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Impact of different renal function equations on direct oral anticoagulant concentrations
Shin-Yi Lin1,2, Ching-Hua Kuo2, Tao-Min Huang3
1Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
Insights
Glomerular filtration rate (GFR) estimates like Cockroft-Gault (CrCL) and CKD-EPI can identify patients with high dabigatran or rivaroxaban concentrations. Elderly patients on dabigatran may have increased drug levels with CKD-EPI estimates.
Area of Science:
- Pharmacology
- Nephrology
- Clinical Chemistry
Background:
- Non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran, rivaroxaban, and apixaban are crucial for preventing thromboembolism in atrial fibrillation.
- Accurate assessment of renal function is vital for safe and effective NOAC dosing, as impaired kidney function can lead to supratherapeutic drug concentrations and increased bleeding risk.
- Various equations exist to estimate glomerular filtration rate (GFR), but their correlation with NOAC concentrations requires further investigation.
Purpose of the Study:
- To investigate the correlation between GFR estimated by different renal function equations and NOAC concentrations in atrial fibrillation patients.
- To compare the performance of Cockroft-Gault (CrCL), CKD-EPI, and MDRD equations in identifying patients with potentially high NOAC levels.
Main Methods:
- A cohort of 511 atrial fibrillation patients aged ≥20 years using dabigatran, rivaroxaban, or apixaban were enrolled.
- Drug concentrations were measured using ultra-high-performance liquid chromatography with tandem mass spectrometry.
- GFR was estimated using CrCL, CKD-EPI (creatinine and cystatin C), and MDRD equations. Multivariate regression analyzed associations between GFR estimates and drug concentrations.
Main Results:
- Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than expected (p < 0.001).
- CKD-EPI and MDRD classified fewer patients with GFR < 50 mL/min than CrCL across all NOAC groups.
- Both CrCL and CKD-EPI were associated with higher-than-expected dabigatran or rivaroxaban concentrations, but not with apixaban.
- In elderly patients (≥75 years), CKD-EPI may correlate with higher dabigatran trough concentrations.
Conclusions:
- Cockroft-Gault (CrCL) and CKD-EPI equations are useful for identifying patients with high trough concentrations of dabigatran or rivaroxaban.
- The choice of renal function equation may influence the identification of patients at risk for supratherapeutic NOAC levels.
- Further research may be needed to refine GFR estimation for optimal NOAC management, particularly in elderly populations and for specific drugs like dabigatran.
Abstract:
The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.
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