Mean CrCl Research Articles

Prognostic impact of renal function trajectories and temporal variability amongst anticoagulated atrial fibrillation patients: a subgroup analysis of the SPORTIF III and V trials

Abstract Background Renal function is a major determinant of major adverse outcomes in patients with atrial fibrillation (AF). Scarce data are available about the impact of renal function trajectories and creatinine clearance (CrCl) temporal variability, on prognosis. Aim To evaluate the progression and impact of renal function impairment and variability on outcomes over a long-term follow-up observation in a cohort of anticoagulated AF patients. Methods We included warfarin-treated AF patients in SPORTIF trials with available creatinine clearance (according to Cockroft-Gault) at baseline and at least 4 evaluations throughout their follow-up. Patients with a BMI ≥45 kg/m2 were excluded from the analysis. Average successive variability (ASV) was used as measure of variability. Results Among 3665 original patients, 3366 (91.8%) were included in this analysis. Median [IQR] CHA2DS2-VASc score was 3 [2–4] and HAS-BLED was 3 [2–4]. At baseline, 876 (26.0%) patients had CKD (CrCl <60 mL/min), with 14 (0.4%) patients having severe CKD (<30 mL/min), with a mean (SD) CrCl of 86.7 (47.4) mL/min. Over a mean (SD) 577.1 (122.1) days of follow-up, a total of 521 new CKD cases were found with an overall incidence of 13.1 per 100 patient-years, with 91 new severe CKD cases (1.71 per 100 patient-years). Across follow-up, prevalence of CKD and severe CKD increased progressively (both p<0.001) [Figure]. Mean (SD) AVS was −0.567 (±2.803) mL/min. According to AVS, patients were divided into quartiles: i) Q1: +34.012/+0.450; ii) Q2: +0.449/−0.443; iii) Q3: −0.443/−1.503; Q4: −1.505/−19.750. While no difference was found in stroke/systemic embolism, rate of major bleeding was higher in Q4 (4.5%) and Q1 (4.0%) than in other quartiles (Q2 2.5%, Q3 2.0%; p=0.009) as well as all-cause death (Q4: 6.7%; p=0.003 compared to other quartiles). A Cox multivariate adjusted model documented that AVS Q1 and Q4 were independently associated with a higher risk of major bleeding, while Q4 was associated with a higher risk of all-cause death (Table). Conclusion In a cohort of AF patients treated with warfarin, characterized by a progressive increase in the proportion with CKD and severe CKD, the largest reduction in CrCl throughout follow-up was associated to an increased risk of major bleeding and all-cause death. Renal Function Trajectories Funding Acknowledgement Type of funding source: None

Percutaneous Coronary Intervention Does Not Lower Cardiovascular Outcomes in Patients with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is associated with an increased risk of adverse cardiovascular outcomes, in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). However, most studies used bare-metal stents or first-generation drug-eluting stents, and less guideline-directed therapy to reduce cardiovascular risk was reported in CKD patients. This study investigates the impact of moderate-CKD on patients undergoing PCI in the current era. Methods: Patient level data were pooled from 2 multicenter randomized trials (BIONICS and NIREUS trials) with a near “all-comers” design, comparing PCI with ridaforolimus-eluting stents vs. zotarolimus-eluting stents in patients with CAD. Patients were classified according to the presence or absence of moderate-CKD, defined as creatinine clearance (CrCl) <60 mL/min. We compared baseline characteristics, angiographic findings, and clinical outcomes 1-year post-PCI. Results: 236/2,201 (10.7%) patients had CKD, mean CrCl of 50.3 + 7.8 mL/min. These patients were generally older and more often with hypertension than non-CKD patients, but the use of guideline-directed therapy was similar between the groups. CKD was associated with an increased risk of cardiovascular death (hazard ratio [HR] 6.08; 95% CI 2.11–17.51; p < 0.001), but with a reduced occurrence of repeated revascularization, including ischemia-driven revascularization (HR 0.47; 95% CI 0.24–0.92; p < 0.05). The rate of repeated angiography per severe cardiovascular adverse event was significantly lower in the CKD than the non-CKD group (23/38 [61%] vs. 253/334 [76%], p < 0.05). Conclusions: Moderate-CKD in patients with CAD was associated with higher rates of all-cause and cardiovascular mortality, yet with a lower risk of revascularization 1-year following PCI. Lack of guideline-directed medical therapy does not explain the adverse outcome of CKD patients.

Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation and chronic kidney disease.

Direct oral anticoagulants (DOACs) are effective alternatives to warfarin for stroke prevention in patients with atrial fibrillation (AF) including patients with CKD III. However, data on patient outcomes with DOACs for advanced CKD are limited, while warfarin use is controversial. A retrospective study of patients with AF using DOACs and CKD stages III-V was conducted. The primary outcomes were stroke or systemic embolism and major bleeding while on DOAC therapy among CKD IV and V patients. Rates of outcomes from the DOAC trials and from previous studies of warfarin in CKD were referenced. Of 316 patients reviewed, 152 were included with mean CrCl of 38.8mL/min. Stroke and systemic embolism occurred at a rate of 1.17 per 100 person-years, with no significant difference between CKD IV/V and CKD III (P=.567). Rates were comparable to DOAC use from the DOAC trials, and lower than rates in studies of warfarin in CKD IV/V patients. There was a nonstatistically significant trend toward increased major bleeding in CKD IV/V patients. Rates of major bleeding in CKD III to V subjects were comparable to published rates for warfarin users with similar levels of renal impairment. In our study, DOACs appeared to be as efficacious and safe in CKD IV and V as in CKD III. In addition, DOACs appeared to be more effective than, and as safe as warfarin when compared with reference studies of patients with advanced CKD. Our findings support the use of DOACs for thromboembolism prevention in patients with advanced CKD and AF.

P4769Optimal rivaroxaban dose in Asian patients with atrial fibrillation and normal or mildly impaired renal function

Abstract Background Although rivaroxaban 15 mg was only given to patients with creatinine clearance (CrCl) &lt;50mL/min in the pivotal clinical trial, this dose has been commonly prescribed in Asian patients with non-valvular atrial fibrillation (AF) regardless of renal function. There is a paucity of information regarding the clinical outcomes of rivaroxaban 15 mg compared to rivaroxaban 20 mg in patients with CrCl ≥50mL/min. This study aimed to examine the effectiveness and safety of two doses of rivaroxaban in Asian patients with AF and CrCl ≥50mL/min. Methods Using the Korean National Health Insurance Service database, patients with AF and normal or mildly impaired renal function (CrCl ≥50mL/min) and naïve to rivaroxaban or warfarin were included from January 2014 to December 2016. Three separate 1:1 propensity score-matched cohorts were conducted: rivaroxaban 20 mg (R20) vs. warfarin (n=15,584), rivaroxaban 15 mg (R15) vs. warfarin (n=11,554), and R20 vs. R15 (n=10,392). Hazard ratios (HRs) for ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding, major bleeding, all-cause death, and composite clinical outcome were analyzed. Results Among the pooled total study population, mean age was 66.9±10.9 years, 62.2% were male, mean CHA2DS2-VASc score was 3.16±1.79, and mean CrCl was 83.6±42.0 mL/min (median 78.4 mL/min, IQR 67.7–91.0 mL/min). A substantial proportion (42.6%) of patients with CrCl ≥50 mL/min were prescribed off-label R15 for stroke prevention in the Korean AF population. Compared to warfarin, both R20 and R15 showed significantly lower risk for ischemic stroke, major bleeding (mainly through reduction of ICH), and all-cause death (Figure). Overall, both R20 and R15 had better results for the composite clinical outcome compared to warfarin (HR: 0.617, 95% CI: 0.550–0.691 for R20, and HR: 0.759, 95% CI: 0.675–0.853 for R15). Compared to off-label R15, on-label R20 showed a nonsignificant trend toward lower risks of ischemic stroke, hospitalization for GI bleeding, hospitalization for major bleeding, and all-cause death. Overall, on-label R20 had better results for the composite clinical outcome compared to off-label R15 in patients with CrCl ≥50 mL/min (HR: 0.852, 95% CI: 0.735–0.988). This benefit was consistently observed in patients aged ≥80 years and those &lt;50 kg. In patients with CrCl 50–60 mL/min, R20 showed a nonsignificant trend toward a higher risk of hospitalization for major bleeding compared to R15 (HR: 1.828, 95% CI 0.994–3.452). Conclusions Among Asians with AF and CrCl ≥50mL/min, both R20 and R15 were associated with reduced risk of ischemic stroke, ICH, major bleeding, and all-cause death without significantly increased risk of GI bleeding compared with warfarin. In patients with CrCl ≥50mL/min, on-label R20 showed better results for the composite clinical outcome compared to off-label R15.

Real-life behaviour of direct oral anticoagulants in a Spanish cohort with non-valvular atrial fibrillation: Refase Registry

Aim: To analyse the effectiveness and safety of DOAC (direct oral anticoagulants) in non-valvular atrial fibrillation (NVAF) patients attending clinical practice.Methods: Retrospective study of AF patients who started treatment with DOAC from January 1, 2013 to December 31, 2016 in three Spanish hospitals. Mean follow-up was 1.6 years. The primary outcomes were rates of all-cause death, ischaemic stroke, and bleeding. These outcomes were also studied depending on correct dosage adjustment and standard/adjusted dose.Results: The study included 2494 patients (age = 76.0 ± 9.5 years, CHA2DS2-VASc = 4.0 ± 1.6). The most prescribed DOAC was rivaroxaban (41.1%). Patients taking dabigatran were the youngest (mean age = 73.1 ± 10.3 years), with better kidney function (mean CrCl = 80.6 ± 35.8 ml/min) and lower CHA2DS2-VASc (3.7 ± 1.4) and HAS-BLED (2.1 ± 0.9) scores. Patients taking apixaban were the oldest, and had the highest CHA2DS2-VASc and HAS-BLED scores (4.3 ± 1.6 and 2.6 ± 0.9, respectively). Rates of stroke/major bleeding/intracranial bleeding were 1.8/3.0/0.3 events per 100 patient-years, respectively, with no differences among DOAC. Based on dose adjustment according to technical data, it was observed that 517 patients (23.5%) received DOAC doses inconsistent with labelling (p < .001) and, within this group, under-dosed patients had a higher death rate although it did not reach a significant result after multivariate adjustment.Conclusions: The results of safety and efficacy are very similar to those of other previously published national registries. There were no differences among the different types of DOAC regarding outcomes. However, it was found that people taking the adjusted dose of the drug seemed to have a higher risk of death. A non-negligible proportion of patients received DOAC doses inconsistent with labelling (mostly underdose).

Oral mucosa and salivary findings in non-diabetic patients with chronic kidney disease

IntroductionChronic kidney disease (CKD) and dialysis treatment could affect oral mucosa and cause qualitative or quantitative changes of saliva. ObjectiveThe aim of the study was to investigate oral manifestations, unstimulated salivary flow rate (USFR), salivary pH value and biochemical composition of saliva in non-diabetic patients with CKD. DesignThe study group (PD) consisted of 50 pre-dialysis patients diagnosed with CKD, positive control group (HD) of 25 haemodialysis patients and negative control (H) of 25 age and gender-matched healthy persons. Creatinine clearance rate (CrCl) was calculated from the blood creatinine using the Cockcroft-Gault formula. After a detailed intraoral examination, whole unstimulated saliva samples were collected to determine salivary pH value, and biochemical composition using a spectrophotometric method. ResultsStatistical analysis revealed that PD subjects had more oral lesions (p < 0.05) and symptoms (p < 0.001) than controls. The mean CrCl was significantly lower (p < 0.05) in CKD subjects with pale mucosa, xerostomia, dysgeusia, and uremic odour, comparing to those without listed symptoms. PD subjects had significantly decreased USFR and increased pH, urea and creatinine than H controls (p < 0.05). A moderately strong positive correlation between serum and salivary creatinine in both PD (p < 0.05) and HD (p < 0.05) groups was found. ConclusionThis study confirmed that xerostomia and dysgeusia are major symptoms among pre-dialysis patients. Their presence along with uremic odour and pale mucosa is directly related to decreased kidney function. On the diagnostic point, decreased USFR, especially hyposalivation and increased salivary creatinine, should be considered a significant indicator of CKD in stages before dialysis therapy.

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of β-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for β-lactams and therapeutic failure. The performance of CLCr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing<4×MIC was 12%, with a significant association with CLCr (P < 0.0001). A threshold of CLCr ≥ 170 mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77–0.99) and 0.65 (95% CI 0.58–0.71) for predicting β-lactam underdosing<4×MIC. Mean CLCr values ≥170 mL/min were significantly associated with subexposure<4xMIC [OR = 10.1 (2.4–41.6); P = 0.001]. Patients with subexposure<4×MIC presented higher rates of therapeutic failure [OR = 6.3 (1.2–33.2); P = 0.03]. Mean CLCr values ≥170 mL/min remain a risk factor for subexposure to β-lactams despite high doses of β-lactams administered continuously. β-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.

Changes in Kidney Function Associated With Daily Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Preexposure Prophylaxis Use in the United States Demonstration Project.

HIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings. Demonstration project in 2 sexually transmitted infection clinics and a community health center. We evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI). From October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR <70 mL/min/1.73 m; independent predictors of this outcome were age ≥40 years (OR 3.79, 95% CI: 1.43 to 10.03) and baseline eGFR <90 mL/min/1.73 m (OR 9.59, 3.69-24.94). In a demonstration setting, daily tenofovir-disoproxil-fumarate/emtricitabine PrEP leads to reduced CrCl and eGFR; however, these eGFR changes are based on very small changes in serum creatinine and seem to be nonprogressive after the first 12 weeks. Future studies are needed to understand the prognostic significance of these small changes.

Everolimus as a Calcineurin Inhibitor-Sparing Immunosuppressive Agent in Lung Transplant Recipients With Renal Impairment

SESSION TITLE: Transplant SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Calcineurin inhibitors (CNI) are considered a key component of maintenance immunosuppression following lung transplantation. However, CNI nephrotoxicity is a common and serious problem amongst lung transplant recipients. Everolimus (ERL), an inhibitor of the mechanistic target of rapamycin (mTOR), has been used as a CNI sparing immunosuppressive agent to allow renal recovery in patients with progressive renal impairment. Nevertheless, there is limited evidence to support the efficacy of this strategy to prevent rejection. This study aimed to evaluate the effect of ERL on renal and lung function in lung transplant recipients. METHODS: We conducted a retrospective analysis within a state-wide lung transplant service in Australia. Medical and pharmacy records were used to identify lung transplant recipients who were commenced on ERL from 2004 to 2015. Patients who received at least 6 consecutive months of ERL therapy during this period were included in the analysis. We recorded renal function and lung function 6 months before and 6 months after the initiation of ERL. Creatinine clearance (CrCl), derived from the Cockroft-Gault equation, was used as a measure of renal function. Lung function was reported as the percent predicted FEV1 and FVC. RESULTS: 44 patients were included in the analysis. The mean age was 49 ± 15 years. ERL was initiated at a median of 476 days (interquartile range 219-1247) post-transplant. The indication for ERL was renal impairment in 94%, malignancy in 4% and CNI related neurotoxicity in 2% of patients. After initiating ERL, 46% of patients had CNI ceased and the rest had a substantial dose reduction. At ERL initiation, mean CrCl was 52.6 ± 3.3 ml/min, mean percent predicted FEV1 70 ± 3% and FVC 77 ± 3%. In the 6 months prior to commencing ERL, there was a mean change in CrCl of -8.9 ± 2.4 ml/min (P=0.003), FEV1 -3.4 ± 1.9% (p=0.696), and FVC -1.2 ± 1.5% (p=1.000). 6 months after initiating ERL, the mean change in CrCl was +11.2 ± 2.4 ml/min (p<0.0001), FEV1 -5.3 ± 1.7% (p=0.024), and FVC -3.9 ± 1.4% (p=0.049). Excluded from the analysis were 8 patients who were on ERL for less than 6 months. 6 patients had ERL ceased; 2 for rejection, 2 for suspected pneumonitis, 1 for drug intolerance and 1 to aid wound healing after a motor vehicle accident. There were 2 deaths during this period; one due to chest sepsis and the other from liver failure, neither of which could be directly related to toxicity from ERL. These 8 patients received ERL for at least 3 months and were included in a 3-months analysis. At 3 months, there was a similar increase in CrCl of +11.6 ± 2.3 ml/min (p<0.0001) and no significant change in FEV1 and FVC. CONCLUSIONS: In lung transplant recipients with renal impairment, the use of ERL as a CNI sparing agent is associated with improvement in renal function. However, the efficacy of this maintenance immunosuppression strategy in preventing rejection requires elucidation with further studies. CLINICAL IMPLICATIONS: The use of ERL allows CNI withdrawal and renal recovery in lung transplant recipients with renal impairment. These patients should be closely followed up with frequent monitoring of lung function. DISCLOSURE: The following authors have nothing to disclose: Shaun Yo, Tim Coughlan, Steve Ivulich, Eldho Paul, Gregory Snell, Solomon Menahem No Product/Research Disclosure Information

Pharmacokinetics of Cabotegravir in Subjects with Severe Renal Impairment

BackgroundCabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes glucuronidation via UGT1A1 with <1% renal elimination of unchanged CAB. Renal impairment may affect PK of drugs that are primarily metabolized or secreted in bile; thus impact of renal impairment on CAB pharmacokinetics was evaluated.MethodsThis was a multi-center, single-dose study of oral CAB 30mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/minute; not on renal replacement therapy) and to healthy controls (CLcr ≥90 mL/minute) matched for gender, age (±10 years), and body mass index (BMI) (±25%) (8 per group). Serial PK for plasma CAB concentrations were collected through 168 hours post dose and unbound CAB concentrations determined at 2 and 24 hours post dose. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated.ResultsSixteen subjects completed study; 12 (75%) male, mean age 54 years (range:35–69), mean BMI 28 kg/m2 (range: 24–35), and mean CLcr 22 mL/minute (range: 17–29) and 121 mL/minute (range: 95–162) for renal impaired and healthy subjects, respectively. CAB PK parameters were similar between severe renal impairment and healthy subjects. Based on preliminary PK, GLS mean ratios (90% CI) for AUC(0-¥), Cmax, C24, CL/F, and t1/2 were 0.97 (0.835, 1.14), 1.01 (0.865, 1.17), 1.02 (0.868, 1.20), 1.03 (0.881, 1.20) and 0.93 (0.831, 1.04), respectively. Although highly protein bound, the unbound fraction was higher in subjects with severe renal impairment with GLS mean ratio (90%CI) of 1.31 (0.843, 2.03) at 2 hours and 1.51 (1.19, 1.92) at 24 hours post dose. One renal impairment subject developed grade 3 lipase elevation considered drug-related by investigator, otherwise all reported adverse events (AE) were Grade 1 in severity with no serious AEs reported.ConclusionPlasma CAB exposures in subjects with severe renal impairment were similar to healthy subjects; therefore, no dose adjustment of CAB is required in renal impairment. Although no data are available, CAB PK is not expected to be affected in subjects undergoing dialysis given CAB’s non-renal clearance and high plasma protein binding (~99%).Disclosures R. Parasrampuria, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; C. Fu, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary

Fosfomycin tromethamine for the Treatment of Cystitis in Abdominal Solid Organ Transplant Recipients With Renal Dysfunction.

Urinary tract infection (UTI) after abdominal solid organ transplantation (SOT) is associated with significant morbidity and mortality. Fosfomycin tromethamine (FOS), a uroselective antibiotic, is FDA approved for uncomplicated UTIs in women and is used off-label for complicated UTIs and prostatitis in men. Literature supporting the use of FOS in the SOT population is limited, and efficacy is questioned in the setting of renal dysfunction. To evaluate the success of FOS for the treatment of cystitis in SOT patients with renal dysfunction. This was a single-center, retrospective study using medical records. SOT recipients receiving at least 1 dose of FOS for treatment of cystitis between January 1, 2009, and April 30, 2015, were included. Treatment outcomes were analyzed with respect to renal function. A total of 76 courses of FOS were identified in 64 patients. The renal dysfunction arm (creatinine clearance [CrCl] < 40 mL/min) included 33 patients with 39 FOS courses; the normal renal function arm (CrCl ≥ 40 mL/min) included 31 patients with 37 FOS courses. Mean CrCl was 23.3 ± 9.7 mL/min for the renal-dysfunction group and 65 ± 29.3 mL/min for the normal renal function group ( P < 0.01). No significant difference in treatment success was noted between CrCl <40 mL/min and CrCl ≥40 mL/min (31 [80%] vs 34 [92%], P = 0.12) in a unilateral analysis. After adjusting for confounders in a multivariable analysis, there was no difference in the risk of failure between CrCl <40 mL/min and CrCl ≥40 mL/min groups ( P = 0.70). FOS appears to be successful for the treatment of cystitis in SOT recipients in the setting of renal dysfunction.

An open-label study of the pharmacokinetics and pharmacodynamics of dabigatran etexilate 150 mg once daily in Caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery

BackgroundIn adults with moderate renal impairment (creatinine clearance [CrCl] 30–50mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of dabigatran etexilate is 150mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. MethodsSingle-arm, open-label phase 4 study (NCT01184989) in Caucasian patients receiving dabigatran etexilate 75mg 1–4h after surgery and 150mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total dabigatran concentrations (day 6±1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). ResultsOf 112 patients (mean CrCl 42.5mL/min, age 79.1years, 69.6% female), 100 completed the study. Geometric mean trough and peak dabigatran concentrations were 47.5ng/mL (10th–90th percentile 19.7–120) and 166ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ±15%. ConclusionsThese findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150mg qd dose of dabigatran etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of dabigatran levels would be helpful.

Crystal structure of trans-di-chlorido-(1,4,8,11-tetra-aza-undecane-κ(4) N)chromium(III) perchlorate determined from synchrotron data.

The structure of the title complex, [CrCl2(2,3,2-tet)]ClO4 (2,3,2-tet is 1,4,8,11-tetra-aza-undecane, C7H20N4), has been determined from synchrotron data. The Cr(III) ion is coordinated by the four N atoms of the 1,4,8,11-tetra-aza-undecane ligand in the equatorial plane and two chloride ions in an axial arrangement, displaying a slightly distorted octa-hedral coordination environment. The two H atoms of the secondary amines are grouped on the same side of the equatorial N4 plane (meso-RS conformation). The Cr-N bond lengths range from 2.069 (2) to 2.084 (2) Å, while the mean Cr-Cl bond length is 2.325 (2) Å. The crystal structure is stabilized by inter-molecular hydrogen-bonding inter-actions between the primary and secondary amine groups of the 2,3,2-tet ligands, the Cl ligands and the O atoms of the perchlorate counter-anion, forming corrugated layers parallel to (010).

Safe limits of contrast vary with hydration volume for prevention of contrast-induced nephropathy after coronary angiography among patients with a relatively low risk of contrast-induced nephropathy.

Few studies have investigated the safe limits of contrast to prevent contrast-induced nephropathy (CIN) based on hydration data. We aimed to investigate the relative safe maximum contrast volume adjusted for hydration volume in a population with a relatively low risk of CIN. The ratios of contrast volume-to-creatinine clearance (V/CrCl) and hydration volume to body weight (HV/W) were determined in patients undergoing cardiac catheterization. Receiver-operator characteristic curve analysis based on the maximum Youden index was used to identify the optimal cutoff for V/CrCl in all patients and in HV/W subgroups. Eighty-six of 3273 (2.6%) patients with mean CrCl 71.89±27.02 mL/min developed CIN. Receiver-operator characteristic curve analysis indicated that a V/CrCl ratio of 2.44 was a fair discriminator for CIN in all patients (sensitivity, 73.3%; specificity, 70.4%). After adjustment for other confounders, V/CrCl >2.44 continued to be significantly associated with CIN (adjusted odds ratio, 4.12; P<0.001) and the risk of death (adjusted hazard ratio, 2.62; P<0.001). The mean HV/W was 12.18±7.40. We divided the patients into 2 groups (HV/W ≤12 and >12 mL/kg). The best cutoff value for V/CrCl was 1.87 (sensitivity, 67.9%; specificity, 64.4%; adjusted odds ratio, 3.24; P=0.011) in the insufficient hydration subgroup (HV/W, ≤12 mL/kg; CIN, 1.32%) and 2.93 (sensitivity, 69.0%; specificity, 65.0%; adjusted odds ratio, 3.04; P=0.004) in the sufficient hydration subgroup (HV/W, >12 mL/kg; CIN, 5.00%). The V/CrCl ratio adjusted for HV/W may be a more reliable predictor of CIN and even long-term outcomes after cardiac catheterization. We also found a higher best cutoff value for V/CrCl to predict CIN in patients with a relatively sufficient hydration status, which may be beneficial during decision-making about contrast dose limits in relatively low-risk patients with different hydration statuses.

Safety of cisplatin in patients with urothelial carcinoma (UC) and renal dysfunction.

321 Background: Patients (pts) with UC and creatinine clearance (CrCl) &lt; 60 ml/min are considered cisplatin-ineligible. Since the safety of cisplatin use in patients with CrCl &lt; 60 has not been comprehensively studied, we conducted a retrospective study in this population. Methods: Data were requested and retrospectively collected from 5 collaborating institutions. All patients had stage 2 or higher UC and CrCl &lt; 60. Patient characteristics including age, sex, indication for chemotherapy (neoadjuvant, adjuvant or metastatic disease), schedule, total dose of cisplatin, adverse effects, renal function, blood cell counts and radiologic tumor response were collected. Descriptive statistics were employed with no baseline assumptions. Results: 104 patients were evaluable with a mean age of 63.7+ 8.1 yrs (range 41-77yrs) and 63.5% (n=66) were men. Mean CrCl by Cockroft-Gault formula was 50.8 + 8.0 ml/min (range 26-59 ml/min). Baseline ECOG performance status was 0 in 71.8% (n=74); 1 in 20.3% (n=21) and 2 in 7.8% (n=8) of patients. 40.4% (n=42) received chemotherapy for metastatic disease and the rest received perioperative chemotherapy. Of the patients with metastatic disease, 7.1% patient had complete response (CR), 40.5 % patients had partial response. Mean total dose of cisplatin used in all patients was 414.32±198.01 mg, with 81.7% (n=85) patients receiving ≥70mg/m2 dose per cycle. Percentage of patients with any toxicity with baseline CrCl &lt;45 and &gt;45 were 43.5% and 39.5%, respectively (p=0.81). Neutropenic infection occurred in 16.3% and thrombocytopenic bleed in 8.6%. Grade 3 renal toxicity was seen in only one patient (0.96%) and no toxic deaths were reported. Conclusions: This retrospective clinical experience in pts with UC with CrCl &lt;60 ml/min and mostly ECOG-PS 0-1 suggests that cisplatin-based chemotherapy is feasible and warrants exploration given CRs induced in metastatic disease. Incorporation of prophylactic growth factors and modified schedules may mitigate myelosuppression.

Effect of Primary Percutaneous Coronary Intervention on Renal Function in Acute ST Elevation Myocardial Infarction.

Effect of Primary Percutaneous Coronary Intervention on Renal Function in Acute ST Elevation Myocardial Infarction Objectives: Assess the effect of primary percutaneous coronary intervention (PCI) on renal function in the setting of acute ST elevation myocardial infarction (STEMI). Methods: Retrospective chart review of 270 STEMI patients that underwent primary PCI. Creatinine clearance was calculated using the re-expressed 4–variable Modification of Diet in Renal Disease (MDRD) formulas upon presentation to emergency room and prior to discharge from hospital or death. Results: Mean creatinine level upon presentation was 1.14 ± 0.43 mg/dl and upon discharge 1.07 ± 0.51 mg/dl (p=0.013). Mean CrCl on admission was 77 ± 27 ml/min/1.73m2 and improved to 86 ± 31 ml/min/1.73m2 upon discharge (p<0.001). This improvement was observed in patients with all stages of chronic kidney disease (CKD), including stage III (47 ± 9 vs 55 ± 18 ml/min/1.73m2, p=0.001) and stage IV (24 ± 4 vs 29 ± 10 ml/min/1.73m2; p=0.13). Statistically significant improvement in CrCl (79 ± 28 vs. 86 ± 31 ml/min/1.73m2, p < 0.001) was observed in African American patients (72% of study group). Conclusion: In STEMI patients, primary PCI does not appear to be associated with worsening, but rather an improvement, in renal function upon hospital discharge.

Tobramycin exposure from active calcium sulfate bone graft substitute

BackgroundBone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T).MethodsNine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417).ResultsThe patients were 52 +/− 20 years old, their mean body weight was 73 +/− 17 kg and their mean CLCr was 119 +/− 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively.ConclusionsOsteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.

A comparison of CKD-EPI estimated glomerular filtration rate and measured creatinine clearance in recently admitted critically ill patients with normal plasma creatinine concentrations

BackgroundThe Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) has been widely integrated into clinical practice. Although useful in screening for CKD, its’ application in critically ill patients with normal plasma creatinine concentrations remains uncertain. The aim of this study was to assess the performance of CKD-EPI eGFR in comparison to creatinine clearance (CLCR) in this setting.MethodsThis prospective observational study was performed in a tertiary level, university affiliated intensive care unit (ICU). Study participants had to have an expected ICU length of stay > 24 hours, a plasma creatinine concentration < 121 μmol/L, and no history of prior renal replacement therapy or CKD. CKD-EPI eGFR was compared against 8-hour measured urinary CLCR. Data capture occurred within 48 hours of admission.ResultsOne hundred and ten patients (n = 110) were enrolled in the study. 63.6% were male, the mean age was 50.9 (16.9) years, 57.3% received invasive mechanical ventilation, and 30% required vasopressor support. The mean CLCR was 125 (45.1) ml/min/1.73 m2, compared to a CKD-EPI eGFR of 101 (23.7) ml/min/1.73 m2 (P < 0.001). Moderate correlation was evident (r = 0.72), although there was significant bias and imprecision (24.4 +/− 32.5 ml/min/1.73 m2). In those patients with a CKD-EPI eGFR between 60–119 ml/min/1.73 m2 (n = 77), 41.6% displayed augmented renal clearance (CLCR ≥ 130 ml/min/1.73 m2), while 7.8% had a CLCR < 60 ml/min/1.73 m2.ConclusionsThese data suggest CKD-EPI eGFR and measured CLCR produce significantly disparate results when estimating renal function in this population. Clinicians should consider carefully which value they employ in clinical practice, particularly drug dose modification.

Predicting silent cerebral microischemia in patients with non-valvular atrial fibrillation and structurally normal hearts: the CHADS2, CHA2DS2-VASc and -R scores

Purpose: To evaluate the ability of the CHADS2 and CHA2DS2-VASc scores alone and combined with creatinine clearance (CrCl) to predict silent cerebral lesions in patients with non-valvular atrial fibrillation (AF) and structurally normal hearts. Methods: Magnetic resonance brain imaging (MRI) was performed in consecutive patients initially diagnosed with first-diagnosed lone AF. Patients with prior AF ablation were excluded. In addition to the classic scores, the CHADS2-R and CHA2DS2-VASc-R were calculated by adding 1 point for CrCl≤90ml/min. Results: Of 33 patients aged 54.4±14.4y, 26 were males (78.8%) and 15 (45.5%) had paroxysmal AF. Mean systolic and diastolic blood pressures were 118.2±12.7 and 74.4±7.9 mmHg, respectively, mean CrCl was 110.9±27.5 mL/min, and mean LVEF 61.9±5.8%. Mean score values were: CHADS2 0.67±1.02, CHA2DS2-VASc 1.03±1.05, CHADS2-R 0.9±1.2 and CHA2DS2-VASc-R 1.3±1.8. Mean 13.7±8.2 years from first AF, 15 patients (45.5%) remained lone AF, 5 (15.1%) aged >60, 12 (36.4%) developed hypertension (plus coronary disease, 1 patient) and 1 (3.0%) developed pulmonary disease; 4 patients had suffered symptomatic ischemic stroke; 17 (51.5%) were taking oral anticoagulation (5 awaiting cardioversion). MRI detected silent microischemia in 17 patients (51.5%), microangiopathy in 4 (12.1%) and no microbleeds; microischemic lesions were detected in 5/15 patients (33.3%) with lone AF and 12/18 (66.7%) with hypertension, p=0.059. On the univariate logistic regression the CHADS2, CHA2DS2-VASc, CHADS2-R and CHA2DS2-VASc-R were all significantly related to microischemia (OR 5.7; 95% CI, 1.3-25.9; p=0.023, 4.7; 95% CI, 1.3-16.4; p=0.016, 5.3; 95% CI, 1.4-19.8; p=0.014 and 4.6; 95% CI, 1.4-14.9; p=0.011, respectively). On the multivariable analysis, only the CHA2DS2-VASc-R was significantly related to cerebral microischemia (OR 3.7; 95% CI, 1.2-11.8; p=0.027). The prediction ability (c-statistic) of the CHADS2, CHA2DS2-VASc, CHADS2-R and CHA2DS2-VASc-R scores was 0.72; 95% CI, 0.53-0.91; p=0.040, 0.75; 95% CI, 0.58-0.93; p=0.018, 0.78; 95% CI,0.62-0.96; p=0.007 and 0.80; 95% CI, 0.63-0.96; p=0.006, respectively. Conclusions: The inclusion of the CrCl cut-off value reflecting even subtle renal dysfunction improved the prediction ability of the thromboembolic risk scores for silent cerebral microischemic lesions in AF patients with lone AF or hypertension and structurally normal hearts, who are often perceived as low risk population. Compared with the CHADS2 and CHADS2-R, the CHA2DS2-VASc and CHA2DS2-VASc-R scores, respectively, had better prediction ability for the presence of silent cerebral lesions in these AF patients.

Assessing renal function in acute coronary syndromes: does it really matter how we do it?

Background: According ESC guidelines renal function should be assessed using estimated Glomerular Rate Filtration (eGRF) calculated using Modification of Diet in Renal Disease (MDRD) equation, although in daily clinical practice Creatinine Clearance (CrCl) calculated with the Cockroft-Gault (CG) formula is more often used. Purpose: To assess if eGFR using MDRD equation has more prognostic impact than CrCl calculated with CG formula in acute coronary syndromes (ACS). Population: 2076 patients admitted for ACS between 2004 and 2011 in a Coronary Care Unit. Primary endpoint was death or myocardial infarction in the follow up. Results: The mean age of patients was 68±13 years and 67.5% were male. Approximately one third of study population (30.5%) had diabetes, 35.6% were elderly and 74.5% had hypertension. Regarding type of ACS, 39.5% of patients had ST elevation; 29.8% of patients reached the primary endpoint in the follow up. Mean admission creatinine was 1.22±0.87mg/dL. Mean eGFR was 70.82±25.91mL/min/1.73m2 and mean CrCl was 70.87±32.98mL/min. Using MDRD equation, 6.7% of patients had eGFR<30.0mL/min/1.73m2; otherwise, using CG formula, 9.0% of patients had CrCl<30.0mL/min. Comparing both equation the Concordance Correlation Coefficient was k=0.629 and Spearman Correlation Coefficient was 0.872, with great discrepancy for higher eGFR values. Area under the curve (AUC) of MDRD ROC curve was 0.613 (0.586; 0.639), p<0.001, while AUC of CG curve was 0.614 (0.587; 0.640), p<0.001. Comparing both ROC curves p value was not statistically different (0.888). Conclusion: In ACS patients, renal function has an important prognostic value. Although ESC guidelines recommend MDRD formula, CrCl using CG formula has the same prognostic value regarding death or myocardial infarction.