Impact of different renal function equations on direct oral anticoagulant concentrations

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.

Potential risks of substituting estimated glomerular filtration rate for estimated creatinine clearance for dosing of direct oral anticoagulants in atrial fibrillation and chronic kidney disease

Background In the clinical trials with direct oral anticoagulants (DOAC) estimates of creatinine clearance (CrCl) with Cockcroft-Gault equation were used to assess renal functions. Recently, most laboratories report renal function estimated with the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, which may lead to impaired dosing of DOACs by physicians. Purpose To compare estimated glomerular filtration rate and estimated creatinine clearance in a large group of patients with atrial fibrillation and chronic kidney disease. Methods Physicians from 423 institutions in the Czech Republic were asked to enroll 5 consecutive outpatients with atrial fibrillation (AF) treated by a DOAC with stage 3 chronic kidney disease and glomerular filtration rate (eGFR) 30–59 ml/min estimated by MDRD or CKD EPI equations into the registry. Besides eGFR, serum creatinine values were recorded and CrCl calculated by the Cockroft-Gault formula. Results of CrCl and eGFR obtained in individual patients were compared and statistically analyzed using two-sample t-test. Results A total of 2115 patients were enrolled. Mean CrCl was 47.43 ml/min, mean eGFR calculated by MDRD and CKD-EPI was lower 43.88 and 43.53 ml/min (P for difference &lt;0.001 for both). Mean difference between CrCl and eGFR in individual patients calculated by MDRD and CKD-EPI was 8.8 and 9.41 ml/min. A difference beween CrCl and eGFR &gt;10 ml/min was found in 31.5% and 34.8% patients when using MDRD and CKD-EPI formulas. The respective differences between CrCl and eGFR between 4.1 and 10 ml/min were found in 28.5% (MDRD) and 30.8% (CKD-EPI). At CrCl above or below 50 ml/min, 24.0% and 24.2% were misclassified when using eGFR calculated by MDRD and CKD-EPI. At CrCl above or below 30 ml/min, 9.8% (MDRD) and 10.0% (CKD-EPI) patients were misclassified (please see Figures). Conclusions When eGFR estimated by MDRD or CKD-EPI is used to assess renal function and guide DOAC dosing instead of CrCl calculated by the Cockroft-Gault formula in patients with AF and stage 3 CKD, more than a third of patients is misclassified and wrong DOAC dose can be recommended. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer-Ingelheim Differences between CrCl and CKD-EPI Differences between CrCl and MDRD

Electrical Activity of the Heart in the Older Adults Suffering from Chronic Kidney Disease: Ethnic and Age Characteristics

The aim of the study was to investigate the ethnic and age-related characteristics of the electrical activity of the heart in older adults with chronic kidney disease (CKD). Methods and Results: A total of 522 patients aged between 60 and 89 years with different stages of CKD were examined. For a comparative analysis, we formed 3 ethnic groups (Yakuts, Evens, and Russians) and 2 age groups (60-74 years and 75-89 years). All patients underwent ECG. The laboratory analysis included determining the blood creatinine level for further calculation of the GFR using the Cockcroft&Gault formula, followed by determining the stage of CKD. A decrease in renal function was more typical for people of 75-89 years. The results of the study confirmed the close relationship of CKD in older adults with the pathology of the cardiovascular system. Changes in the electrical activity of the heart predominated in Russians, compared to other ethnic groups, and were less pronounced in the Evens.

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

Adverse outcomes after worsening renal function in patients with atrial fibrillation: the Fushimi AF Registry

Background Patients with atrial fibrillation (AF) commonly coexist with chronic kidney disease (CKD). Non-vitamin K antagonist oral anticoagulants (NOAC) are recommended for stroke prevention in patients with non-valvular atrial fibrillation (AF), and worsening renal function (WRF) as well as CKD is an important issue in using NOAC. However, little is known about the clinical outcomes of patients after WRF. Purpose We aimed to investigate outcomes after WRF in AF patients. Methods The Fushimi AF Registry is a community-based prospective survey of the AF patients in our city. Follow-up data including prescription status were available for 4,441 patients. Of them, 1,890 patients who have baseline and at least 1 follow-up creatinine clearance (CrCl) measurements, estimated by the Cockcroft-Gault formula, were analyzed in the present study. WRF was defined as a decrease of ≥20% from baseline CrCl measurement at any time point during follow-up. We evaluated demographics and outcomes after WRF in AF patients. Results During the median follow-up period of 2,194 days, mean CrCl decrease of 2.2 ml/min/year was observed and WRF occurred in 981 patients (51.9%). Patients with WRF were significantly more often female (with vs. without WRF; 40.3% vs. 35.4%; p=0.03), older (73.4 vs. 71.1 years of age; p&lt;0.01), more often paroxysmal type (49.9% vs. 47.1%; p&lt;0.01), and more likely to have prior stroke (17.9% vs. 12.7%; p&lt;0.01), heart failure (30.8% vs. 24.8%; p&lt;0.01), diabetes (31.7% vs. 27.1%; p=0.03), and coronary artery disease (19.9% vs. 12.1%; p&lt;0.01) than those without WRF. Co-existing of CKD and mean CrCl at baseline were comparable (37.4% vs. 36.9%; p=0.82, 65.3 vs. 63.5 ml/min; p=0.66, respectively). Mean CHA2DS2-VASc score was significantly higher in WRF patients (3.55 vs. 3.03; p&lt;0.01). On landmark analysis, all-cause mortality occurred in 135 patients (8.6 /100 person-years) after WRF and 82 patients (1.7 /100 person-years) without WRF, with an adjusted hazard ratio (HR) of 6.33 (95% confidence interval [CI], 4.33–9.50; p&lt;0.01), adjusted by sex, age, body weight, serum creatinine, type of AF, oral anticoagulant prescription and comorbidities. Stroke or systemic embolism occurred in 45 patients after WRF (3.0 /100 person-years) and 78 (1.7 /100 person-years) patients without WRF (adjusted HR 1.60 [95% CI, 1.04–2.49; p=0.03]) (Figure). Conclusions AF patients after WRF had higher incidence of various adverse events. Incidence of Adverse Outcomes Funding Acknowledgement Type of funding source: Other. Main funding source(s): The Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development. Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical.

Should We Continue Assessing Glomerular Filtration Rate with the Cockroft–Gault Formula in NOAC-Treated Patients? The Magnitude of the Problem

Despite the proven superiority of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) over the Cockcroft–Gault (CG) formula, current guidelines recommend the latter to assess renal function in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). To assess the relationship between the CG and the recommended CKD-EPI formulas, in a cohort of atrial fibrillation (AF) patients treated with NOACs, and the misclassifications introduced by the CG formula for renal function levels, we estimated renal function with three equations: CG, CKD-EPI with body surface adjustment (1.73 mL/m2, CKD-EPI) and without such adjustment (CKD-EPI_noBSA), in all consecutive AF patients discharged from NOACs from the Cardiology Division of a main city hospital between February 1st and May 31st 2018. We compared the different estimates of glomerular filtration rate and potential renal function class misclassifications. We reclassified 37/115 patients (32.1%) when switching from the CG to the CKD-EPI; and 24/115 (20.8%) switching from the CG to the CKD-EPI_noBSA formulas. Class reallocation was distributed across all levels of renal function, but mostly affected the “hyper-normal” function. In estimating consequences of such reallocation, a change in NOAC dosages would have occurred in 10/115 patients (8.7%) when switching from the CG to the CKD-EPI formula and in 10/115 patients when switching from the CG to the CKD-EPI_noBSA formula. Although the CG method has been traditionally used to calculate renal function in all NOAC studies, a renal dysfunction class reallocation occurs in a substantial fraction of hospital-admitted AF patients with the use of better estimates of renal function.

Criteria for assessing renal allograft dysfunction

The significance of the glomerular filtration rate calculated by the Cockcroft - Gault formula as one of the highly sensitive criteria for assessing renal allograft dysfunction is substantiated. The study demonstrated that in the group of patients with an increased level of daily proteinuria there is a significantly lower level of serum creatine in comparison with the group of patients with a normal level of daily proteinuria. Moreover, in patients with a normal level of daily proteinuria, there are significantly higher values of glomerular filtration rate calculated by the Cockcroft - Gault formula, compared with patients with an increased level of daily proteinuria. Thus, it is shown that the level of serum creatinine currently used in clinical practice, as a laboratory marker of renal allograft dysfunction, does not allow to detect impaired renal allograft function at the earliest possible date. It has been demonstrated that the glomerular filtration rate calculated by the Cockcroft - Gault formula is a highly sensitive and specific laboratory marker of renal transplant dysfunction. Determining the glomerular filtration rate calculated by the Cockcroft - Gault formula makes it possible to diagnose renal allograft dysfunction at the earliest stages, which will significantly improve the survival of the transplanted kidney due to timely changes in patient management tactics and correction of immunosuppressive therapy.

P0264ASSESSMENT OF GFR IN MORBIDLY OBESE PATIENTS USING DIFFERENT EQUATIONS: WHICH IS THE BEST?

Background and Aims Obesity is a potent risk factor for the development of kidney disease. The prevalence of abdominal obesity in Egyptians based upon the European cut-off points was 30.2% for men and 70.9% for women. To detect the best formula for estimation of glomerular filtration rates in morbidly obese individuals. Method: In this prospective study 82 morbidly obese patients were included, Age: 15 to 65 years, Morbidly obese patient (BMI &gt; 40 Kg/m2), Creatinine clearance calculated from a 24-h urine was done, Estimated glomerular filtration rate (eGFR): It was assessed to be correlated with creatinine clearance and detect the most suitable formula for morbidly obese patients. Cockcroft-Gault formula: Cockcroft-Gault formula (for total body weight): ockcroft-Gault formula (for adjusted body weight): Cockcroft-Gault formula (for lean body weight), MDRD-eGFR (Modification of Diet in Renal Disease equation) (Shahbaz & Gupta, 2019), CKD-epidemiology (CKD-EPI): (Levey, et al, 2009) Results Demogrphic criteria of the studdied patients Conclusion: The equations that had the nearest values to creatinine clearance were CG-TBW-GFR and CGAjBW- GFR, both of them had a moderate reliability with more agreement for the CG-TBW-GFR equation . The CG-TBW-GFR formula was the most reliable one to measure GFR, followed by the CG-AjBW-GFR formula, while the CG-IBW, CG-LBW, MDRD-GFR and CKD-EPI-GFR formulae were not reliable at all .