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Tyler Knight,1 Caroline Schaefer,1 Holly Krasa,2 Dorothee Oberdhan,2 Arlene Chapman,3 Ronald D Perrone4 1Covance Market Access Services Inc., Gaithersburg, MD, 2Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD, 3Emory University, Atlanta, GA, 4Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA Background: Autosomal dominant polycystic kidney disease (ADPKD) results in kidney cyst development and enlargement, resulting in chronic kidney disease (CKD) leading to renal failure. This study sought to determine if ADPKD patients in the early stages of CKD contribute to a sizable economic burden for the US health care system. Methods: This was a retrospective, matched cohort study, reviewing medical resource utilization (MRU) and costs for adults in a US private-payer claims database with a diagnosis code of ADPKD (ICD-9-CM 753.13). ADPKD patients were matched by age grouping (0–17, 18–34, 35–44, 45–54, 55–64, and 65+ years) and sex to controls to understand the burden of ADPKD. Descriptive statistics on 6-month MRU and costs were assessed by CKD stages, dialysis use, or previous renal transplant. Results: The analysis included ADPKD patients in CKD stages 1–5 (n=316 to n=860), dialysis (n=586), and post-transplant (n=615). Mean ages did not differ across CKD stages (range 43–56 years). Men were the majority in the later stages but the minority in the early stages. The proportion of patients with at least one hospitalization increased with CKD stage, (12% to >40% CKD stage 2 to stage 5, dialysis or post-transplant). The majority had at least one hospital outpatient visit and at least one pharmacy claim. Total 6-month per-patient costs were greater among ADPKD patients than in age-matched and sex-matched healthy non-ADPKD controls (P

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium

Leslie Citrome,1 Anna Eramo,2 Clement Francois,2 Ruth Duffy,3 Susan N Legacy,3 Steve J Offord,3 Holly B Krasa,3 Stephen S Johnston,4 Alice Guiraud-Diawara,5 Siddhesh A Kamat,3 Patricia Rohman3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, 2Lundbeck, Deerfield, IL, 3Otsuka America Pharmaceuticals, Princeton, NJ, 4Truven Health Analytics, Bethesda, MD, USA; 5Lundbeck SAS, Issy-les-Moulineaux, France Purpose: Atypical antipsychotics (AAs), an effective treatment for schizophrenia, have a range of pharmacologic properties leading to differences in tolerability as well as heterogeneity in treatment response. Individual patient characteristics must be considered when making treatment choices, especially from an adverse event (AE) or tolerability perspective. Despite the availability of numerous AAs, after appraising patient characteristics at the time of treatment selection, physicians may quickly run out of tolerable treatment options. Patients and methods: AE risk factors, defined as having either a prior history of an AE or a risk factor for that AE, were determined for Medicaid-insured and Commercially insured patients using database analysis. Patients receiving AA treatment between January 1, 2010 and December 31, 2012 defined the index date of first observed AA prescription during this period. Nine AAs were evaluated for association with AE risk factors as informed by drug prescribing information from the different manufacturers and published meta-analyses. The proportion of patients with pre-index AE risk factors prescribed an AA associated with that risk factor was then determined. Results: A high proportion of patients (>80%) were prescribed an AA associated with extrapyramidal symptoms or akathisia despite experiencing extrapyramidal symptoms or akathisia prior to AA treatment initiation. Similar trends were observed among patients with diabetes (>60%) and obesity (>40%). From the nine treatment options available, the number of optimal choices for individual patient segments were limited based on their prior history, including those with cardiometabolic and cardiovascular comorbidities (four); experiencing prolactin elevation-related problems (seven); needing to avoid excessive sedation (four); or at risk of extrapyramidal symptoms or akathisia (two). Options were then further restricted among patients in more than one segment when multiple pre-index AE risk factors were combined. Conclusion: When combining patient risk profile with antipsychotic AE profile, physicians may quickly run out of tolerable treatment options for individual patients, despite the availability of many AAs, suggesting a need for additional treatment options with better tolerability and without compromising efficacy. Keywords: schizophrenia, atypical antipsychotics, tolerability, comorbidities, treatment

Rationale & Objective: Using OVERTURE (NCT01430494) study data on patient-perceived health, health care utilization, and productivity in autosomal dominant polycystic kidney disease (ADPKD), this research was conducted to characterize the burden of illness in patients with ADPKD and assess whether patient-reported outcome (PRO) assessment scores predict clinical and health-economic outcomes., Study Design: Data were analyzed from a prospective, observational study., Setting & Participants: The study cohort comprised 3,409 individuals with ADPKD in 20 countries who were aged 12-78 years and were in chronic kidney disease (CKD) stages G1-G5 and Mayo risk subclasses 1A-1E., Predictors: Scores on PRO instruments, including disease-specific assessments [ADPKD-Impact Scale (ADPKD-IS), and ADPKD-Urinary Impact Scale (ADPKD-UIS)] and generic measures were assessed., Outcomes: Clinical variables [eg, height-adjusted total kidney volume (htTKV), estimated glomerular filtration rate (eGFR), and abdominal girth] and health-economic outcomes were assessed., Analytical Approach: Associations among variables were evaluated using Spearman correlations, logistic regression, and generalized linear mixed effects repeated measures models., Results: Baseline CKD stage and Mayo risk classification showed little correlation with baseline PRO scores; however, scores on disease-specific instruments and measures of physical functioning were worse at more severe CKD stages. PRO scores predicted hospitalizations and sick days at 6-18 months, with strongest associations noted for the ADPKD-IS. PRO scores were not associated with htTKV and eGFR, but worse PRO scores were associated with greater abdominal girth. Poor baseline ADPKD-IS scores were positively associated with occurrence of ADPKD-related symptoms up to 18 months, including kidney pain (OR, 5.30; 95% CI, 2.75-10.24), hematuria (OR, 4.58; 95% CI, 1.99-10.53), and urinary tract infection (OR, 4.41; 95% CI, 1.93-10.11; P  < 0.001 for all)., Limitations: A limitation of the study was the maximum 18 months of follow-up available to assess outcomes., Conclusions: PRO scores predicted clinical and health-economic outcomes, such as hospitalization and absence from work, underscoring the importance of quality of life assessment of individuals with ADPKD., Plain-Language Summary: Patient-reported outcomes (PROs) are increasingly recognized as important parameters for assessing the clinical and humanistic burden of autosomal dominant polycystic kidney disease (ADPKD). We analyzed data from the observational OVERTURE study to better characterize disease impact on quality of life and determine whether patient-perceived burden might predict outcomes. Scores on PRO assessment instruments predicted hospitalizations and sick days at 6-18 months, with associations strongest for the disease-specific ADPKD-Impact Scale. Compared to patients who rated their health-related quality of life as good, those with poor baseline scores were significantly more likely to report ADPKD-related signs and symptoms up to 18 months of follow-up. These findings support using disease-specific PRO assessment instruments to assess and predict the impact of ADPKD., (© 2023 The Authors.)

Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD., Methods: This prospective study enrolled a large international population ( N  = 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity., Results: Most subjects (84.4%) completed ≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up., Conclusion: Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function., (© 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Background: Falls and hip fractures among older people are associated with high morbidity and mortality. Hyponatraemia may be a risk for falls/hip fractures, but the effect of hyponatraemia duration is not well understood., Aims: To evaluate individuals with periods of sub-acute and chronic hyponatraemia on subsequent risk for serious falls and/or hip fractures., Methods: Retrospective cohort study in the period 1 January 1998 to 14 June 2016 within an integrated health system of individuals aged ≥55 years with ≥2 outpatient serum sodium measurements. Hyponatraemia was defined as sodium <135 mEq/L with sub-acute (<30 days) and chronic (≥30 days) analysed as a time-dependent exposure. Multivariable Cox proportional-hazards modelling was used to estimate hazard ratios (HR) for serious falls/hip fractures based on sodium category., Results: Among 1 062 647 individuals totalling 9 762 305 sodium measurements, 96 096 serious falls/hip fracture events occurred. Incidence (per-1000-person-years) of serious falls/hip fractures were 11.5, 27.9 and 19.8 for normonatraemia, sub-acute and chronic hyponatraemia. Any hyponatraemia duration compared to normonatraemia had a serious falls/hip fractures HR (95%CI) of 1.18 (1.15, 1.22), with sub-acute and chronic hyponatraemia having HR of 1.38 (1.33, 1.42) and 0.91 (0.87, 0.95), respectively. Examined separately, the serious falls HR was 1.37 (1.32, 1.42) and 0.92 (0.88, 0.96) in sub-acute and chronic hyponatraemia, respectively. Hip fracture HR were 1.52 (1.42, 1.62) and 1.00 (0.92, 1.08) for sub-acute and chronic hyponatraemia, respectively, compared to normonatraemia., Conclusions: Our findings suggest that early/sub-acute hyponatraemia appears more vulnerable and associated with serious falls/hip fractures. Whether hyponatraemia is a marker of frailty or a modifiable risk factor for falls remains to be determined., (© 2019 Royal Australasian College of Physicians.)

Objective: Patient support programs, such as the ASSURE Program for long-acting injectable aripiprazole, are designed to help support access to medications, including long-acting injectable (LAI) antipsychotics for patients with schizophrenia. This study was conducted to evaluate adherence to long-acting injectable aripiprazole among patients utilizing the program local care centers (LCC)., Methods: Data collected from participating LCC between October 2014 and February 2018 were utilized. Characteristics of patients receiving injections at LCC and participating in additional support services of the program, types of program offering utilized and patient cost share for long-acting injectable aripiprazole were described. Adherence, measured as the proportion of days covered (PDC) during follow-up, was estimated in patients utilizing the LCC for 6 months and 9 months. Patients with PDC ≥80% were considered adherent to treatment., Results: Two hundred and thirty-four patients received at least one injection at participating LCC and enrolled in the patient support program. Mean (SD) age was 37.3 (13.5) years; 60.7% were male; 32.5% were covered by Medicare. In total, 157 and 87 patients were actively utilizing the LCC for at least 6 months and 9 months, respectively. PDC of 97% and 98% were reported among patients with 6 months and 9 months of follow-up, respectively, and patients were considered adherent to long-acting injectable aripiprazole during follow-up., Conclusion: Patients utilizing the LCC demonstrated high medication adherence, suggesting that injection services provided by the centers may reduce barriers to treatment and help patients with schizophrenia remain on LAI antipsychotic treatment.

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by multitudes of expanding renal cysts associated with mononuclear interstitial infiltrates. Monocyte chemotactic protein-1 is produced in the kidneys and excreted in the urine (uMCP1) of these patients in increased amounts. In the TEMPO 3:4 trial, tolvaptan slowed the rate of increase in total kidney volume (TKV) and the rate of decline in estimated glomerular filtration rate (eGFR). In a sub-analysis, we determined whether tolvaptan administration for up to 3 years changed the urinary excretion of MCP-1 referenced to creatinine in 869 treated subjects compared with 438 placebo subjects., Methods: Treatment group differences of uMCP1 at 0.75, 12, 24 and 36 months were evaluated by ANCOVA with factor of treatment and covariate baseline., Results: At baseline, mean uMCP1 was 429 ± 224 pg/mg in the tolvaptan and 434 ± 233 pg/mg in the placebo groups, ∼4-fold greater than normal. Log uMCP1 associated positively with log TKV ( r = 0.2645, P < 0.0001) and negatively with eGFR ( r = -0.1555 P < 0.0001) and fasting urine osmolality ( r = -0.1933, P < 0.0001). Tolvaptan reduced uMCP1 13.8 ± 4.4% (P < 0.0001) below placebo-treated subjects at 24 months and 14.4 ± 3.7% (P < 0.0001) at 36 months, and to the same extent in females and males. The effect of tolvaptan on uMCP1 excretion at 36 months extended across CKD Stage 1 (11.1 ± 6.4%, P = 0.0595), CKD 2 (13.9 ± 5.4%, P = 0.0050) and CKD 3 (21.4 ± 8.0%, P = 0.0020)., Conclusion: Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion of MCP-1 relative to placebo., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Introduction: Dementia is a prevalent condition in older adults associated with decline in cognitive and functional abilities and substantial burden. This study assessed the prevalence and impact of subjective memory impairment in the United States., Methods: The 2011 to 2014 National Health and Nutrition Examination Survey, a population-based, nationally representative survey, was analyzed. Data included medical examinations, self-reported cognitive and functional limitations, and health care utilization over 1 year. Participants were aged ≥65 years and completed both interview and medical examination components. Descriptive analyses of patient characteristics were performed, and complex survey regression models were used to test associations., Results: Of 2431 survey participants included, 53.1% had no memory impairment, 40.1% had early-stage memory impairment, and 6.6% had late-stage memory impairment. In adjusted analyses, late-stage versus no impairment was associated with more functional limitations (odds ratio [OR] = 7.26, P  < .001), greater health care utilization (OR = 2.46, P  < .001), and higher likelihood of seeing a mental health specialist (OR = 3.06, P  = .001)., Discussion: Consistent with previous research, individuals with late-stage memory impairment had significantly greater functional limitations and higher health care utilization versus individuals with early-stage or no memory impairment.

Background: This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia., Study Design: Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study., Setting & Participants: 57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration >120-<135 mEq/L) at 16 sites., Intervention: Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance., Outcomes: Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations., Results: Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P<0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03)., Limitations: There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating., Conclusions: Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Subjects with autosomal dominant polycystic kidney disease (ADPKD) who were taking tolvaptan experienced aminotransferase elevations more frequently than those on placebo in the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) clinical trial., Methods: An independent, blinded, expert Hepatic Adjudication Committee re-examined data from TEMPO 3:4 and its open-label extension TEMPO 4:4, as well as from long-term (>14 months) non-ADPKD tolvaptan trials, using the 5-point Drug-Induced Liver Injury Network classification., Results: In TEMPO 3:4, 1445 subjects were randomized 2:1 (tolvaptan vs. placebo) and 1441 had post-baseline assessments of hepatic injury. Sixteen patients on tolvaptan and one on placebo had significant aminotransferase elevations judged to be at least probably related to study drug. No association with dose or systemic exposure was found. Two of 957 subjects taking tolvaptan (0.2 %) and zero of 484 taking placebo met the definition of a Hy's Law case. One additional Hy's Law case was identified in a TEMPO 4:4 subject who had received placebo in the lead study. The onset of a hepatocellular injury occurred between 3 and 18 months after starting tolvaptan, with gradual resolution over the subsequent 1-4 months. None of the events were associated with liver failure or chronic liver injury/dysfunction. No imbalance in hepatic events was observed between tolvaptan and placebo in lower-dose clinical trials of patients with hyponatremia, heart failure, or cirrhosis., Conclusions: Although hepatocellular injury following long-term tolvaptan treatment in ADPKD subjects was infrequent and reversible, the potential for serious irreversible injury exists. Regular monitoring of transaminase levels is warranted in this patient population.