SUMMARY  

• Estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), and serum creatinine (SrCr) are measures used to assess renal function.^1,2 For the majority of patients, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula-derived eGFR, Modification of Diet in Renal Disease (MDRD) equation-derived eGFR, or the Cockcroft-Gault equation-derived CrCl is used to estimate renal function; however, values obtained from these calculations may not be interchangeable.^1,3,4
• In the phase 2 and phase 3 trials that evaluated the safety and efficacy of XARELTO for venous thromboembolism (VTE) prevention after total knee or hip replacement surgery (RECORD), stroke prevention in nonvalvular atrial fibrillation (NVAF) patients (ROCKET AF), acute coronary syndrome (ATLAS-ACS), and VTE treatment (EINSTEIN DVT and EINSTEIN PE), the Cockcroft-Gault formula was used to calculate CrCl, utilizing the patients’ actual body weight and correction for gender within the equation.⁵
• eGFR was used to assess renal function in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study.⁶
• Vascular Outcomes Study of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) used eGFR to assess renal function.⁷

BACKGROUND

eGFR, CrCl, and SrCr are measures used to assess renal function. SrCr should not be used alone to estimate renal function.^1,2 For the majority of patients, CKD-EPI formula-derived eGFR, MDRD equation-derived eGFR, or the Cockcroft-Gault equation-derived CrCl, is used to estimate renal function. However, values obtained from these calculations may not be interchangeable.^1,3 In some situations, collection of 24-hour urine samples for measurement of CrCl or measurement of clearance of an exogenous filtration marker may provide better estimates of glomerular filtration rate (GFR) than the prediction equations.⁸

Current guidelines on the management of chronic kidney disease recommend the use of eGFR calculated using SrCr results and the CKD-EPI equation.^9,10 SrCr levels can be affected by factors including age, muscle mass, and the consumption of some meat and some drugs.¹¹ The CKD-EPI equation adjusts results for age, sex, and ethnicity.⁹ The CKD-EPI equation is also recommended over the MDRD study equation because of greater accuracy and less bias.¹¹

Please refer to renal guidelines such as The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines⁹ for eGFR and CrCl calculations. When presented with different kidney function estimates that potentially translate into different drug dosing decisions, clinicians must use their clinical judgment to determine which dosing consideration optimizes the risk:benefit ratio for the patient’s specific clinical scenario.³

CLINICAL DATA

CrCl

During phase 1 and phase 3 studies that evaluated the safety and efficacy of XARELTO for venous thromboembolism prevention after total knee or hip replacement surgery (RECORD), stroke prevention in nonvalvular atrial fibrillation patients (ROCKET AF), acute coronary syndrome (ATLAS-ACS) and VTE treatment (EINSTEIN DVT and EINSTEIN PE), renal function was assessed using CrCl. Dosing is adjusted based on CrCl. CrCl was calculated using the Cockcroft-Gault formula. The Cockcroft-Gault formula incorporated the patients’ actual body weight and correction was made for gender within the equation.⁵ See Figure: Cockcroft-Gault Formula.¹²

eGFR

Estimated GFR, calculated using the CKD-EPI equation, was utilized in clinical studies that evaluated the safety and efficacy of XARELTO alone or in combination with aspirin for coronary artery disease or peripheral artery disease (COMPASS and VOYAGER PAD).^6,7

In the COMPASS study, renal dysfunction (eGFR<60 mL/min/1.73 m²) was listed as a possible risk factor for patients <65 years of age with documented atherosclerosis as a condition for inclusion. Patients with eGFR <15 mL/min/1.73 m² were excluded. SrCr levels used in the eGFR calculation were measured at the screening/run-in visit.⁶

Exclusion criteria for VOYAGER PAD included any condition requiring dialysis or renal replacement therapy, or a renal impairment at screening assessed with an eGFR <15 mL/min/1.73 m².¹³ If a patient's eGFR was <30 mL/min/1.73 m² prior to the procedure, it must have remained to be >15 mL/min/1.73 m² 72 hours after the procedure to enroll and randomize the patient.¹³

• CKD-EPI Equation⁹: Cr in (mg/dL): eGFR = 141 x min (SCr/κ, 1)^α x max (SCr /κ, 1)^-1.209 x 0.993^Age x 1.018 [if female] x 1.159 [if Black]
  • κ = 0.7 (females) or 0.9 (males); α = -0.329 (females) or -0.411 (males)
  • min = indicates minimum of SCr/κ or 1; max = indicates maximum of SCr/κ or 1

There are no specific dosing recommendations based on GFR.¹⁴

Interchangeability of Renal Clearance Estimates

Estimated CrCl and eGFR may not be interchangeable. The formula for calculation of CrCl takes body weight into account and is expressed in mL/min. The MDRD and CKD-EPI equations for estimating GFR does not consider body weight and is expressed in mL/min/1.73m².¹⁵

A retrospective data analysis of the National Health and Nutrition Examination Survey (NHANES) 2011/2012 and a research database utilized simulations to analyze differences in dosing recommendations for stroke prevention in NVAF if eGFR were substituted for CrCl. Estimated CrCl was calculated using the Cockcroft-Gault formula and eGFR was calculated using the MDRD equation and the CKD-EPI formula. Renal clearance estimates according to all methods were highly correlated (P<0.001). However, in the NHANES sample, 38% of subjects with a CrCl <50 mL/min would not have been correctly classified using either of the eGFR equations (even after body surface area correction). In the research database samples, 47% to 56% of subjects would not have been correctly classified.¹⁶ Additional references on differences in renal function estimates depending on the equation used are provided below.¹⁷

• A retrospective study (n=454) by Cabeza et al (2018) in NVAF patients taking direct oral anticoagulants at a single cardiology clinic in Spain showed that eGFR equations tend to overestimate renal function relative to Cockcroft-Gault.¹⁸

Yao et al (2023)¹⁹ conducted a retrospective study in patients with atrial fibrillation (AF) with and without chronic kidney disease (CKD) to evaluate differences in nonvitamin K antagonist oral anticoagulant (NOAC) dose eligibility and renal dosing utilizing eCrCl compared to eGFR in patients from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II (ORBIT-AF II) trial, a registry database of patients with AF. Patients were also assessed for clinical outcomes based on undertreatment, overtreatment and appropriate renal dosing of NOACs.

• Creatinine clearance was estimated using the Cockcroft-Gault equation and GFR was estimated using the MDRD eGFR and CKD-EPI equations.
• Of the 8727 patients (median age, 71 years) included in this investigation, 48.9%, 44.6%, and 6.5% of patients were taking XARELTO, apixaban, and dabigatran, respectively.
• Overall, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients.
• In the CKD population (n=2184; eCrCl <60 ml/min), agreement between eCrCl and eGFR was 79.9% to 80.7%.
• In patients receiving XARELTO, agreement between eCrCl and MDRD eGFR for eligibility and renal dosing occurred in 88.48% of patients; 4.4% of patients potentially received a lower dose than would be recommended by eCrCl and 7.12% of patients received XARELTO when it was contraindicated based on eCrCl. Results were similar between eCrCl and CKD-EPI eGFR.
• In the CKD population receiving XARELTO, agreement between eCrCl and eGFR was 58.1% to 60.6%; using MDRD eGFR, 9.1% of patients potentially received a lower dose than would be recommended by eCrCl and 32.8% of patients received XARELTO when it was contraindicated based on eCrCl.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 June 2024.