Clinical characteristics and disease outcomes in non-diabetic chronic kidney disease: retrospective analysis of a US healthcare claims database.

BACKGROUND: The observational, real-world evidence FLIEDER study aimed to describe patient clinical characteristics and investigate clinical outcomes in non-diabetic patients with chronic kidney disease (CKD) using data collected from routine clinical practice in the United States. METHODS: Between 1 January, 2008-31 December, 2018, individuals aged ≥ 18 years, with non-diabetic, stage 3-4 CKD were indexed in the Optum® Clinformatics® Data Mart US healthcare claims database using International Classification of Diseases-9/10 codes for CKD or by laboratory values (estimated glomerular filtration rate [eGFR] 15-59 mL/min/1.73 m2). The primary outcomes were hospitalization for heart failure, a composite kidney outcome of end-stage kidney disease/kidney failure/need for dialysis and worsening of CKD stage from baseline. The effects of the intercurrent events of a sustained post-baseline decline in eGFR ≥ 30%, ≥ 40%, and ≥ 57% on the subsequent risk of the primary outcomes were also assessed. RESULTS: In the main study cohort (N = 504,924), median age was 75.0 years, and 60.5% were female. Most patients (94.7%) had stage 3 CKD at index. Incidence rates for hospitalization for heart failure, the composite kidney outcome, and worsening of CKD stage from baseline were 4.0, 10.3, and 4.4 events/100 patient-years, respectively. The intercurrent event analysis demonstrated that a relative decline in kidney function from baseline significantly increased the risk of cardiorenal events. CONCLUSIONS: This real-world study highlights that patients with non-diabetic CKD are at high risk of serious adverse clinical outcomes, and that this risk is amplified in patients who experienced greater post-baseline eGFR decline.

CKD Prevalence Among Patients With and Without Type 2 Diabetes: Regional Differences in the United States.

RATIONALE & OBJECTIVE: Regional variation in chronic kidney disease (CKD) prevalence in patients with or without type 2 diabetes mellitus (T2DM) has not been well characterized. STUDY DESIGN: Spatial and temporal comparative analysis. SETTING & PARTICIPANTS: MarketScan databases were used to identify patients with CKD overall and subgroups of patients with CKD with and without T2DM in the United States. OUTCOMES: Spatial patterns in CKD prevalence based on year, regional clusters of CKD between years, and characteristics of patients in high-prevalence states. ANALYTICAL APPROACH: Geomapping was used to visualize the state-level data of CKD prevalence generated from 2013 to 2018. We used univariate local indicators of spatial association (LISA) to evaluate geographic differences in prevalence, differential LISA for changes in CKD prevalence over time, and the χ2 test to identify patient characteristics in the top-20th percentile states for the prevalence of CKD. RESULTS: In univariate LISA, low-low clusters, in which a state has a low CKD prevalence and the surrounding states have a below-average CKD prevalence, were observed in the northwest region throughout the study period, regardless of the T2DM status, indicating a consistently low prevalence of CKD clustered in these areas. High-high clusters were observed, regardless of the T2DM status, in the southeast region in more recent years, suggesting an increased CKD prevalence in this region. LIMITATIONS: Health care insurance enrollment might not have been representative of the United States; the estimates were based on claims data that likely underestimated the true prevalence. CONCLUSIONS: Geographic disparities in CKD prevalence appear increasingly magnified, with an increase in the southeastern region of the United States. This increase is especially problematic because patients with CKD in high-prevalence states experience a greater likelihood of chronic conditions than those in the rest of the United States.

Assessment of QT(c)-prolonging potential of BX471 in healthy volunteers. A 'thorough QT study' following ICH E14 using various QT(c) correction methods.

AIMS: Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting 'thorough QT(c) studies' according to ICH E14. A broad range of QT correction methods and analysis strategies was employed. METHODS A double-blind, placebo- and positive-controlled, single-centre, three-way cross-over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett's (QT(c)B), Fridericia's (QT(c)F) and several regression-based corrections. RESULTS: There was a significant QT(c)F prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QT(c) prolongation [QT(c)F estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QT(c)B estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression-based QT correction methods yielded similar results to Fridericia's correction [e.g. using a linear regression across the study population, QT(c) estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression-based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat. CONCLUSIONS: BX471 does not cause meaningful QT(c) prolongation. Three QT correction methods may be sufficient in future studies: Bazett's (required by regulatory authorities), Fridericia's (as the most reliable fixed formula) and a regression-based correction (individually or population-based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).

Radiation dosimetry of beta-amyloid tracers 11C-PiB and 18F-BAY94-9172.

UNLABELLED: Beta-amyloid (Abeta) imaging has great potential to aid in the diagnosis of Alzheimer disease and the development of therapeutics. The radiation dosimetry of Abeta radioligands may influence their application; therefore, we calculated and compared the effective doses (EDs) of 11C-PiB and a new 18F-labeled ligand, 18F-BAY94-9172. METHODS: Attenuation-corrected whole-body scans were performed at 0, 15, 30, 45, and 60 min after injection of 350+/-28 MBq (mean+/-SD) of 11C-PiB in 6 subjects and at 0, 20, 60, 120, and 180 min after injection of 319+/-27 MBq of 18F-BAY94-9172 in 3 subjects. Coregistered CT was used to define volumes of interest (VOIs) on the PET images. The source organs were the brain, lungs, liver, kidneys, spleen, and vertebrae. The VOIs for the contents of the gallbladder, urinary bladder, lower large intestine, upper large intestine, and small intestine were also defined. Total activity in each organ at each time point was calculated by use of reference organ volumes. The resultant time-activity curves were fitted with constrained exponential fits, and cumulated activities were determined. A dynamic bladder voiding model was used. The OLINDA/EXM program was used to calculate the whole-body EDs from the acquired data. RESULTS: For 11C-PiB, the highest absorbed doses were in the gallbladder wall (44.80+/-29.30 microGy/MBq), urinary bladder wall (26.30+/-8.50 microGy/MBq), liver (19.88+/-3.58 microGy/MBq), and kidneys (12.92+/-3.37 microGy/MBq). The ED was 5.29+/-0.66 microSv/MBq. For 18F-BAY94-9172, the highest doses were also in the gallbladder wall (132.40+/-43.40 microGy/MBq), urinary bladder wall (24.77+/-7.36 microGy/MBq), and liver (39.07+/-8.31 microGy/MBq). The ED was 14.67+/-1.39 microSv/MBq. CONCLUSION: The estimated organ doses for 11C-PiB were comparable to those reported in earlier research. With the doses used in published studies (300-700 MBq), the EDs would range from 1.6 to 3.7 mSv. The ED of 18F-BAY94-9172 was 30% lower than that of 18F-FDG and, at the published dose of 300 MBq, would yield an ED of 4.4 mSv. The dosimetry of both Abeta radioligands is suitable for clinical and research applications.

Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism.

BACKGROUND: Amyloid-beta (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD. METHODS: 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. (18)F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD. FINDINGS: (18)F-BAY94-9172 binding matched the reported post-mortem distribution of Abeta plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90-120 min after injection, higher neocortical SUVR was observed in AD patients (2.0 [SD 0.3]) than in healthy controls (1.3 [SD 0.2]; p<0.0001) or FTLD patients (1.2 [SD 0.2]; p=0.009). Visual interpretation was 100% sensitive and 90% specific for detection of AD. INTERPRETATION: (18)F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Abeta imaging into clinical practice.