed  Google Scholar 

  94. Neve A, Corrado A, Cantatore FP (2013) Osteocalcin: skeletal and extraskeletal effects. J Cell Physiol 228:1149–1153

    CAS  PubMed  Google Scholar 

  95. Bacchetta J, Boutroy S, Guebre-Egziabher F et al (2009) The relationship between adipokines, osteocalcin and bone quality in chronic kidney disease. Nephrol Dial Transpl 24:3120–3125

    CAS  Google Scholar 

  96. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–5270

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Luo XH, Zhao LL, Yuan LQ, Wang M, Xie H, Liao EY (2009) Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification. J Bone Miner Res 24(8):1461–1468

    CAS  PubMed  Google Scholar 

  98. Confavreux CB, Szulc P, Casey R, Boutroy S, Varennes A, Vilayphiou N, Goudable J, Chapurlat RD (2013) Higher serum osteocalcin is associated with lower abdominal aortic calcification progression and longer 10-year survival in elderly men of the MINOS cohort. J Clin Endocrinol Metab 98(3):1084–1092

    CAS  PubMed  Google Scholar 

  99. Weijs B, Blaauw Y, Rennenberg RJ, Schurgers LJ, Timmermans CC, Pison L, Nieuwlaat R, Hofstra L, Kroon AA, Wildberger J, Crijns HJ (2011) Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J. 32(20):2555–2562

    CAS  PubMed  Google Scholar 

  100. Koos R, Mahnken AH, Mühlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kühl HP (2005) Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 96:747–749

    CAS  PubMed  Google Scholar 

  101. Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, Ten Cate H, Leiner T, Vermeer C, de Leeuw PW, Kroon AA (2010) Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood 115:5121–5123

    CAS  PubMed  Google Scholar 

  102. Han KH, O’Neill WC (2016) Increased peripheral arterial calcification in patients receiving warfarin. J Am Heart Assoc. 5(1):25

    CAS  Google Scholar 

  103. Tantisattamo E, Han KH, O’Neill WC (2015) Increased vascular calcification in patients receiving warfarin. Arterioscler Thromb Vasc Biol 35(1):237–242

    CAS  PubMed  Google Scholar 

  104. Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, Naso A, Miozzo D, Giannini S, Avolio M, Foschi A, Rizzo MA, Gallieni M, Vertebral Fractures And Vascular Calcifications Study Group (2015) Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol. 13(2):248–258

    CAS  PubMed  Google Scholar 

  105. Fusaro M, Gallieni M, Rebora P, Rizzo MA, Luise MC, Riva H, Bertoli S, Conte F, Stella A, Ondei P, Rossi E, Valsecchi MG, Santoro A, Genovesi S (2016) Atrial fibrillation and low vitamin D levels are associated with severe vascular calcifications in hemodialysis patients. J Nephrol. 29(3):419–426

    CAS  PubMed  Google Scholar 

  106. Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J (2004) Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 104:3231–3232

    CAS  PubMed  Google Scholar 

  107. Koos R, Krueger T, Westenfeld R, Kühl HP, Brandenburg V, Mahnken AH, Stanzel S, Vermeer C, Cranenburg EC, Floege J, Kelm M, Schurgers LJ (2009) Relation of circulating matrix gla-protein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost 101:706

    CAS  PubMed  Google Scholar 

  108. Yamamoto K, Koretsune Y, Akasaka T, Kisanuki A, Ohte N, Takenaka T, Takeuchi M, Yoshida K, Iwade K, Okuyama Y, Hirano Y, Takeda Y, Tsukamoto Y, Kinugasa Y, Nakatani S, Sakamoto T, Iwakura K, Sozu T, Masuyama T, Japanese Aortic Stenosis Study-2 (JASS-2) Investigators (2017) Effects of vitamin K antagonist on aortic valve degeneration in non-valvular atrial fibrillation patients: prospective 4-year observational study. Thromb Res 160:69–75

    CAS  PubMed  Google Scholar 

  109. Chatrou MLL, Winckers K, Hackeng TM, Reutelingsperger CP, Schurgers LJ (2012) Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev 26:155–166

    CAS  PubMed  Google Scholar 

  110. Hayashi M, Takamatsu I, Kanno Y, Yoshida T, Abe T, Sato Y (2012) Japanese Calciphylaxis study Group A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant 27:1580–1584

    CAS  PubMed  Google Scholar 

  111. Plank F, Beyer C, Friedrich G, Stühlinger M, Hintringer F, Dichtl W, Wildauer M, Feuchtner G (2018) Influence of vitamin K antagonists and direct oral anticoagulation on coronary artery disease: a CTA analysis. Int J Cardiol 260:11–15

    PubMed  Google Scholar 

  112. Di Lullo L, Tripepi G, Ronco C, D’Arrigo G, Barbera V, Russo D, Di Iorio BR, Uguccioni M, Paoletti E, Ravera M, Fusaro M, Bellasi A (2019) Cardiac valve calcification and use of anticoagulants: preliminary observation of a potentially modifiable risk factor. Int J Cardiol 278:243–249

    PubMed  Google Scholar 

  113. De Vriese AS, Caluwé R, Pyfferoen L, De Bacquer D, De Boeck K, Delanote J, De Surgeloose D, Van Hoenacker P, Van Vlem B, Verbeke F (2019) Multicenter randomized controlled trial of vitamin K antagonist replacement by rivaroxaban with or without vitamin K2 in hemodialysis patients with atrial fibrillation: the valkyrie study. J Am Soc Nephrol 5:1. https://doi.org/10.1681/asn.2019060579

    Article  Google Scholar 

  114. Garza-Mayers AC, Shah R, Sykes DB, Nigwekar SU, Kroshinsky D (2018) The successful use of apixaban in dialysis patients with calciphylaxis who require anticoagulation: a retrospective analysis. Am J Nephrol 48(3):168–171

    CAS  PubMed  Google Scholar 

  115. Moe SM, Nickolas TL (2016) Fractures in patients with CKD: time for action. Clin J Am Soc Nephrol 11(11):1929–1931

    PubMed  PubMed Central  Google Scholar 

  116. Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006) Vitamin K and prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 166:1256–1261

    CAS  PubMed  Google Scholar 

  117. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81

    CAS  PubMed  Google Scholar 

  118. Caraballo PJ, Heit JA, Atkinson EJ et al (1999) Long-term use of oral anticoagulants and the risk of fracture. Arch Intern Med 159:1750–1756

    CAS  PubMed  Google Scholar 

  119. Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 166:241–246

    CAS  PubMed  Google Scholar 

  120. Rejnmark L, Vestergaard P, Mosekilde L (2007) Fracture risk in users of oral anticoagulants: a nationwide case–control study. Int J Cardiol 118:338–344

    PubMed  Google Scholar 

  121. Jamal SA, Browner WS, Bauer DC, Cummings SR (1998) Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 128:829–832

    CAS  PubMed  Google Scholar 

  122. Pilon D, Castilloux AM, Dorais M, LeLorier J (2004) Oral anticoagulants and the risk of osteoporotic fractures among elderly. Pharmacoepidemiol Drug Saf 13:289–294

    CAS  PubMed  Google Scholar 

  123. Woo C, Chang LL, Ewing SK, Bauer DC (2008) Single-point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc 56:1171–1176

    PubMed  PubMed Central  Google Scholar 

  124. Sato Y, Honda Y, Jun I (2010) Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis. 29:73–78

    CAS  PubMed  Google Scholar 

  125. Misra D, Zhang Y, Peloquin C, Choi HK, Kiel DP, Neogi T (2014) Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int 25(6):1677–1684

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Fusaro M, Dalle Carbonare L, Dusso A, Arcidiacono MV, Valenti MT, Aghi A, Pasho S, Gallieni M (2015) Differential effects of dabigatran and warfarin on bone volume and structure in rats with normal renal function. PLoS One 10(8):e0133847

    PubMed  PubMed Central  Google Scholar 

  127. Klüter T, Weuster M, Brüggemann S, Menzdorf L, Fitschen-Oestern S, Steubesand N, Acil Y, Pufe T, Varoga D, Seekamp A, Lippross S (2015) Rivaroxaban does not impair fracture healing in a rat femur fracture model: an experimental study. BMC Musculoskelet Disord. 16:79

    PubMed  PubMed Central  Google Scholar 

  128. Morishima Y, Kamisato C, Honda Y, Furugohri T, Shibano T (2013) The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats. Thromb Res 131(1):59–63

    CAS  PubMed  Google Scholar 

  129. Lau WC, Chan EW, Cheung CL, Sing CW, Man KK, Lip GY, Siu CW, Lam JK, Lee AC, Wong IC (2017) Association between dabigatran vs warfarin and risk of osteoporotic fractures among patients with nonvalvular atrial fibrillation. JAMA 317(11):1151–1158

    CAS  PubMed  Google Scholar 

  130. Gu ZC, Zhou LY, Shen L, Zhang C, Pu J, Lin HW, Liu XY (2018) Non-vitamin K Antagonist oral anticoagulants vs. Warfarin at risk of fractures: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 9:348

  131. Marzec LN, Wang J, Shah ND, Chan PS, Ting HH, Gosch KL, Hsu JC, Maddox TM (2017) Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. J Am Coll Cardiol 69(20):2475–2484

    CAS  PubMed  Google Scholar 

  132. Fosbøl EL, Vinding NE, Lamberts M, Staerk L, Gundlund A, Gadsbøll K, Køber L, Gislason GH, Olesen JB (2018) Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation. Europace 20(6):e78–e86

    PubMed  Google Scholar 

  133. USRDS Annual Data Report. Volume 1, Chapter 1: CKD in general population

Download references

Author information

Authors and Affiliations

  1. Nephrology, Dialysis, and Transplantation, University of Genoa and Policlinico San Martino, Genoa, Italy

    Maura Ravera, Elisabetta Bussalino & Ernesto Paoletti

  2. National Research Council (CNR), Institute of Clinical Physiology (IFC), Pisa, Italy

    Maria Fusaro

  3. Department of Medicine, University of Padova, Padua, Italy

    Maria Fusaro

  4. Department of Nephrology and Dialysis, Parodi-Delfino Hospital, Colleferro, Rome, Italy

    Luca Di Lullo

  5. Nephrology and Dialysis Unit, IRCCS “Casa Sollievo della Sofferenza” Scientific Institute for Research and Health Care, San Giovanni Rotondo, Italy

    Filippo Aucella

Authors
  1. Maura Ravera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabetta Bussalino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Fusaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luca Di Lullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Filippo Aucella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ernesto Paoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maura Ravera.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ravera, M., Bussalino, E., Fusaro, M. et al. Systematic DOACs oral anticoagulation in patients with atrial fibrillation and chronic kidney disease: the nephrologist’s perspective. J Nephrol 33, 483–495 (2020). https://doi.org/10.1007/s40620-020-00720-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-020-00720-5

Keywords

Search

Navigation