Comparative efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation and chronic kidney disease

Aim To compare efficacy and safety of direct oral anticoagulants (DOACs) for prevention of stroke in patients with nonvalvular atrial fibrillation and reduced creatinine clearance.
Material and methods Systematic search for literature and indirect comparison of DOACs were performed.
Results The indirect comparison included five randomized clinical trials. The DOACs were comparable by the efficacy of preventing stroke and systemic embolism. The safety profiles had differences. Apixaban significantly decreased the relative risk of major bleeding compared to rivaroxaban by 27 % (relative risk (RR) 0.73; 95 % confidence interval (CI): 0.55–0.98). The apixaban advantage was even greater in the group of patients with a creatinine clearance <50 ml/min: RR was reduced by 48 % compared to rivaroxaban (RR=0.52; 95 % CI: 0.32–0.84), by 50 % compared to dabigatran 300 mg/day (RR=0.50; 95 % CI: 0.31–0.81), and by 48 % compared to dabigatran 220 mg/day (RR=0.52; 95 % CI: 0.32–0.85)
Conclusion The indirect comparison of DOACs showed that their efficacy was comparable. With respect of safety, apixaban is the preferrable DOAC for patients with atrial fibrillation and creatinine clearance below 50 ml/min.

1. Lip GYH, Freedman B, De Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: Past, present and future: Comparing the guidelines and practical decision-making. Thrombosis and Haemostasis. 2017;117(7):1230–9. DOI: 10.1160/TH16-11-0876

2. Olesen JB, Lip GYH, Kamper A-L, Hommel K, Køber L, Lane DA et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. New England Journal of Medicine. 2012;367(7):625–35. DOI: 10.1056/NEJMoa1105594

3. Shea MK, Booth SL. Vitamin K, Vascular Calcification, and Chronic Kidney Disease: Current Evidence and Unanswered Questions. Current Developments in Nutrition. 2019;3(9):nzz077. DOI: 10.1093/cdn/nzz077

4. Chan KE, Giugliano RP, Patel MR, Abramson S, Jardine M, Zhao S et al. Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF. Journal of the American College of Cardiology. 2016;67(24):2888–99. DOI: 10.1016/j.jacc.2016.02.082

5. Baker WL, Phung OJ. Systematic Review and Adjusted Indirect Comparison Meta-Analysis of Oral Anticoagulants in Atrial Fibrillation. Circulation: Cardiovascular Quality and Outcomes. 2012;5(5):711–9. DOI: 10.1161/CIRCOUTCOMES.112.966572

6. Fernandez MM, Wang J, Ye X, Kwong WJ, Sherif B, Hogue S et al. Systematic review and network meta-analysis of the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants among patients with nonvalvular atrial fibrillation and CHADS2 score ⩾ 2. SAGE Open Medicine. 2015;3:205031211561335. DOI: 10.1177/2050312115613350

7. Skjøth F, Larsen T, Rasmussen L, Lip GYH. Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: An indirect comparison analysis. Thrombosis and Haemostasis. 2014;111(05):981–8. DOI: 10.1160/TH14-02-0118

8. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. Journal of Clinical Epidemiology. 1997;50(6):683– 91. DOI: 10.1016/S0895-4356(97)00049-8

9. Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ. 2003;326(7387):472– 472. DOI: 10.1136/bmj.326.7387.472

10. Song F, Xiong T, Parekh-Bhurke S, Loke YK, Sutton AJ, Eastwood AJ et al. Inconsistency between direct and indirect comparisons of competing interventions: meta-epidemiological study. BMJ. 2011;343:d4909. DOI: 10.1136/bmj.d4909

11. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Medicine. 2009;6(7):e1000097. DOI: 10.1371/journal.pmed.1000097

12. Rebrova O.Yu., Fedyaeva V.K., Hachatryan G.R. Adaptation and validation of the Cochrane questionnaire to assess risks of bias in randomized controlled trials. Medical Technologies. Assessment and choice. 2015;1(19):9–17.

13. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2009;361(12):1139–51. DOI: 10.1056/NEJMoa0905561

14. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation Clinical Perspective: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation. 2011;123(21):2363–72. DOI: 10.1161/CIRCULATIONAHA.110.004747

15. Fox KAA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. European Heart Journal. 2011;32(19):2387–94. DOI: 10.1093/eurheartj/ehr342

16. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. European Heart Journal. 2012;33(22):2821– 30. DOI: 10.1093/eurheartj/ehs274

17. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM et al. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016;134(1):24–36. DOI: 10.1161/CIRCULATIONAHA.116.022361

18. Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND et al. Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation. Journal of the American Heart Association. 2016;5(6):e003725. DOI: 10.1161/JAHA.116.003725

19. Douros A, Durand M, Doyle CM, Yoon S, Reynier P, Filion KB. Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies. Drug Safety. 2019;42(10):1135–48. DOI: 10.1007/s40264-019-00842-1

20. Zhang J, Tang J, Cui X, Wang B, Bu M, Bai Y et al. Indirect comparison of novel Oral anticoagulants among Asians with non-Valvular atrial fibrillation in the real world setting: a network meta-analysis. BMC Cardiovascular Disorders. 2019;19(1):182. DOI: 10.1186/s12872-019-1165-5

21. Lip GYH, Keshishian A, Li X, Hamilton M, Masseria C, Gupta K et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients: The ARISTOPHANES Study. Stroke. 2018;49(12):2933–44. DOI: 10.1161/STROKEAHA.118.020232

22. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European Heart Journal. 2018;39(16):1330– 93. DOI: 10.1093/eurheartj/ehy136

23. Petrov V.I., Shatalova O.V., Gerasimenko A.S., Gorbatenko V.S. Safety of Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Chronic Kidney Disease. Rational Pharmacotherapy in Cardiology. 2019;15(4):530–7. DOI: 10.20996/1819-6446-2019-15-4-530-537

24. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European Journal of Cardio-Thoracic Surgery: Official Journal of the European Association for CardioThoracic Surgery. 2016;50(5):e1–88. DOI: 10.1093/ejcts/ezw313