XARELTO - Creatinine Clearance or Estimated Glomerular Filtration Rate in Adults

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 Peripheral Artery Disease (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 (CKD) 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

Creatinine Clearance

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 NVAF 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

Estimated Glomerular Filtration Rate

eGFR, 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 PAD (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: creatinine in mg/dL: eGFR = 141 × min (SCr/κ, 1)^α × max (SCr/κ, 1)^-1.209 × 0.993^Age × 1.018 [if female] × 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 do not consider body weight, and GFR 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 DOACs 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 large, contemporary observational study of patients included in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II), a national prospective registry of individuals with atrial fibrillation. The study evaluated potential misclassification of NOAC renal dosing when eGFR was used instead of the standard estimated creatinine clearance (eCrCl), examined clinical outcomes among patients who were appropriately dosed vs those undertreated or overtreated for each NOAC, and assessed whether differences in misclassification rates and outcomes varied according to baseline renal function, including in patients with CKD.

• CrCl 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.

Matsuoka et al (2026)²⁰ conducted the DIRECT-Extend registry study, a pooled analysis of 3 large-scale real-world datasets of patients with NVAF receiving anticoagulation therapy, to evaluate the relationship between renal function and ischemic and bleeding events, with an additional analysis stratified by each direct oral anticoagulant (DOAC).

• The 3 large-scale real-world datasets of patients with NVAF receiving anticoagulation therapy comprised the DIRECT registry (n=2543), SAKURA-AF registry (n=3268), and Osaka University Hospital registry (n=1742).
• Patients who visited or were admitted to the study institutions (Osaka University Hospital, Osaka Keisatsu Hospital, and 63 facilities participating in SAKURA-AF) and who were newly prescribed oral anticoagulants for NVAF were enrolled.
• The Osaka University Hospital registry enrolled patients prescribed DOACs between March 2011 and December 2021.
• The DIRECT registry enrolled patients from June 2011 to November 2017 and follow-up was extended to November 2023 using additional collected data.
• Patients in the SAKURA-AF registry were enrolled between September 2013 and December 2015 and followed until December 2017.
• Based on CrCl calculated using the Cockcroft-Gault formula, patients were categorized into category 1 (CrCl ≥50 mL/min; n=5331 [73.6%]), category 2 (CrCl, 30 to <50 mL/min; n=1554 [21.5%]), and category 3 (CrCl, 15 to <30 mL/min; n=354 [4.9%]).
• Among 7512 patients, 273 were excluded due to missing CrCl data (n=253) or CrCl <15 mL/min (n=20), resulting in 7239 eligible patients.
• With respect to DOAC-specific analysis, the number of patients receiving XARELTO was 1847. Declining CrCl was associated with increased risk of ischemic events in patients receiving XARELTO (P=0.003). In a sensitivity analysis of appropriately dosed anticoagulants, similar findings were observed.
• Table: Event Rates of Primary Endpoints for XARELTO describes the results of a multivariable Cox proportional hazards model.

Oh et al (2025)²¹ reported the XARENAL study, a multicenter, prospective, observational, noninterventional, single‑arm cohort study conducted to assess the safety profile of XARELTO in adult patients (≥19 years) with NVAF and renal impairment (CrCl, 15-49 mL/min) in routine clinical practice in Korea.

• Eligible patients had moderate to severe renal impairment, defined as documented CrCl of 15-49 mL/min within 6 months prior to enrollment, and were prescribed XARELTO for prevention of stroke and non-central nervous system systemic embolism per physician’s decision.
  • eGFR was calculated using the CKD-EPI formula.
• A total of 941 patients were screened across 29 study sites in Korea between December 2018 and July 2021; 924 patients (98.2%) met inclusion criteria, 912 (96.9%) completed the study, and 888 (94.4%) were included in the full analysis set.
• CrCl groups of 15-29 mL/min (severe group; n=175) and 30-49 mL/min (moderate group; n=713) were analyzed.
• In both CrCl groups, 81.7% of patients in the severe group and 90.9% of patients in the moderate group received XARELTO 15 mg once daily, whereas 17.7% of patients in the severe group and 8.8% of patients in the moderate group received XARELTO 10 mg.
• Among these, 106 patients in the severe group and 395 patients in the moderate group were included in the analysis.
  • The mean±SD change in eGFR from baseline to the final visit was 4.1±21.4 in the severe renal impairment group and 1.7±27.7 in the moderate renal impairment group.
  • The median annualized change in eGFR from baseline to the final visit was similar between the severe and moderate renal impairment groups.

Hung et al (2025)²² conducted a retrospective study in adult patients (≥18 years) with NVAF from the New Territories West Cluster, Hospital Authority of Hong Kong, China, to compare renal outcomes among XARELTO, dabigatran, and apixaban.

• The primary composite endpoint included >30% decline in eGFR, acute kidney injury (AKI), doubling of serum creatinine, and renal failure, whichever came first. Secondary endpoints included individual components of the primary endpoint and percentage change in eGFR per year.
• By December 31, 2017 (data cutoff), 2420 patients received at least 1 novel oral anticoagulants (NOAC) prescription, 1153 of whom were included in the subsequent analyses (949 for XARELTO [n=235] vs dabigatran [n=714], 872 for apixaban [n=204] vs dabigatran [n=668], and 431 for apixaban [n=204] vs XARELTO [n=227]).
  • XARELTO and apixaban were introduced in November 2013 and April 2014, respectively, which defined the cohort start dates.
• In the XARELTO vs dabigatran group, the mean±SD follow-up was 2.51±1.33 years, with 12.2±11.7 renal function tests. Baseline characteristics, including eGFR, were balanced after weighting.
  • The weighted rate of the primary endpoint, reported as an event rate presented as the number of events per 100 person-years, was 16.26 (95% CI, 13.17-19.84) for XARELTO and 11.54 (95% CI, 9.90-13.33) for dabigatran (hazard ratio [HR], 1.43; 95% CI, 1.20-1.70; P<0.001).
  • Regarding individual components, patients who received XARELTO showed a higher incidence of >30% decline in eGFR (HR, 1.37; 95% CI, 1.14-1.65; P<0.001) and AKI (HR, 1.30; 95% CI, 1.03-1.63; P=0.026) compared with dabigatran, with no significant difference in the rate of doubling of serum creatinine and renal failure.
• In the apixaban vs XARELTO group, the mean±SD follow-up was 2.54±1.61 years, with 12.8±12.2 renal function tests. The rate of the primary endpoint was numerically lower with apixaban vs XARELTO but not statistically significant (HR, 0.82; 95% CI, 0.56-1.19; P=0.294).
• In the apixaban vs dabigatran group, the mean±SD follow-up was 2.23±1.13 years, with 10.9±10.0 renal function tests. No significant differences were reported for the primary or secondary endpoints; for the primary endpoint, HR was 1.05 (95% CI, 0.75-1.49; P=0.762).
• Dabigatran was superior to XARELTO in patients with baseline eGFR ≥60 mL/min/1.73 m² (mean eGFR, 79.8 mL/min/1.73 m²), a subgroup analysis showed an HR of 1.50 (95% CI, 1.07-2.11; P<0.001) for XARELTO vs dabigatran, with no significant differences in patients with baseline eGFR <60 mL/min/1.73 m².
  • Apixaban was significantly superior to XARELTO in patients with eGFR ≥60 mL/min/1.73 m² (mean eGFR, 80.4 mL/min/1.73 m²), HR was 0.62 (95% CI, 0.31-0.94; P=0.010); no differences observed between apixaban and XARELTO in patients with worse baseline renal function.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 May 2026.