Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study.
ABSTRACT: In clinical trials of dabigatran and rivaroxaban for stroke prevention in atrial fibrillation (AF), drug eligibility and dosing were determined using the Cockcroft-Gault equation to estimate creatine clearance as a measure of renal function. This cross-sectional study aimed to compare whether using estimated glomerular filtration rate (eGFR) by the widely available and widely used Modified Diet in Renal Disease (MDRD) equation would alter prescribing or dosing of the renally excreted new oral anticoagulants.Of 4712 patients with known AF within a general practitioner-registered population of 930 079 in east London, data were available enabling renal function to be calculated by both Cockcroft-Gault and MDRD methods in 4120 (87.4%).Of 4120 patients, 2706 were <80 years and 1414 were ?80 years of age. Among those ?80 years, 14.9% were ineligible for dabigatran according to Cockcroft-Gault equation but would have been judged eligible applying MDRD method. For those <80 years, 0.8% would have been incorrectly judged eligible for dabigatran and 5.3% would have received too high a dose. For rivaroxaban, 0.3% would have been incorrectly judged eligible for treatment and 13.5% would have received too high a dose.Were the MDRD-derived eGFR to be used instead of Cockcroft-Gault in prescribing these new agents, many elderly patients with AF would either incorrectly become eligible for them or would receive too high a dose. Safety has not been established using the MDRD equation, a concern since the risk of major bleeding would be increased in patients with unsuspected renal impairment. Given the potentially widespread use of these agents, particularly in primary care, regulatory authorities and drug companies should alert UK doctors of the need to use the Cockcroft-Gault formula to calculate eligibility for and dosing of the new oral anticoagulants in elderly patients with AF and not rely on the MDRD-derived eGFR.
Project description:Background Clinical significance of dosing dabigatran with different estimates of renal function for treatment of atrial fibrillation (AF) is unknown. Renal function is routinely estimated by the chronic kidney disease epidemiology initiative equation (CKD-EPI) and used to guide dosing. The aim of this study was to investigate the risk of adverse outcomes for patients with AF when different estimators of renal function are used. Material and Methods AF patient data were extracted from national administrative databases. Renal function was estimated using Cockcroft-Gault, CKD-EPI, and CKD-EPI adjusted for body surface area (CKD-EPI-BSA). Outcomes of cerebrovascular accident (CVA), systemic embolism (SE), and hemorrhage were extracted. Results In total, 2,425 patients were identified, of which there were hospitalizations for 138 (5.7%) hemorrhagic events, 45 (1.9%) CVA/SE, and 33 (1.4%) unspecified CVA. The level of agreement between Cockcroft-Gault with CKD-EPI and CKD-EPI-BSA yielded a weighted kappa statistic of 0.47 and 0.71, respectively. CKD-EPI and CKD-EPI-BSA significantly overestimated renal function in elderly patients resulting in higher recommended doses compared with Cockcroft-Gault. The hazard ratio for a hemorrhagic event was 2.32 (95% confidence interval, 1.22-4.42; p = 0.01) when a high dose was given compared with normal dose, based on Cockcroft-Gault. Conclusion Both CKD-EPI and CKD-EPI-BSA equations significantly overestimated renal function in the elderly population compared with the Cockcroft-Gault equation. This may lead to dose selection errors for dabigatran, particularly for those with severe impairment, increasing the risk of adverse outcome. Hence, CKD-EPI and CKD-EPI-BSA equations should not be substituted for the Cockcroft-Gault equation in the elderly for the purpose of renal dosage adjustments.
Project description:We assessed 1-year outcomes in patients with atrial fibrillation enrolled in the EurObservational Research Programme AF General Pilot Registry (EORP-AF), in relation to kidney function, as assessed by glomerular filtration rate (eGFR). In a cohort of 2398 patients (median age 69 years; 61% male), eGFR (ml/min/1.73?m(2)) calculated using the CKD-EPI formula was ?80 in 35.1%, 50-79 in 47.2%, 30-49 in 13.9% and <30 in 3.7% of patients. In a logistic regression analysis, eGFR category was an independent predictor of stroke/TIA or death, with elevated odds ratios associated with severe to mild renal impairment, ie. eGFR?<?30?ml/min/1.73?m(2) [OR 3.641, 95% CI 1.572-8.433, p?<?0.0001], 30-49?ml/min/1.73?m(2) [OR 3.303, 95% CI 1.740-6.270, p?=?0.0026] or 50-79?ml/min/1.73?m2 [OR 2.094, 95% CI 1.194-3.672, p?=?0.0003]. The discriminant capability for the risk of death was tested among various eGFR calculation algorithms: the best was the Cockcroft-Gault equation adjusted for BSA, followed by Cockcroft-Gault equation, and CKD-EPI equation, while the worst was the MDRD equation. In conclusion in this prospective observational registry, renal function was a major determinant of adverse outcomes at 1 year, and even mild or moderate renal impairments were associated with an increased risk of stroke/TIA/death.
Project description:Current HIV treatment guidelines recommend using the Cockcroft-Gault equation for drug dosing adjustments. The use of newer glomerular filtration rate (GFR) estimating equations for drug dosing and the appropriateness of physician antiretroviral dosing based on estimated kidney function have not been studied in an HIV-positive population.We evaluated concordance between measured and estimated GFR for the assignment of kidney function categories designated by the US Food and Drug Administration (FDA) Guidance for industry for pharmacokinetic studies, and appropriateness of physician antiretroviral drug dosing for level of kidney function in 200 HIV-positive patients on stable antiretroviral therapy. Estimated kidney function was determined using the Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD) Study and Cockcroft-Gault equations.For assignment of FDA-designated kidney function categories, concordance rates between measured and estimated GFR using the CKD-EPI, MDRD Study and Cockcroft-Gault equations were 79%, 71% and 77%, respectively. This pattern was consistent across most subgroups. When actual prescribed dosages were compared with recommended dosages based on the level of estimated kidney function, 3-19% of study participants were prescribed higher than recommended dosages. The largest discordance between prescribed and recommended dosages was observed for the Cockcroft-Gault equation.The CKD-EPI equation has the highest concordance with measured GFR for the assignment of FDA-designated kidney function categories. Its use may lead to lower dosing-related errors in HIV-infected US adults on stable antiretroviral therapy. More education is required with respect to dose adjustment for level of kidney function.
Project description:We aimed to compare the ability of preoperative estimated glomerular filtration rate (eGFR), calculated using five different equations, to predict adverse renal outcomes after cardiovascular surgery. Cohorts of 4,125 adult patients undergoing elective cardiovascular surgery were evaluated. Preoperative eGFR was calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) II, re-expressed MDRD II, Chronic Kidney Disease Epidemiology Collaboration, and Mayo quadratic (Mayo) equations. The primary outcome was postoperative acute kidney injury (AKI), defined by Kidney Disease: Improving Global Outcomes Definition and Staging criteria based on changes in serum creatinine concentrations within 7 days. The MDRD II and Cockcroft-Gault equations yielded the highest (88.1 ± 26.7 ml/min/1.73 m2) and lowest (79.6 ± 25.5 ml/min/1.73 m2) mean eGFR values, respectively. Multivariable analysis showed that a preoperative decrease in renal function according to all five equations was independently associated with an increased risk of postoperative AKI. The area under the receiver operating characteristics curve for predicting postoperative AKI was highest for the Mayo equation (0.713). Net improvements in reclassification and integrated discrimination were higher for the Mayo equation than for the other equations. The Mayo equation was the most accurate in predicting postoperative AKI in patients undergoing cardiovascular surgery.
Project description:The widespread use of antiretroviral therapies (ART) has increased life expectancy in HIV patients, predisposing them to chronic non-communicable diseases including Chronic Kidney Disease (CKD). We performed a systematic review and meta-analysis (PROSPERO registration number CRD42016036246) to determine the global and regional prevalence of CKD in HIV patients.We searched PubMed, Web of Science, EBSCO and AJOL for articles published between January 1982 and May 2016. CKD was defined as estimated glomerular filtration rate (eGFR) <60ml/min using the MDRD, Cockcroft-Gault or CKD-EPI equations. Random effects model was used to combine prevalence estimates from across studies after variance stabilization via Freeman-Tukey transformation.Sixty-one eligible articles (n = 209,078 HIV patients) in 60 countries were selected. The overall CKD prevalence was 6.4% (95%CI 5.2-7.7%) with MDRD, 4.8% (95%CI 2.9-7.1%) with CKD-EPI and 12.3% (95%CI 8.4-16.7%) with Cockcroft-Gault; p = 0.003 for difference across estimators. Sub-group analysis identified differences in prevalence by WHO region with Africa having the highest MDRD-based prevalence at 7.9% (95%CI 5.2-11.1%). Within Africa, the pooled MDRD-based prevalence was highest in West Africa [14.6% (95%CI 9.9-20.0%)] and lowest in Southern Africa (3.2%, 95%CI 3.0-3.4%). The heterogeneity observed could be explained by WHO region, comorbid hypertension and diabetes mellitus, but not by gender, hepatitis B or C coinfection, CD4 count or antiretroviral status.CKD is common in HIV-infected people, particularly in Africa. HIV treatment programs need to intensify screening for CKD with added need to introduce global guidelines for CKD identification and treatment in HIV positive patients.
Project description:We evaluated in elderly subjects (a) the ability of GFR formulas to discriminate chronic kidney disease (CKD), (b) the correlation between renal morphology and function, and (c) the usefulness of combined r-US and GFR formulas to detect CKD. A total of 72 patients were enrolled (mean age 80±7 years, male sex 44%, serum creatinine 0.98±0.42 mg/dL, and CKD 57%). Cockcroft-Gault showed the highest sensitivity (78%) and specificity (94%) for CKD and was correlated with kidney volume (R=0.68, P<0.001). All formulas failed to provide a reliable estimate of GFR. In multivariate analysis, Cockcroft-Gault<52 mL/min and kidney sinus section area<28 cm2 showed the highest accuracy for the identification of CKD subjects (AUC 0.90, P<0.001). MDRD and CKD-EPI differed significantly for GFR≥90 mL/min.Cockcroft-Gault<52 mL/min was able to discriminate subjects with CKD but all formulas failed to provide a reliable estimate of GFR. The combined use of r-US and Cockcroft-Gault formula improved the ability to discriminate CKD in elderly subjects.
Project description:AIMS: Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys). METHODS: A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations. RESULTS: The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38-94 years) taking dabigatran etexilate was 60 µg/L (range 9-279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R (2), 95 % CI) 32 % (9-55), 37 % (12-60), 41 % (16-64) and 47 % (20-69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R (2) values for each equation was not statistically significant (p = 0.74). DISCUSSION: Estimates of renal function using the four equations accounted for 32-47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.
Project description:AIM:For drug dosing adaptation, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, after 'de-indexation' by body surface area (BSA). In pharmacology, the Cockcroft-Gault (CG) equation is still recommended to adapt drug dosage. In the context of obesity, adjusted ideal body weight (AIBW) is sometimes preferred to actual body weight (ABW) for the CG equation. The aim of the present study was to compare the performance of the different GFR-estimating equations, non-indexed or de-indexed by BSA for the purpose of drug-dosage adaptation in obese patients. METHODS:We analysed data from patients with a body mass index (BMI) higher than 30 kg m(-2) who underwent a GFR measurement. eGFR was calculated using the CKD-EPI and Modification of Diet in Renal Disease (MDRD) equations, de-indexed by BSA, and the CG equation, using either ABW, AIBW or lean body weight (LBW) for the weight variable and compared with measured GFR, expressed in ml min(-1). RESULTS:In our population of obese patients, use of the AIBW instead of the ABW in the CG equation, markedly improved the overall accuracy of this equation [57% for CGABW and 79% for CGAIBW (P < 0.05)]. For high BMI (over 40 kg m(-2)), the accuracy of the CG equations is no different when using LBW than when using AIBW. The MDRD and CKD-EPI equations de-indexed by the BSA also performed well, with an overall higher accuracy for the MDRD de-indexed equation [(80% and 76%, respectively (P < 0.05)]. CONCLUSIONS:The de-indexed MDRD equation appeared to be the most suitable for estimating the non-indexed GFR for the purpose of drug dosage adaptation in obese patients.
Project description:<h4>Background</h4>A high dose of anti-infective agents is recommended when treating infectious meningitis. High creatinine clearance (CrCl) may affect the pharmacokinetic / pharmacodynamic relationships of anti-infective drugs eliminated by the kidneys. We recorded the incidence of high CrCl in intensive care unit (ICU) patients admitted with meningitis and assessed the diagnostic accuracy of two common methods used to identify high CrCl.<h4>Methods</h4>Observational study performed in consecutive patients admitted with community-acquired acute infectious meningitis (defined by >7 white blood cells/mm3 in cerebral spinal fluid) between January 2006 and December 2009 to one medical ICU. During the first 7 days following ICU admission, CrCl was measured from 24-hr urine samples (24-hr-UV/P creatinine) and estimated according to Cockcroft-Gault formula and the simplified Modification of Diet in Renal Disease (MDRD) equation. High CrCl was defined as CrCl >140 ml/min/1.73 m2 by 24-hr-UV/P creatinine. Diagnostic accuracy was performed with ROC curves analysis.<h4>Results</h4>Thirty two patients were included. High CrCl was present in 8 patients (25%) on ICU admission and in 15 patients (47%) during the first 7 ICU days for a median duration of 3 (1-4) days. For the Cockcroft-Gault formula, the best threshold to predict high CrCl was 101 ml/min/1.73 m2 (sensitivity: 0.96, specificity: 0.75, AUC?=?0.90?±?0.03) with a negative likelihood ratio of 0.06. For the simplified MDRD equation, the best threshold to predict high CrCl was 108 ml/min/1.73 m2 (sensitivity: 0.91, specificity: 0.80, AUC?=?0.88?±?0.03) with a negative likelihood ratio of 0.11. There was no difference between the estimated methods in the diagnostic accuracy of identifying high CrCl (p?=?0.30).<h4>Conclusions</h4>High CrCl is frequently observed in ICU patients admitted with community-acquired acute infectious meningitis. The estimated methods of CrCl could be used as a screening tool to identify high CrCl.
Project description:BACKGROUND: Glomerular filtration rate (GFR) is used in the calculation of carboplatin dose. Glomerular filtration rate is measured using a radioisotope method (radionuclide GFR (rGFR)), however, estimation equations are available (estimated GFR (eGFR)). Our aim was to assess the accuracy of three eGFR equations and the subsequent carboplatin dose in an oncology population. PATIENTS AND METHODS: Patients referred for an rGFR over a 3-year period were selected; eGFR was calculated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations. Carboplatin doses were calculated for those patients who had received carboplatin chemotherapy. Bias, precision and accuracy were examined. RESULTS: Two hundred and eighty-eight studies met the inclusion/exclusion criteria. Paired t-tests showed significant differences for all three equations between rGFR and eGFR with biases of 12.3 (MDRD), 13.6 (CKD-EPI) and 7.7 ml min(-1) per 1.73 m(2) (CG). An overestimation in carboplatin dose was seen in 81%, 87% and 66% of studies using the MDRD, CKD-EPI and CG equations, respectively. CONCLUSION: The MDRD and CKD-EPI equations performed poorly compared with the reference standard rGFR; the CG equation showed smaller bias and higher accuracy in our oncology population. On the basis of our results we recommend that the rGFR should be used for accurate carboplatin chemotherapy dosing and where unavailable the use of the CG equation is preferred.