Search

Objective: First-line (1L) maintenance avelumab prolonged overall survival (OS) in patients with advanced urothelial carcinoma (aUC) in JAVELIN Bladder 100. OS was measured from maintenance initiation in patients with disease control following 1L platinum-based therapy (PBT). The OS impact of maintenance for the 1L PBT-treated population is unknown since it was not measured from 1L initiation, nor can it be benchmarked with other 1L therapies. To characterize the OS impact of maintenance avelumab, we used an oncology simulation model to estimate the OS of maintenance-eligible and -ineligible patients with aUC from 1L PBT initiation., Methods: We developed a simulated cohort of 1L PBT-treated patients with aUC, including those who did and did not receive maintenance avelumab. Eligibility was assessed at 5.6 months post 1L PBT initiation based on the JAVELIN trial design. Among the 1L-treated population, 58% (95% credible interval [CrI] 49-67%) were projected to be eligible (calculated from contemporary phase 3 trials); of those, 85% were assumed to receive maintenance. The model estimated median OS (mOS) among a maintenance-ineligible simulated cohort which when combined with the maintenance-eligible cohort yielded an estimated OS in the overall maintenance- intended population from 1L PBT initiation., Results: Approximately half of the modeled 1L PBT-treated population received maintenance. Estimated mOS was 10.1 months (95% CrI 7.5-13.5) for the maintenance-ineligible cohort, 29.3 months (95% CrI 24.8-33.9) for the maintenance-eligible, received maintenance cohort, and 15.9 months (95% CrI 13.2-19.1) in the overall maintenance-intended, 1L PBT-treated population, including those eligible and ineligible for maintenance., Conclusion: The model shows that maintenance avelumab has a modest impact on OS in the overall 1L PBT-treated population of patients with aUC. While maintenance avelumab improves OS for eligible patients, a large proportion of the maintenance-intended population may not receive maintenance due to ineligibility or physician/patient choice., Competing Interests: MDG is a paid consultant for AbbVie, Aileron Therapeutics, Alligator, Asieris, Astellas, AstraZeneca, Basilea, Bicycle, BioMotiv, Bristol Myers Squibb, Curis, Dendreon, Dracen Pharmaceutical, Dragonfly, EMD Serono, Genentech, Gilead, Fujifilm, GSK, Incyte, Inovio Pharmaceuticals, Janssen, Lilly, Merck, Novartis, Numab Therapeutics, Pfizer, Seagen, Urogen; has equity ownership in Rappta Therapeutics; holds patents/royalties for “Methods and compositions for treating cancer and related methods (20120322792)”; and has received research funding from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech, Janssen, Merck, and Novartis. HSW and ZH are employees of, and own stock in, Seagen. HSW is a former employee of and owns stock in Amgen Inc. At the time of this study MF was an employee of Seagen, and owns stock in Seagen. BB and JT are employees of Curta and paid consultants to Seagen in connection with this project. EL is an employee of Astellas. TP is a paid consultant for Incyte, has received consultancy fees and research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Roche, Incyte, Ipsen Biopharm Limited, Johnson & Johnson, Mash Up Ltd, Merck, MSD, Novartis, Pfizer, and Seagen; and has received travel costs from AstraZeneca, Roche, Ipsen Biopharmaceuticals, MSD, and Pfizer. The authors report no other conflicts of interest in this work., (© 2023 Galsky et al.)

Objectives: New and emerging therapies have significantly changed the bladder cancer (BC) treatment landscape and can potentially affect spending and patient care in CMS' Oncology Care Model (OCM), a service delivery and payment model for voluntarily participating practices. The objectives of this analysis were to estimate health care resource utilization (HCRU) and benchmark spending per OCM episode of BC, and to model spending drivers and quality metrics., Study Design: Retrospective cohort study., Methods: A retrospective cohort study was conducted of OCM episodes triggered by receipt of anticancer therapy among Medicare beneficiaries from 2016 to 2018. Based on this, an average performance estimation was conducted to assess the impact of hypothetical changes in novel therapy use by OCM practices., Results: BC accounted for approximately 3% (n = 60,099) of identified OCM episodes. Relative to low-risk episodes, high-risk episodes were associated with greater HCRU and worse OCM quality metrics. Mean spending per high-risk episode was $37,857 (low-risk episode: $9204), with $11,051 spent on systemic therapies and $7158 on inpatient services. In the estimation, high- and low-risk BC exceeded the spending target by 1.7% and 9.4%, respectively. This did not affect payments to practices and no retrospective payments were necessary., Conclusions: As 3% of OCM episodes were attributed to BC, with only one-third classified as high-risk, controlling expenditure on novel therapies for advanced BC is unlikely to affect overall practice performance. The average performance estimation further emphasized the minimal impact that novel therapy spending in high-risk BC has on OCM payments to practices.

Objective: We demonstrate a new model framework as an innovative approach to more accurately estimate and project prevalence and survival outcomes in oncology., Methods: We developed an oncology simulation model (OSM) framework that offers a customizable, dynamic simulation model to generate population-level, country-specific estimates of prevalence, incidence of patients progressing from earlier stages (progression-based incidence), and survival in oncology. The framework, a continuous dynamic Markov cohort model, was implemented in Microsoft Excel. The simulation runs continuously through a prespecified calendar time range. Time-varying incidence, treatment patterns, treatment rates, and treatment pathways are specified by year to account for guideline-directed changes in standard of care and real-world trends, as well as newly approved clinical treatments. Patient cohorts transition between defined health states, with transitions informed by progression-free survival and overall survival as reported in published literature., Results: Model outputs include point prevalence and period prevalence, with options for highly granular prevalence predictions by disease stage, treatment pathway, or time of diagnosis. As a use case, we leveraged the OSM framework to estimate the prevalence of bladder cancer in the United States., Conclusion: The OSM is a robust model that builds upon existing modeling practices to offer an innovative, transparent approach in estimating prevalence, progression-based incidence, and survival for oncologic conditions. The OSM combines and extends the capabilities of other common health-economic modeling approaches to provide a detailed and comprehensive modeling framework to estimate prevalence in oncology using simulation modeling and to assess the impacts of new treatments on prevalence over time., Competing Interests: BB, JT, and LB are employees of Curta Inc., paid consultants to Seagen Inc. in connection with this study. HSW and ZH are employees and stockholders of Seagen Inc. HSW is also stockholder of Amgen Inc. and Teva Pharmaceuticals. CM is an employee and stockholder of Astellas, Inc. and also a stockholder of Merck and J&J. MDG has served as an advisory board member and consultant for Aileron Therapeutics, Astellas, AstraZeneca, Basiliea, BioMotiv, BMS, Dendreon, Dracen, Dragonfly, EMD Serono, Genentech, GSK, Incyte, Inovio Pharmaceuticals, Janssen, Lilly, Merck, Novartis, Numab, Pfizer, Seagen Inc., and Urogen; has equity ownership in Rappta Therapeutics; holds patents/royalties for “Methods and compositions for treating cancer and related methods (20120322792)”; and has received research funding from AstraZeneca, BMS, Dendreon, Genentech, Janssen, Merck, and Novartis., (© 2022 Bloudek et al.)

Despite a high disease burden, real-world data on treatment patterns in patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) in Canada are limited. This retrospective, longitudinal cohort study describes treatment patterns and survival in a population of patients with de novo unresectable la/mUC from Alberta, Canada, diagnosed between 1 January 2015 and 31 December 2019, followed until mid-2020. The outcomes of interest were systemic therapy treatment patterns and overall survival (OS). Of 206 patients, most (65.0%, n = 134) did not receive any systemic therapies. Of 72 patients (35.0%) who received first-line systemic therapy, the median duration of treatment was 2.8 months (IQR 3.3). Thirty-five patients (48.6% of those who received first-line therapy) received subsequent second-line therapy, for a median of 3.0 months (IQR 3.3). In all patients ( n = 206), the median OS from diagnosis was 5.3 months (95% CI, 4.5-7.0). In patients who received treatment, the median OS from the initiation of first-line and second-line systemic therapy was 9.1 (6.4-11.6) and 4.6 months (3.9-19.2), respectively. The majority of patients did not receive first-line systemic therapy, and, in those who did, survival outcomes were poor. This study highlights the significant unmet need for safe and efficacious therapies for patients with la/mUC in Canada.

Background: Heart failure is rising in prevalence but relatively little is known about the experiences and journey of patients and their caregivers. The goal of this paper is to present the symptom and symptom impact experiences of patients with heart failure and their caregivers., Methods: This was a United States-based study wherein in-person focus groups were conducted. Groups were audio recorded, transcribed and a content-analysis approach was used to analyze the data., Results: Ninety participants (64 patients and 26 caregivers) were included in the study. Most patients were female (52.0%) with mean age 59.3 ± 8 years; 55.6% were New York Heart Association Class II. The most commonly reported symptoms were shortness of breath (81.3%), fatigue/tiredness (76.6%), swelling of legs and ankles (57.8%), and trouble sleeping (50.0%). Patients reported reductions in social/family interactions (67.2%), dietary changes (64.1%), and difficulty walking and climbing stairs (56.3%) as the most common adverse disease impacts. Mental-health sequelae were noted as depression and sadness (43.8%), fear of dying (32.8%), and anxiety (32.8%). Caregivers (mean age 55.5 ± 11.2 years and 52.0% female) discussed 33 daily heart failure impacts, with the top three being reductions in social/family interactions (50.0%); being stressed, worried, and fearful (46.2%); and having to monitor their "patience" level (42.3%)., Conclusions: There are serious unmet needs in HF for both patients and caregivers. More research is needed to better characterize these needs and the impacts of HF along with the development and evaluation of disease management toolkits that can support patients and their caregivers., Competing Interests: The authors have read the journal’s policy and the author’s of this manuscript have the following competing interests: GG, HSW, and SA are paid employees of Amgen Inc. CAM, MA, SGM, and NT are paid employees of Evidera. NRD has received research grants unrelated to this work and consultancy support from Amgen, Boehringer Ingelheim, Cytokinetics, Relypsa, Novartis, and SC Pharmaceuticals unrelated to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: Heart failure presents a growing clinical and economic burden in the USA. Robust cost data on the burden of illness are critical to inform economic evaluations of new therapeutic interventions., Objectives: This systematic literature review of heart failure-related costs in the USA aimed to assess the quality of the published evidence and provide a narrative synthesis of current data., Methods: Four electronic databases (MEDLINE, EMBASE, EconLit, and the Centre for Reviews and Dissemination York Database, including the NHS Economic Evaluation Database and Health Technology Assessment Database) were searched for journal articles published between January 2014 and March 2020. The review, registered with PROSPERO (CRD42019134201), was restricted to cost-of-illness studies in adults with heart failure events in the USA., Results: Eighty-seven studies were included, 41 of which allowed a comparison of cost estimates across studies. The annual median total medical costs for heart failure care were estimated at $24,383 per patient, with heart failure-specific hospitalizations driving costs (median $15,879 per patient). Analyses of subgroups revealed that heart failure-related costs are highly sensitive to individual patient characteristics (such as the presence of comorbidities and age) with large variations even within a subgroup. Additionally, differences in study design and a lack of standardized reporting limited the ability to compare cost estimates. The finding that costs are higher for patients with heart failure with reduced ejection fraction compared with patients with preserved ejection fraction highlights the need for differentiating among different heart failure types., Conclusions: The review underpins the conclusion drawn in earlier reviews, namely that hospitalization costs are the key driver of heart failure-related costs. Analyses of subgroups provide a clearer understanding of sources of heterogeneity in cost data. While current cost estimates provide useful indications of economic burden, understanding the nuances of the data is critical to support its application.

Various decision analytic models exist for evaluating the cost-effectiveness of pharmacological interventions for heart failure (HF). Despite this, studies that explore drivers influencing these modeling approaches remain scarce. Through a systematic review of the literature, the present study sought to identify model drivers that emerge from economic evaluations of HF pharmacological interventions. Among the 72 cost effectiveness papers evaluating HF drug interventions, the most frequently identified, top 5 ranked model drivers impacting the incremental cost-effectiveness ratio (ICER) were cost of treatment and utility, identified in 10% of studies, respectively. Other drivers that emerged as top 5 ranked drivers in > 5% of studies included treatment effect on mortality (or cardiovascular mortality), duration of treatment, and baseline cardiovascular mortality. Model drivers reported at the top of tornado diagrams were treatment effect on mortality or on cardiovascular mortality. Collectively, these observations highlight the key importance of treatment effect in driving cost-effectiveness models for HF.

Background Patients hospitalized with heart failure (HF) with reduced ejection fraction have high risk of rehospitalization or death. Despite guideline recommendations based on high-quality evidence, a substantial proportion of patients with HF with reduced ejection fraction receive suboptimal care and/or do not comply with optimal care following hospitalization. Methods and Results This retrospective observational study identified 17 106 patients with HF with reduced ejection fraction with an incident HF-related hospitalization using the Humana Medicare Advantage database (2008-2016). HF medication classes (beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, or mineralocorticoid receptor antagonists) received in the year after hospitalization were recorded, and categorized by treatment intensity (ie, number of concomitant medication classes received: none [23% of patients; n=3987], monotherapy [22%; n=3777], dual therapy [41%; n=7056], or triple therapy [13%; n=2286]). Compared with no medication, risk of primary outcome (composite of death or rehospitalization) was significantly reduced (hazard ratio [95% CI]) with monotherapy (0.68 [0.64-0.71]), dual therapy (0.56 [0.53-0.59]), and triple therapy (0.45 [0.41-0.50]). Nearly half (46%) of patients who received post-discharge medication had no dose escalation. Overall, 59% of patients had follow-up with a primary care physician within 14 days of discharge, and 23% had follow-up with a cardiologist. Conclusions In real-world clinical practice, increasing treatment intensity reduced risk of death and rehospitalization among patients hospitalized for HF, though the use of guideline-recommended dual and triple HF therapy remained low. There are opportunities to improve post-discharge medical management for patients with HF with reduced ejection fraction such as optimizing dose titration and improving post-discharge follow-up with providers.

Background In adults with heart failure, elevated heart rate is associated with lower survival. We determined whether an elevated heart rate was associated with an increased risk of death or heart transplant in children with dilated cardiomyopathy. Methods and Results The study is an analysis of the Pediatric Cardiomyopathy Registry and includes baseline data, annual follow-up, and censoring events (transplant or death) in 557 children (51% male, median age 1.8 years) with dilated cardiomyopathy diagnosed between 1994 and 2011. An elevated heart rate was defined as 2 or more SDs above the mean heart rate of children, adjusted for age. The primary outcomes were heart transplant and death. Heart rate was elevated in 192 children (34%), who were older (median age, 2.3 versus 0.9 years; P <0.001), more likely to have heart failure symptoms (83% versus 67%; P <0.001), had worse ventricular function (median fractional shortening z score, -9.7 versus -9.1; P =0.02), and were more often receiving anticongestive therapies (96% versus 86%; P <0.001) than were children with a normal heart rate. Controlling for age, ventricular function, and cardiac medications, an elevated heart rate was independently associated with death (adjusted hazard ratio [HR] 2.6; P <0.001) and with death or transplant (adjusted HR 1.5; P =0.01). Conclusions In children with dilated cardiomyopathy, elevated heart rate was associated with an increased risk of death and cardiac transplant. Further study is warranted into the association of elevated heart rate and disease severity in children with dilated cardiomyopathy and as a potential target of therapy.

Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are used to reduce low-density lipoprotein (LDL) cholesterol. PCSK9i use after initiation, as well as persistence with or alterations to other LDL-lowering therapy after PCSK9i initiation, is not well understood. Methods and Results We conducted a retrospective study of alirocumab or evolocumab (PCSK9i) new users from July 2015 to December 2017 in the MarketScan Early View database of US commercial insurance beneficiaries. We determined the prevalence of PCSK9i interruption (≥30-day gap in supply) and LDL-lowering therapy use in the year after PCSK9i initiation. The average age of 6151 patients initiating PCSK9i therapy was 63 years, 44.4% were women, and 76.8% had atherosclerotic cardiovascular disease. Overall, 52.2% (95% CI, 50.8%-53.7%) of patients had an interruption in PCSK9i therapy in the first year after treatment initiation and 62.5% remained on PCSK9i therapy at 1-year postinitiation. Also, 27.7% of patients were taking a statin at the time of PCSK9i initiation, with only 22.4% on statin therapy at 1 year after PCSK9i initiation. Ezetimibe use decreased from 20.9% at the time of PCSK9i initiation to 12.0% a year later. By 1 year after PCSK9i initiation, 44.0% of patients had experienced an interruption in all LDL-lowering therapies, and 26.6% were no longer on any LDL-lowering therapies. Conclusions After PCSK9i initiation, statins were often discontinued, whereas more than half of patients experienced an interruption in PCSK9i therapy. These results suggest that many new PCSK9i users may remain at high risk for cardiovascular events because of interruptions in LDL-lowering therapy.

Background: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF., Methods: Patients who met Framingham criteria for HF and had an ejection fraction < 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant "hits" (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX)., Results: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 × 10 -8 ). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population., Conclusions: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts.

Background: Heart failure (HF) is a well-recognized public health concern and imposes high economic and societal costs. Decision analytic models exist for evaluating the economic ramifications associated with HF. Despite this, studies that appraise these modelling approaches for augmenting best-practice decisions remain scarce., Objective: Our objective was to conduct a systematic literature review (SLR) of published economic models for the management of HF and describe their general and methodological features., Methods: This SLR employed a combination of relevant search terms associated with HF, which were used in a number of databases, including MEDLINE, Embase, the National Health Service Economic Evaluation Database, Cost-Effectiveness Analysis Registry, ScHARR Health Utilities Database and Cochrane Library Database. A number of model features (i.e. model structure, specification, outcomes assessed, scenario and sensitivity analysis, key model drivers) were extracted and subsequently summarized., Results: Of 64 publications retained, a selection of modelling approaches were identified, including Markov (n = 28), trial-based analytic (n = 22), discrete-event simulation (n = 6), survival analytic (n = 7) and decision-tree modelling (n = 1) approaches. The bulk of publications employed either a cost-utility (n = 27) or cost-effectiveness (n = 36) analysis and evaluated more than one study outcome, which typically included overall costs (n = 59), incremental cost-effectiveness ratios (n = 55), life-years gained (n = 48) and willingness-to-pay thresholds (n = 37). Most publications focused on patients with chronic HF (n = 40) and used New York Heart Association (NYHA) disease classifications to categorize patients and determine disease severity. Few (n = 19) publications documented the use of hospitalization states for modelling patient outcomes and associated costs. A quality assessment of the included publications revealed most articles demonstrated reasonable methodological value., Conclusions: We identified numerous decision analytic modelling approaches for evaluating the cost effectiveness of pharmacologic treatments in HF. A Markov cohort model approach was most commonly used, and most models relied on NYHA classes as a proxy of HF severity, disease progression and prognosis.

In previous studies, we found modestly decreased and increased risks of second breast cancer events with the use of statins and antibiotics, respectively, after adjustment for surveillance mammography. We evaluated detection bias by comparing receipt of surveillance mammography among users of these 2 disparate classes of medication. Adult women diagnosed with early-stage breast cancer during 1990-2008 (n = 3,965) while enrolled in an integrated health-care plan (Group Health Cooperative; Washington State) were followed for up to 10 years in the Commonly Used Medications and Breast Cancer Outcomes (COMBO) Study. Categories of antibiotic use included infrequent (1-3 dispensings/12 months) and frequent (≥4 dispensings/12 months) use, and categories of statin use included less adherent (1 dispensing/6 months) and adherent (≥2 dispensings/6 months). We examined associations between medication use and surveillance mammography using multivariable generalized estimating equations and evaluated the impact of adjusting for surveillance within Cox proportional hazard models. Frequent antibiotic users were less likely to receive surveillance mammography (odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.82, 0.99) than were nonusers; no association was found among infrequent users (OR = 0.96, 95% CI: 0.90, 1.03). Adherent statin use was associated with more surveillance compared with nonuse (OR = 1.11, 95% CI: 1.01, 1.25), but less adherent statin use was not (OR = 1.03, 95% CI: 0.81, 1.31). No difference in associations between medications of interest and second breast cancer events was observed when surveillance was removed from otherwise adjusted models. The influence of detection bias by medication use warrants further exploration., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients receiving hemodialysis with values outside of target levels for parathyroid hormone (PTH: 150-600 pg/mL), calcium (Ca: 8.4-10.2 mg/dL), and phosphate (P: 3.5-5.5 mg/dL) are at elevated morbidity and mortality risk. We examined whether patients receiving care in dialysis facilities where greater proportions of patients have at least two values out of target have a higher risk of adverse clinical outcomes., Methods: The study cohort consisted of 39,085 prevalent hemodialysis patients in 1298 DaVita dialysis facilities as of September 1, 2009, followed from January 1, 2010, until an outcome, a censoring event, or December 31, 2010. We determined the quintile of the distribution across facilities of the proportion of patients with at least two of three parameters out of, or above, target over a 4-month baseline period. The primary composite outcome was cardiovascular hospitalization or death. Secondary outcomes included death, cardiovascular hospitalization, and parathyroidectomy. Poisson regression models were used to estimate the association of facility quintile with outcomes., Results: Facility quintile was associated with a 7 % increased risk of cardiovascular hospitalization or death (quintile 5 versus 1, RR 1.07, 95 % CI 1.01-1.13) using the out-of-target measure of exposure and a 12 % increased risk (RR 1.12, 95 % CI 1.06-1.19) using the above-target measure. No association was seen for death using either measure. Patients in facility quintiles 3-5 (versus 1) were at increased parathyroidectomy risk (RR ranged from 2.05, 95 % CI 1.10-3.82, for quintile 3 to 2.73, 95 % CI 1.50-4.98, for quintile 5)., Conclusions: Facility level analysis of a large prevalent sample of US patients on hemodialysis demonstrates that patients in facilities with the least control of PTH, Ca, and P had the greatest risk of parathyroidectomy or the combination of cardiovascular hospitalization or death.

Background and Objectives: Fractures are a major source of morbidity and mortality in patients receiving dialysis. We sought to determine whether rates of fractures and tendon ruptures vary geographically., Design, Setting, Participants, & Measurements: Data from the US Renal Data System were used to create four yearly cohorts, 2007-2010, including all eligible prevalent patients on hemodialysis in the United States on January 1 of each year. A secondary analysis comprising patients in a large dialysis organization conducted over the same period permitted inclusion of patient-level markers of mineral metabolism. Patients were grouped into 10 regions designated by the Centers for Medicare and Medicaid Services and divided by latitude into one of three bands: south, <35°; middle, 35° to <40°; and north, ≥40°. Poisson regression was used to calculate unadjusted and adjusted region-level rate ratios for events., Results: Overall, 327,615 patients on hemodialysis were included. Mean (SD) age was 61.8 (15.0) years old, 52.7% were white, and 55.0% were men. During 716,962 person-years of follow-up, 44,014 fractures and tendon ruptures occurred, the latter being only 0.3% of overall events. Event rates ranged from 5.36 to 7.83 per 100 person-years, a 1.5-fold rate difference across regions. Unadjusted region-level rate ratios varied from 0.83 (95% confidence interval, 0.81 to 0.85) to 1.20 (95% confidence interval, 1.18 to 1.23), a 1.45-fold rate difference. After adjustment for a wide range of case mix variables, a 1.33-fold variation in rates remained. Rates were higher in north and middle bands than the south (north rate ratio, 1.18; 95% confidence interval, 1.13 to 1.23; middle rate ratio, 1.13; 95% confidence interval, 1.10 to 1.17). Latitude explained 11% of variation, independent of region. A complementary analysis of 87,013 patients from a large dialysis organization further adjusted for circulating mineral metabolic parameters and protein energy wasting yielded similar results., Conclusions: Rates of fractures vary geographically in the United States dialysis population, even after adjustment for known patient characteristics. Latitude seems to contribute to this phenomenon, but additional analyses exploring whether other factors might influence variation are warranted., (Copyright © 2016 by the American Society of Nephrology.)

Background: Results from studies assessing the association between anticholinergic use and falls are mixed, and prior studies are limited in their ability to control for important potential confounders. Thus, we sought to examine the association between anticholinergic medication use, including over-the-counter medications, and recurrent falls in community-dwelling older women., Methods: We analyzed data from a prospective cohort study of women aged 65 to 79 years from the Women's Health Initiative Observational Study and Clinical Trials. Women were recruited between 1993 and 1998, and analyses included 61,451 women with complete information. Medications with moderate or strong anticholinergic effects were ascertained directly from drug containers during face-to-face interviews. The main outcome measure was recurrent falls (≥2 falls in previous year), which was determined from self-report within 1.5 years subsequent to the medication assessment., Results: At baseline, 11.3 % were using an anticholinergic medication, of which antihistamines (commonly available over-the-counter) were the most common medication class (received by 45.2 % of individuals on anticholinergic medication). Using multivariable GEE models and controlling for potential confounders, the adjusted odds ratio for anticholinergic medication use was 1.51 (95 % CI, 1.43-1.60) for recurrent falls. Participants using multiple anticholinergic medications had a 100 % increase in likelihood of recurrent falls (adjusted odds ratio 2.00, 95 % CI 1.73-2.32). Results were robust to sensitivity analysis., Conclusions: Anticholinergic medication use was associated with increased risk for recurrent falls. Our findings reinforce judicious use of anticholinergic medications in older women. Public health efforts should emphasize educating older women regarding the risk of using over-the-counter anticholinergics, such as first-generation antihistamines.

Background: Anticholinergic medication use has been associated with several negative health outcomes in older adults, but little is known about its risk for fractures., Objective: To examine the association between anticholinergic medication use and fracture outcomes in community-dwelling postmenopausal women., Methods: Utilizing a prospective cohort design, we examined data collected from 137,408 women aged 50-79 years from the Women's Health Initiative observational study and clinical trials not reporting hip fracture at baseline. Medications with moderate or strong anticholinergic effects were identified directly from drug containers during in-person interviews. The main outcome was fractures (hip, lower arm/wrist and total fractures). We performed multivariable Cox proportional hazard survival modelling to assess the association between anticholinergic use and the risk of fractures., Results: At baseline, 10.6% of the women were using an anticholinergic medication, of which antihistamines were the most common medication class (48.4%). The multivariable-adjusted hazard ratios for anticholinergic medication use were 1.08 (95% confidence interval [CI] 0.89-1.30) for hip fracture, 1.01 (95% CI 0.91-1.13) for lower arm/wrist fracture and 1.03 (95% CI 0.98-1.09) for total fractures. We observed no association according to subclass or count of anticholinergic medications, or trends between the duration of anticholinergic use and any of the fracture outcomes., Conclusion: Anticholinergic medication use was not associated with an increased risk of fractures among community-dwelling women. Future research should make efforts to capture over-the-counter medication use and the cumulative anticholinergic burden in relation to important health outcomes for older adults.

Background: Computerized provider order entry (CPOE) is the process of entering physician orders directly into an electronic health record. Although CPOE has been shown to improve medication safety and reduce health care costs, these improvements have been demonstrated largely in the inpatient setting; the cost-effectiveness in the ambulatory setting remains uncertain., Objective: The objective was to estimate the cost-effectiveness of CPOE in reducing medication errors and adverse drug events (ADEs) in the ambulatory setting., Methods: We created a decision-analytic model to estimate the cost-effectiveness of CPOE in a midsized (400 providers) multidisciplinary medical group over a 5-year time horizon- 2010 to 2014-the time frame during which health systems are implementing CPOE to meet Meaningful Use criteria. We adopted the medical group's perspective and utilized their costs, changes in efficiency, and actual number of medication errors and ADEs. One-way and probabilistic sensitivity analyses were conducted. Scenario analyses were explored., Results: In the base case, CPOE dominated paper prescribing, that is, CPOE cost $18 million less than paper prescribing, and was associated with 1.5 million and 14,500 fewer medication errors and ADEs, respectively, over 5 years. In the scenario that reflected a practice group of five providers, CPOE cost $265,000 less than paper prescribing, was associated with 3875 and 39 fewer medication errors and ADEs, respectively, over 5 years, and was dominant in 80% of the simulations., Conclusions: Our model suggests that the adoption of CPOE in the ambulatory setting provides excellent value for the investment, and is a cost-effective strategy to improve medication safety over a wide range of practice sizes., (Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Breast cancer tends to occur in an older age group of women also burdened with comorbidities such as cardiovascular disease (CVD). Numerous medications used to manage CVD (e.g., statins and antihypertensives) are hypothesized to alter breast cancer risk, but there are few studies on breast cancer outcomes. The COmmonly used Medications and Breast Cancer Outcomes (COMBO) cohort was developed to study how medications and co-morbidities influence breast cancer prognosis. Cohort study among adult women, diagnosed with incident early stage breast cancer, and enrolled in an integrated health plan. Data sources included health plan administrative databases, Surveillance, Epidemiology, and End Results tumor registry, and medical records. Statins, angiotensin-converting enzyme inhibitors (ACEI), beta blockers (BB), calcium blockers, and diuretics were the exposures of interest. The outcome was second breast cancer events (SBCE) defined as recurrence or second primary breast cancer. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for SBCE, and components of SBCE. 4,216 women were followed for a median of 6.3 years, and 13.2 % experienced a SBCE (first of: n = 415 recurrences and n = 143 s primary breast cancers). Compared to non-users, we observed an increased risk of second primary breast cancer with ACEI use (HR = 1.66; 95 % CI, 1.06-2.58) and an increased risk of recurrence with BB use (HR = 1.29; 95 % CI, 1.01-1.64). There was suggestion of a reduced risk of SBCE with statin use (HR = 0.82; 95 % CI, 0.62-1.08) and second primary breast cancer with BB use (HR = 0.77; 95 % CI, 0.50-1.19). No differences in outcomes were observed by duration of medication use. A majority of CVD medications evaluated in this study appear safe with respect to SBCE, but ACEI and BB use warrant further evaluation. The study presented is one example of the questions that can be addressed using the COMBO cohort.

Clinical practice guidelines recommend yearly surveillance mammography for breast cancer survivors, yet many women do not receive this service. The objective of this study was to evaluate factors related to long-term surveillance mammography adherence among breast cancer survivors. We conducted a retrospective cohort study among women ≥ 18 years, diagnosed with incident stage I or II breast cancer between 1990 and 2008. We used medical record and administrative health plan data to ascertain covariates and receipt of surveillance mammography for up to 10 years after completing breast cancer treatment. Surveillance included post-diagnosis screening exams among asymptomatic women. We used multivariable repeated measures generalized estimating equation regression models to estimate odds ratios and robust 95 % confidence intervals to examine factors related to the annual receipt of surveillance mammography. The analysis included 3,965 women followed for a median of six surveillance years; 79 % received surveillance mammograms in year 1 but decreased to 63 % in year 10. In multivariable analyses, women, who were < 40 years or 80+ years of age (compared to 50-59 years), current smokers, had greater comorbidity, were diagnosed more recently, had stage II cancer, or were treated with mastectomy or breast conserving surgery without radiation, were less likely than other women to receive surveillance mammography. Women with outpatient visits during the year to primary care providers, oncologists, or both were more likely to undergo surveillance. In this large cohort study of women diagnosed with early-stage invasive breast cancer, we found that important subgroups of women are at high risk for non-adherence to surveillance recommendations, even among younger breast cancer survivors. Efforts should be undertaken to actively engage breast cancer survivors in managing long-term surveillance care.

Studies of the effects of exposures after cancer diagnosis on cancer recurrence and survival can provide important information to the growing group of cancer survivors. Observational studies that address this issue generally fall into one of two categories: 1) those using health plan automated data that contain "continuous" information on exposures, such as studies that use pharmacy records; and 2) survey or interview studies that collect information directly from patients once or periodically postdiagnosis. Reverse causation, confounding, selection bias, and information bias are common in observational studies of cancer outcomes in relation to exposures after cancer diagnosis. We describe these biases, focusing on sources of bias specific to these types of studies, and we discuss approaches for reducing them. Attention to known challenges in epidemiologic research is critical for the validity of studies of postdiagnosis exposures and cancer outcomes.

Background: Antibiotic use may be associated with higher breast cancer risk and breast cancer mortality, but no study has evaluated the relation between antibiotic use and second breast cancer events (SBCE)., Methods: We conducted a retrospective cohort study among women ≥18 years, diagnosed with incident stage I/II breast cancer during 1990-2008. Antibiotic use and covariates were obtained from health plan administrative databases and medical record review. Frequent antibiotic use was defined as ≥4 antibiotic dispensings in any moving 12-month period after diagnosis. Our outcome was SBCE defined as recurrence or second primary breast cancer. We used multivariable Cox proportional hazards models to estimate HR and 95% confidence intervals (CI), accounting for competing risks., Results: A total of 4,216 women were followed for a median of 6.7 years. Forty percent were frequent antibiotic users and 558 (13%) had an SBCE. Results are suggestive of a modest increased risk of SBCE (HR, 1.15; 95% CI, 0.88-1.50) among frequent antibiotic users compared with nonusers. Any potential increased risk was not supported when we evaluated recent use and past use. We observed no dose-response trends for SBCE with increasing duration of antibiotic use nor did we find evidence for altered SBCE risk in the antibiotic classes studied., Conclusions: Frequent antibiotic use may be associated with modestly elevated risk of SBCEs, but the association was not significant., Impact: Additional investigation by antibiotic class and underlying indication are important next steps given the high prevalence of frequent antibiotic use and growing number of breast cancer survivors.