Dapagliflozin Utilization in Chronic Kidney Disease and Its Real-World Effectiveness Among Patients with Lower Levels of Albuminuria in the USA and Japan.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors such as dapagliflozin have been proven effective for slowing chronic kidney disease (CKD) progression in large outcomes trials that mainly included patients with higher levels of albuminuria. Understanding the real-world utilization and effectiveness of these drugs among patients with CKD with lower levels of albuminuria can inform clinical decision-making in this population. METHODS: Claims data from the USA and Japan were used to describe patients with CKD and urinary albumin-to-creatinine ratio (UACR) < 200 mg/g who were eligible for dapagliflozin 10 mg treatment (initiators and untreated) following its approval for CKD. A quantile regression analysis was performed to evaluate the effect of dapagliflozin 10 mg initiation versus no initiation on estimated glomerular filtration rate (eGFR) slope in a propensity score-matched cohort, using a prevalent new-user design. RESULTS: Dapagliflozin initiators (n = 20,407) mostly had stage 3-4 CKD (69-81% across databases). The most common comorbidities were type 2 diabetes, hypertension and cardiovascular disease. At baseline, a renin-angiotensin system inhibitor was prescribed in 53-81% of patients. Eligible but untreated patients were older and had a higher eGFR and lower comorbidity burden than initiators. Following dapagliflozin initiation, the differences in median eGFR slope between initiators and matched non-initiators were 1.07 mL/min/1.73 m2/year (95% confidence interval [CI] 0.40-1.74) in all patients with UACR < 200 mg/g and 1.28 mL/min/1.73 m2/year (95% CI - 1.56 to 4.12) in patients with UACR < 200 mg/g without type 2 diabetes. CONCLUSIONS: Dapagliflozin 10 mg was prescribed to a broad range of patients with CKD. In patients with UACR < 200 mg/g, dapagliflozin initiation was associated with a clinically meaningful attenuation of eGFR slope compared with non-initiation. These findings supplement available clinical efficacy evidence and suggest that dapagliflozin effectiveness may extend to patients with CKD and UACR < 200 mg/g. Graphical Abstract and Video Abstract available for this article. (Video Abstract 245964 kb).

Use of clinical classifications software to address ICD coding transition in large healthcare databases analyzed via high-dimensional propensity scores.

PURPOSE: The EUPAS26595 study characterized the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other antiepileptic drugs using healthcare claims data and a high-dimensional propensity score (hd-PS) for confounding adjustment. The data contained several coding systems by design and an update in International Classification of Diseases (ICD) coding dictionary. Such coding heterogeneity can affect the performance of hd-PS, and manually coding harmonization is not feasible. Our objective was to explore the impact of code aggregation via Clinical Classifications Software (CCS) on the analysis of a large claims-based database using hd-PS. METHODS: Patients with epilepsy, who were new-users of an antiepileptic drug, were identified from the IBM® MarketScan® Research Databases. We used CCS categories to harmonize coding and compared the results with other alternatives. Incidence rate ratios (IRRs) were computed using modified Poisson regression model with a robust variance estimator. RESULTS: For January 2008-October 2015 (before ICD update), 34 833 eligible patients initiated levetiracetam and 52 649 initiated a comparator drug; IRR (95% CI) for ARF for the hd-PS analysis was 1.34 (0.72-2.50) without CCS categories and 1.30 (0.71-2.39) with CCS categories. For January 2008-December 2017 (including ICD coding change), 45 672 eligible patients initiated levetiracetam and 64 664 initiated a comparator drug; IRR (95% CI) for the hd-PS analysis was 1.34 (0.78-2.29) without CCS categories and 1.37 (0.80-2.34) with CCS categories. CONCLUSIONS: Using single-level CCS categories to overcome differences in coding provides consistent results and can be used in studies that use large claims data and hd-PS for adjustment.

Incidence of Acute Renal Failure in Patients Using Levetiracetam Versus Other Antiseizure Medications: A Voluntary Post-Authorization Safety Study.

INTRODUCTION: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs). OBJECTIVE: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs. METHODS: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM® MarketScan® database (USA, January 2008-December 2017). ARF was defined as a diagnosis on inpatient or emergency department claims. We estimated adjusted incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) of ARF in patients initiating levetiracetam versus other ASMs. RESULTS: Overall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17). CONCLUSIONS: The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects.

Health care cost associated with the use of enzyme-inducing and non-enzyme-active antiepileptic drugs in the UK: a long-term retrospective matched cohort study.

BACKGROUND: Some antiepileptic drugs (AEDs) induce expression of hepatic enzymes. This can contribute to comorbidities via interference with metabolic pathways and concomitant drug metabolization, thereby increasing the likelihood of health care interventions. Using medical records, we compared the direct health care cost in patients initiating epilepsy therapy with enzyme-inducing AEDs (EIAEDs) vs non-enzyme-active AEDs (nEAAEDs) over up to 12 years. METHODS: Patients with untreated epilepsy were indexed in the UK Clinical Practice Research Datalink and Hospital Episode Statistics database when prescribed a new EIAED or nEAAED between January 2001 and December 2010. Propensity score matching reduced confounding factors between cohorts. Patients were followed until cohort treatment failure or data cut-off. The primary outcome was the median standardized monthly direct health care cost during follow-up in 2014 £GBP, calculated using published reference costs and compared using a Mann-Whitney U test. RESULTS: The unmatched EIAED cohort (n = 2752) was older (54 vs 46 years), more likely to be male, had more comorbidities, and higher health care resource use/cost during the 1-year pre-index period (median £3014 vs £2516) than the nEAAED cohort (n = 2,137). The most common index EIAED and nEAAED were carbamazepine (63.3%) and lamotrigine (58.0%), respectively. After matching, cohorts had similar features (n = 951 each). Over up to 12 years of follow-up, the median standardized monthly direct health care cost was £229 for the EIAED and £188 for the nEAAED cohorts (p = 0.0091). The median cost was higher for the EIAED cohort in every year of follow-up. In the two cohorts, 25.1% and 20.1% of total mean cost during follow-up was epilepsy-related, with approximately 4.6% and 3.0% for AED acquisition, respectively. The median time to cohort treatment failure was shorter in the matched EIAED cohort (468 vs 1194 days). CONCLUSIONS: Patients in the UK who initiated epilepsy therapy with an EIAED appeared to be at higher risk of complications associated with enzyme induction. In long-term matched cohort analyses, the median total direct health care cost associated with EIAED therapy was higher than with nEAAEDs. Changing current treatment practices could potentially improve patient outcomes and reduce costs.

Temporal trends of main reproductive characteristics in ten urban and rural regions of China: the China Kadoorie biobank study of 300 000 women.

BACKGROUND: Chinese women's reproductive patterns have changed significantly over the past several decades. However, relatively little is known about the pace and characteristics of these changes either overall or by region and socioeconomic status. METHODS: We examined the cross-sectional data from the China Kadoorie Biobank cohort study that recruited 300 000 women born between 1930 and 1974 (mean age: 51 years) from 10 socially diverse urban and rural regions of China. Temporal trends in several self-reported reproductive characteristics, and effect modification of these trends by area and education (as a surrogate for socioeconomic status), were examined. RESULTS: The overall mean age at menarche was 15.4 (standard deviation 1.9) years, but decreased steadily over the 45 birth cohorts from 16.1 to 14.3 years, except for an anomalous increase of ∼1 year for women exposed to the 1958-61 famine in early adolescence. Similarly large changes were seen for other characteristics: mean parity fell (urban: 4.9 to 1.1; rural: 5.9 to 1.4); mean age at first birth increased (urban: 19.0 to 25.9 years; rural: 18.3 to 23.8 years); and birth spacing increased after 1980 to over 5 years. Breastfeeding declined after 1950 in urban and, after 1980, in rural women; and 68% of urban and 48% of rural women experienced a terminated pregnancy. Mean age at menopause increased from 47.9 to 49.3 years. CONCLUSIONS: There have been striking changes in reproductive factors over time and between areas among these Chinese women. Their effects on major chronic diseases should be investigated.

Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology.

Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15-: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = -0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.

Physical activity and sedentary leisure time and their associations with BMI, waist circumference, and percentage body fat in 0.5 million adults: the China Kadoorie Biobank study.

BACKGROUND: Few large studies in China have investigated total physical activity and sedentary leisure time and their associations with adiposity. OBJECTIVE: We investigated determinants of physical activity and sedentary leisure time and their associations with adiposity in China. DESIGN: A total of 466,605 generally healthy participants (age: 30-79 y, 60% female) in the China Kadoorie Biobank were included in this cross-sectional analysis. Self-reported information on a range of activities was collected by interviewer-administered questionnaire. Physical activity was calculated as metabolic equivalent task hours per day (MET-h/d) spent on work, transportation, housework, and nonsedentary recreation. Sedentary leisure time was quantified as hours per day. Adiposity measures included BMI, waist circumference, and percentage body fat (by bioimpedance analysis). Associations were estimated by linear and logistic regression. RESULTS: The mean physical activity was 22 MET-h/d, and the mean sedentary leisure time was 3.0 h/d. For each sex, physical activity was about one-third lower among professionals/administrators than among factory workers, with intermediate levels for other occupational categories. A 1-SD (14 MET-h/d) greater physical activity was associated with a 0.15-unit (95% CI: 0.14, 0.16) lower BMI (in kg/m(2)), a 0.58-cm (95% CI: 0.55, 0.61) smaller waist circumference, and 0.48 (95% CI: 0.45, 0.50) percentage points less body fat. In contrast, a 1-SD (1.5 h/d) greater sedentary leisure time was associated with a 0.19-unit higher BMI (95% CI: 0.18, 0.20), a 0.57-cm larger waist circumference (95% CI: 0.54, 0.59), and 0.44 (95% CI: 0.42, 0.46) percentage points more body fat. For any given physical activity level, greater sedentary leisure time was associated with a greater prevalence of increased BMI, as was lower physical activity for any given sedentary leisure time. CONCLUSIONS: In adult Chinese, physical activity varies substantially by occupation, and lack of physical activity and excess sedentary leisure time are independently and jointly associated with greater adiposity.