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DOACS Better than Warfarin in A-fib Even in CKD Patients

July 6, 2023

Written by Seth Walsh-Blackmore

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Analysis of multiple prior RCTs finds direct oral anticoagulants (DOAC) have improved safety and efficacy vs. warfarin in atrial fibrillation (AF) even as renal function decreases to as low as 25 mL/min.

DOACs awesome AF in CKD?
Patient compliance with outpatient anticoagulation (AC) for AF is improved when initiated during an ED diagnosis1. CKD patients are especially important for AC initiation, as they have an increased baseline risk of thromboembolic events in AF2.

COMBINE-AF is a database of individual patient data from 5 major RCTs comparing DOACs to warfarin or aspirin. This analysis of COMBINE-AF data compares DOACs to warfarin across the spectrum of creatine clearance (CrCl). 

Excluding aspirin treatments, 71,683 AF patients previously randomized to warfarin or DOACs were evaluated for stroke events, mortality, intracranial hemorrhage (ICH), and major bleeding. It was an intention to treat analysis with a median follow-up of 23.1 months.

Utilizing a multivariable stratified Cox proportional hazard model, the authors produced a treatment-by-CrCl effect. Standard dose (per trial protocol) DOAC demonstrated a 4.8% decrease in stroke hazard ratio (HR) (95%CI 1.3 – 8.1%) for every 10-mL/min decrease in CrCl relative to warfarin. This effect was also present for ICH, where the HR decreased by 6.8% (95% CI 0.7 -12.6%) per 10-mL/min. Though not reaching statistical significance, this treatment-by-CrCl effect favored DOACs for mortality and major bleeding.

Additional HRs and categorical analysis by CrCl grouping all show statistically significant differences or a trend without significance favoring DOACs over warfarin. The treatment-by-CrCl effect demonstrates evidence that despite renal metabolism, DOACs outperform warfarin by a wider margin with worsening CKD. However, COMBINE-AF has sparse patient data of CrCl < 25mL/min.

DOACs are now more often prescribed in CKD, but reduced doses are recommended3. The authors compared reduced and standard dose DOACs. The mortality HR increased by 5.8% (95%CI 2.4%-9.2%) for every 10-mL/min decrease in CrCl when using a reduced dose, with no significant treatment by CrCl effect for stroke/bleed. Note that only trials of dabigatran and edoxaban included reduced dose data.

How will this change my practice?
Emergency providers often fail to initiate outpatient AC for AF when indicated4,5, a critical practice gap to close. Fortunately, most CKD patients can and should be initiated on standard dose DOACs, which are more practical to prescribe than warfarin. I will still follow guidelines in patients with very low CrCl and those with ESRD/dialysis regarding dose reductions, given the less robust data.

Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF. Circulation. 2023 Jun 6;147(23):1748-1757. doi: 10.1161/CIRCULATIONAHA.122.062752. Epub 2023 Apr 12.

Works Cited

  1. Atzema CL, Jackevicius CA, Chong A, et al. Prescribing of oral anticoagulants in the emergency department and subsequent long-term use by older adults with atrial fibrillation. CMAJ. 2019;191(49):E1345-E1354. doi:10.1503/cmaj.190747
  2. Masson P, Webster AC, Hong M, Turner R, Lindley RI, Craig JC. Chronic kid- ney disease and the risk of stroke: a systematic review and meta-analysis. Nephrol Dial Transplant. 2015;30:1162–1169. doi: 10.1093/ndt/gfv009
  3. Barra ME, Fanikos J, Connors JM, Sylvester KW, Piazza G, Goldhaber SZ. Evaluation of Dose-Reduced Direct Oral Anticoagulant Therapy. Am J Med. 2016;129(11):1198-1204. doi:10.1016/j.amjmed.2016.05.041
  4. Habeeb E, Papadopoulos T, Lewin AR, Knowles D. Assessment of Anticoagulant Initiation in Patients With New-Onset Atrial Fibrillation During Emergency Department Visit. Clinical and Applied Thrombosis/Hemostasis. 2023;29. doi:10.1177/10760296231172493
  5. Kea B, Waites BT, Lin A, et al. Practice Gap in Atrial Fibrillation Oral Anticoagulation Prescribing at Emergency Department Home Discharge. West J Emerg Med. 2020;21(4):924-934. Published 2020 Jun 29. doi:10.5811/westjem.2020.3.45135

What are your thoughts?