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Real-world 2-year outcome of atrial fibrillation treatment with dabigatran, apixaban, and rivaroxaban in patients with and without chronic kidney disease

  • Cosmo GodinoEmail author
  • Francesco Melillo
  • Francesca Rubino
  • Luca Arrigoni
  • Alberto Cappelletti
  • Patrizio Mazzone
  • Paolo Mattiello
  • Paolo Della Bella
  • Antonio Colombo
  • Anna Salerno
  • Michela Cera
  • Alberto Margonato
  • the INSIghT investigators
IM - ORIGINAL
  • 300 Downloads

Abstract

Patients with non-valvular atrial fibrillation (NVAF) and chronic kidney disease (CKD) are at increased risk of stroke and bleeding. Although direct oral anticoagulant (DOAC) trials excluded patients with severe CKD, a growing portion of CKD patients have been starting DOACs and limited data from real-world outcome in this high-risk setting are available. The INSigHT registry included 632 consecutive NVAF patients that started apixaban (256 patients, 41%), dabigatran (245, 39%) and rivaroxaban (131, 20%) between 2012 and 2015. Based on creatinine clearance, two sub-cohorts were defined: (1) non-CKD group (CrCl 60–89 mL/min, 413 patients) and (2) CKD group (15–59 ml/min, 219). Compared to non-CKD patients, those with CKD, were at higher ischemic (CHA2DS2-VASc 4.5 vs 2.9, p < 0.001) and hemorrhagic risk (HAS-BLED 2.4 vs 1.8, p < 0.001). At 2-year follow-up, the overall ISTH-major bleeding and thromboembolic event rates were 5.2% and 2.3% and no significant difference between non-CKD and CKD patients for both efficacy and safety endpoints were observed. In non-CKD patients, the 2-year ISTH-major bleeding rates were higher in rivaroxaban group (HR 2.9, 95% CI 1.1–7.3; p = 0.047) while dabigatran showed non-significant excess in thromboembolic events (HR 4.3, 95% CI 0.9–20.8; p = 0.068). In CKD patients, a significantly higher rate of thromboembolic events was observed in rivaroxaban (HR 6.3, 95% CI 1.1–38.1; p = 0.044). This real-world, non-insurance database registry shows remarkable 2-year safety and efficacy profile of DOACs even in patients with moderate to severe CKD. Head to head differences between DOACs are exploratory, hypothesis generating and warrant further investigation in larger studies.

Keywords

Non-valvular atrial fibrillation Direct oral anticoagulant Chronic kidney disease 

Notes

Compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Statement of human and animal rights

The study was in accordance with the ethical standards of the institutional research committee.

Informed consent

All patients provided informed consent for data collection.

Supplementary material

11739_2019_2100_MOESM1_ESM.jpg (66 kb)
Supplementary file1 (JPG 66 kb)

References

  1. 1.
    Das M, Aronow WS, McClung JA, Belkin RN (2006) Increased prevalence of coronary artery disease, silent myocardial ischemia, complex ventricular arrhythmias, atrial fibrillation, left ventricular hypertrophy, mitral annular calcium, and aortic valve calcium in patients with chronic renal insufficiency. Cardiol Rev 14:14–17.  https://doi.org/10.1097/01.crd.0000148162.88296.9f CrossRefGoogle Scholar
  2. 2.
    Nelson SE, Shroff GR, Li S, Herzog CA (2012) Impact of chronic kidney disease on risk of incident atrial fibrillation and subsequent survival in medicare patients. J Am Heart Assoc 1:1–11.  https://doi.org/10.1161/JAHA.112.002097 CrossRefGoogle Scholar
  3. 3.
    Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, Singer DE (2009) Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation:the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 119:1363–1369.  https://doi.org/10.1161/CIRCULATIONAHA.108.816082 CrossRefGoogle Scholar
  4. 4.
    Reinecke H, Brand E, Mesters R, Schäbitz WR, Fisher M, Pavenstädt H, Breithardt G (2009) Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc Nephrol 20:705–711.  https://doi.org/10.1681/ASN.2007111207 CrossRefGoogle Scholar
  5. 5.
    Bonde AN, Lip GY, Kamper AL, Hansen PR, Lamberts M, Hommel K, Hansen ML, Gislason GH, Torp-Pedersen C, Olesen JB (2015) Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease. J Am Coll Cardiol 64:2471–2482.  https://doi.org/10.1016/j.jacc.2014.09.051 CrossRefGoogle Scholar
  6. 6.
    Friberg L, Benson L, Lip G (2015) Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J 36:297–306.  https://doi.org/10.1093/eurheartj/ehu139 CrossRefGoogle Scholar
  7. 7.
    Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, Acton RT, Allon M (2009) Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 20:912–921.  https://doi.org/10.1681/ASN.2008070802 CrossRefGoogle Scholar
  8. 8.
    Volterrani M, Iellamo F, Cappelletti A et al (2018) NOAC in “ real world ” patients with atrial fibrillation in Italy : results from the ISPAF ‑ 2 (Indagine Sicoa Paziente Con Fibrillazione Atriale) survey study. Intern Emerg Med 218:2.  https://doi.org/10.1007/s11739-018-1896-9 Google Scholar
  9. 9.
    Nielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB (2015) Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. 5:418–429.  https://doi.org/10.1007/s00392-014-0797-9 CrossRefGoogle Scholar
  10. 10.
    Heidbuchel H, Verhamme P, Alings M et al (2017) Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 38(27):2137–2149.  https://doi.org/10.1093/eurheartj/ehw058 Google Scholar
  11. 11.
    Nielsen PB, Skjøth F, Søgaard M, Kjældgaard JN, Lip GY, Larsen TB (2017) Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. The BMJ 365:1–10.  https://doi.org/10.1136/bmj.j510 Google Scholar
  12. 12.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrilation. N Engl J Med 365:883–891.  https://doi.org/10.1056/NEJMoa1009638 CrossRefGoogle Scholar
  13. 13.
    Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with nonvalvular atrial fibrilation. N Engl J Med 361:1139–1151.  https://doi.org/10.1056/NEJMoa0905561 CrossRefGoogle Scholar
  14. 14.
    Giugliano RP, Ruff CT, Braunwald E et al (2013) Edoxaban versus warfarin in patients with atrial Fibrillation. N Engl J Med 369:2093–2104.  https://doi.org/10.1056/NEJMoa1310907 CrossRefGoogle Scholar
  15. 15.
    Granger CB, Alexander JH, McMurray JJ et al (2011) Apixaban versus Warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992.  https://doi.org/10.1056/NEJMoa1107039 CrossRefGoogle Scholar
  16. 16.
    Kirchhof P, Benussi S, Kotecha D et al (2016) ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37:2893–2962.  https://doi.org/10.1093/eurheartj/ehw210 CrossRefGoogle Scholar
  17. 17.
    Prisco D, Ageno W, Becattini C (2017) Italian intersociety consensus on DOAC use in internal medicine Italian intersociety consensus on DOAC use in internal medicine. Intern Emerg Med 12(3):387–406.  https://doi.org/10.1007/s11739-017-1628-6 CrossRefGoogle Scholar
  18. 18.
    Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W (2010) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 1:202–204.  https://doi.org/10.1111/j.1538-7836.2009.03678.x CrossRefGoogle Scholar
  19. 19.
    Chaudhuri S, Ganjam K, Ganti V, Motwani R (2003) Robust and efficient fuzzy match for online data cleaning. Proc 2003 ACM SIGMOD Int Conf Manag data 203:313–324.  https://doi.org/10.1145/872757.872796 CrossRefGoogle Scholar
  20. 20.
    Lydersen S (2015) Statistical review: frequently given comments. Ann Rheum Dis 74:323–325.  https://doi.org/10.1136/annrheumdis-2014-206186 CrossRefGoogle Scholar
  21. 21.
    Conover WJ (1999) Practical nonparametric statistics, 3rd edn. Wiley, New YorkGoogle Scholar
  22. 22.
    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 367:625–635.  https://doi.org/10.1056/NEJMoa1105594 CrossRefGoogle Scholar
  23. 23.
    Chan KE, Giugliano RP, Patel MR, Abramson S, Jardine M, Zhao S, Perkovic V, Maddux FW (2016) Anticoagulant agents in patients with advanced chronic kidney disease or on dialysis with AF. J Am Coll Cardiol 67:2888–2899.  https://doi.org/10.1016/j.jacc.2016.02.082 CrossRefGoogle Scholar
  24. 24.
    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 80:181–189.  https://doi.org/10.1038/ki.2011.44 CrossRefGoogle Scholar
  25. 25.
    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.  https://doi.org/10.1159/000312877 CrossRefGoogle Scholar
  26. 26.
    Böhm M, Ezekowitzet M, Connolly S, 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.  https://doi.org/10.1016/j.jacc.2015.03.577 CrossRefGoogle Scholar
  27. 27.
    Insights From ROCKET AF, On-Treatment Outcomes in Patients with Worsening Renal Function with Rivaroxaban Compared with Warfarin (2016) On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with Warfarin: Insights From ROCKET AF. Circulation 2016(1):37–47.  https://doi.org/10.1161/CIRCULATIONAHA.116.021890
  28. 28.
    Miyazawa K, Pastori D, Lip GY (2018) Changes in renal function in patients with atrial fibrillation: efficacy and safety of the non-vitamin K antagonist oral anticoagulants. Am Heart J 198:166–168.  https://doi.org/10.1016/j.ahj.2017.11.015 CrossRefGoogle Scholar
  29. 29.
    Sardar P, Chatterjee S, Herzog E, Nairooz R, Mukherjee D, Halperin JL (2014) Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can J Cardiol 30:888–897.  https://doi.org/10.1016/j.cjca.2014.04.015 CrossRefGoogle Scholar
  30. 30.
    Loo SY, Coulombe J, Dell'Aniello S, Brophy JM, Suissa S, Renoux C (2018) Comparative effectiveness of novel oral anticoagulants in UK patients with non-valvular atrial fibrillation and chronic kidney disease: a matched cohort study. BMJ 8:1–10.  https://doi.org/10.1136/bmjopen-2017-019638 Google Scholar
  31. 31.
    Diener HC, Aisenberg J, Ansell J et al (2017) Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation : part 2. Eur Heart J 38:860–868.  https://doi.org/10.1093/eurheartj/ehw069 CrossRefGoogle Scholar
  32. 32.
    Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, Ezekowitz MD, Reilly PA, Siegbahn A, Yusuf S, Wallentin L (2014) Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 129:961–970.  https://doi.org/10.1161/CIRCULATIONAHA.113.003628 CrossRefGoogle Scholar
  33. 33.
    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 (2012) 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.  https://doi.org/10.1093/eurheartj/ehs274 CrossRefGoogle Scholar
  34. 34.
    Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM (2011) Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 32:2387–2394.  https://doi.org/10.1093/eurheartj/ehr342 CrossRefGoogle Scholar
  35. 35.
    Andò G, Capranzano P (2017) Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with chronic kidney disease: a systematic review and network meta-analysis. Int. J. Cardiol 231:162–169.  https://doi.org/10.1016/j.ijcard.2016.11.303 CrossRefGoogle Scholar
  36. 36.
    Desai J, Kolb JM, Weitz JI, Aisenberg J (2013) Gastrointestinal bleeding with the new oral anticoagulants—defining the issues and the management strategies. Thromb Haemost 110:205–212.  https://doi.org/10.1160/TH13-02-0150 CrossRefGoogle Scholar
  37. 37.
    Beyer-Westendorf J, Ebertz F, Förster K, Gelbricht V, Michalski F, Köhler C, Werth S, Endig H, Pannach S, Tittl L, Sahin K, Daschkow K, Weiss N (2015) Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 113:1247–1257.  https://doi.org/10.1160/TH14-11-0954 CrossRefGoogle Scholar
  38. 38.
    Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, van Eickels M, Turpie AG (2016) XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 37:1145–1153.  https://doi.org/10.1093/eurheartj/ehv466 CrossRefGoogle Scholar
  39. 39.
    Vedovati MC, Verdecchia P, Giustozzi M, Molini G, Conti S, Pierpaoli L, Valecchi F, Aita A, Agnelli G, Becattini C (2017) Permanent discontinuation of non vitamin K oral anticoagulants in real life patients with non-valvular atrial fibrillation. Int J Cardiol 236:363–369.  https://doi.org/10.1016/j.ijcard.2017.01.098 CrossRefGoogle Scholar
  40. 40.
    Ho MH, Ho CW, Cheung E, Chan PH, Hai JJ, Chan KH, Chan EW, Leung GK, Tse HF, Siu CW (2014) Continuation of dabigatran therapy in ‘real-world " practice in Hong Kong. PLoS ONE 9:1–7.  https://doi.org/10.1371/journal.pone.0101245 Google Scholar
  41. 41.
    Halvorsen S, Ghanima W, Fride Tvete I, Hoxmark C, Falck P, Solli O, Jonasson C (2016) A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants. Eur Heart J 3:28–36.  https://doi.org/10.1093/ehjcvp/pvw031 Google Scholar

Copyright information

© Società Italiana di Medicina Interna (SIMI) 2019

Authors and Affiliations

  • Cosmo Godino
    • 1
    Email author
  • Francesco Melillo
    • 1
  • Francesca Rubino
    • 1
  • Luca Arrigoni
    • 1
  • Alberto Cappelletti
    • 1
  • Patrizio Mazzone
    • 2
  • Paolo Mattiello
    • 3
  • Paolo Della Bella
    • 2
  • Antonio Colombo
    • 4
  • Anna Salerno
    • 1
  • Michela Cera
    • 1
  • Alberto Margonato
    • 1
  • the INSIghT investigators
  1. 1.Cardiology Unit, Cardio-Thoracic-Vascular DepartmentSan Raffaele Scientific InstituteMilanItaly
  2. 2.Arrhythmia and Electrophysiology UnitSan Raffaele Scientific InstituteMilanItaly
  3. 3.Information Systems UnitSan Raffaele Scientific InstituteMilanItaly
  4. 4.Interventional Cardiovascular UnitSan Raffaele Scientific InstituteMilanItaly

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