DOACs vs. Warfarin: COMBINE AF Kidney Analysis

Jun 16, 2023
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Authors:
Harrington J, Carnicelli AP, Hua K, et al.
Citation:
Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF. Circulation 2023;147:1748-1757.
Summary By:
Debabrata Mukherjee, MD, FACC

Quick Takes

  • This network meta-analysis reports that the benefits of direct oral anticoagulants (DOACs) over warfarin are retained in patients with reduced kidney function.
  • There was no creatinine clearance value for which standard-dose DOAC use resulted in a higher risk of bleeding, intracranial hemorrhage (ICH), stroke/systemic embolism, or death than warfarin.
  • Inappropriate dose reduction of DOACs in patients with kidney dysfunction may result in a higher risk of thromboembolism and death without reducing the risk of bleeding or ICH.

Study Questions:

What are the safety and efficacy outcomes of direct oral anticoagulants (DOACs) and warfarin across the continuous spectrum of kidney function (down to a creatinine clearance [CrCl] of 25 mL/min), with a particular focus on patients with reduced kidney function?

Methods:

The investigators used the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), and performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous CrCl. A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death.

Results:

Among the 71,683 patients (mean age, 70.6 ± 9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5 ± 30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin (pinteraction = 0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; pinteraction = 0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; pinteraction = 0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; pinteraction = 0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence of death and S/SE.

Conclusions:

The authors report that standard-dose DOACs are safer and more effective than warfarin down to a CrCl of ≥25 mL/min.

Perspective:

This network meta-analysis reports that the benefits of DOACs over warfarin are retained in patients with reduced kidney function. Furthermore, patients with low CrCl randomized to standard-dose DOACs compared with lower-dose DOACs had a significantly lower hazard of S/SE and death without significantly increased bleeding or ICH. There was no CrCl value for which standard-dose DOAC use resulted in a higher risk of bleeding, ICH, S/SE, or death than warfarin. These data suggest that inappropriate dose reduction of DOACs in patients with kidney dysfunction may result in a higher risk of thromboembolism and death without reducing the risk of bleeding or ICH. Overall, these results support the use of DOACs over warfarin down to a CrCl of ≥25 mL/min and underscore the importance of prescribing guideline-supported doses of DOACs for the prevention of S/SE.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Acute Kidney Injury, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Creatinine, Embolism, Geriatrics, Hemorrhage, Intracranial Hemorrhage, Traumatic, Kidney, Metabolic Syndrome, Renal Insufficiency, Primary Prevention, Stroke, Thromboembolism, Vascular Diseases, Warfarin


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