Benchmarking Maintenance Therapy Survival in First-Line Platinum-Based Chemotherapy-Treated Patients with Advanced Urothelial Carcinoma Using Simulated Disease Modeling.

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.

Health care resource utilization, quality metrics, and costs of bladder cancer within the Oncology Care Model.

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.

Oncology Simulation Model: A Comprehensive and Innovative Approach to Estimate and Project Prevalence and Survival in Oncology.

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.

Understanding Treatment Patterns and Outcomes among Patients with De Novo Unresectable Locally Advanced or Metastatic Urothelial Cancer: A Population-Level Retrospective Analysis from Alberta, Canada.

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.

The impact of heart failure on patients and caregivers: A qualitative study.

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.

Health State Utilities of Patients with Heart Failure: A Systematic Literature Review.

BACKGROUND AND OBJECTIVES: New treatments and interventions are in development to address clinical needs in heart failure. To support decision making on reimbursement, cost-effectiveness analyses are frequently required. A systematic literature review was conducted to identify and summarize heart failure utility values for use in economic evaluations. METHODS: Databases were searched for articles published until June 2019 that reported health utility values for patients with heart failure. Publications were reviewed with specific attention to study design; reported values were categorized according to the health states, 'chronic heart failure', 'hospitalized', and 'other acute heart failure'. Interquartile limits (25th percentile 'Q1', 75th percentile 'Q3') were calculated for health states and heart failure subgroups where there were sufficient data. RESULTS: The systematic literature review identified 161 publications based on data from 142 studies. Utility values for chronic heart failure were reported by 128 publications; 39 publications published values for hospitalized and three for other acute heart failure. There was substantial heterogeneity in the specifics of the study populations, methods of elicitation, and summary statistics, which is reflected in the wide range of utility values reported. EQ-5D was the most used instrument; the interquartile limit for mean EQ-5D values for chronic heart failure was 0.64-0.72. CONCLUSIONS: There is a wealth of published utility values for heart failure to support economic evaluations. Data are heterogenous owing to specificities of the study population and methodology of utility value elicitation and analysis. Choice of value(s) to support economic models must be carefully justified to ensure a robust economic analysis.

Real-World Analysis of Guideline-Based Therapy After Hospitalization for Heart Failure.

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.

Elevated Heart Rate and Survival in Children With Dilated Cardiomyopathy: A Multicenter Study From the Pediatric Cardiomyopathy Registry.

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.

A Systematic Review of Medical Costs Associated with Heart Failure in the USA (2014-2020).

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.

Correction: Evaluating risk prediction models for adults with heart failure: A systematic literature review.

[This corrects the article DOI: 10.1371/journal.pone.0224135.].

Use of Low-Density Lipoprotein-Lowering Therapies Before and After PCSK9 Inhibitor Initiation.

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.

Evaluating risk prediction models for adults with heart failure: A systematic literature review.

BACKGROUND: The ability to predict risk allows healthcare providers to propose which patients might benefit most from certain therapies, and is relevant to payers' demands to justify clinical and economic value. To understand the robustness of risk prediction models for heart failure (HF), we conducted a systematic literature review to (1) identify HF risk-prediction models, (2) assess statistical approach and extent of validation, (3) identify common variables, and (4) assess risk of bias (ROB). METHODS: Literature databases were searched from March 2013 to May 2018 to identify risk prediction models conducted in an out-of-hospital setting in adults with HF. Distinct risk prediction variables were ranked according to outcomes assessed and incorporation into the studies. ROB was assessed using Prediction model Risk Of Bias ASsessment Tool (PROBAST). RESULTS: Of 4720 non-duplicated citations, 40 risk-prediction publications were deemed relevant. Within the 40 publications, 58 models assessed 55 (co)primary outcomes, including all-cause mortality (n = 17), cardiovascular death (n = 9), HF hospitalizations (n = 15), and composite endpoints (n = 14). Few publications reported detail on handling missing data (n = 11; 28%). The discriminatory ability for predicting all-cause mortality, cardiovascular death, and composite endpoints was generally better than for HF hospitalization. 105 distinct predictor variables were identified. Predictors included in >5 publications were: N-terminal prohormone brain-natriuretic peptide, creatinine, blood urea nitrogen, systolic blood pressure, sodium, NYHA class, left ventricular ejection fraction, heart rate, and characteristics including male sex, diabetes, age, and BMI. Only 11/58 (19%) models had overall low ROB, based on our application of PROBAST. In total, 26/58 (45%) models discussed internal validation, and 14/58 (24%) external validation. CONCLUSIONS: The majority of the 58 identified risk-prediction models for HF present particular concerns according to ROB assessment, mainly due to lack of validation and calibration. The potential utility of novel approaches such as machine learning tools is yet to be determined. REGISTRATION NUMBER: The SLR was registered in Prospero (ID: CRD42018100709).

Economic Evaluations of Pharmacological Treatments in Heart Failure Patients: A Methodological Review with a Focus on Key Model Drivers.

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.

Genetics of heart rate in heart failure patients (GenHRate).

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.

Evaluating Cost-Effectiveness Models for Pharmacologic Interventions in Adults with Heart Failure: A Systematic Literature Review.

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.

A Survey of Women's Awareness of and Reasons for Lack of Postfracture Osteoporotic Care.

OBJECTIVES: To identify women's beliefs and other factors associated with lack of osteoporosis (OP) pharmacotherapy (OP-RX) during the 6 months after a fragility fracture, including the woman's perspective on fracture risk, OP, and treatment. DESIGN: Cross-sectional. SETTING: Group Health Cooperative, a mixed-model delivery system. PARTICIPANTS: Female Group Health Cooperative enrollees aged 55 and older with an OP-related fracture according to diagnostic and procedure codes from January 1, 2013, to March 30, 2014 (N = 985). MEASUREMENTS: OP-RX and participant characteristics were ascertained from electronic health records including medications dispensed. A mailed survey was used to obtain data on health behaviors; OP-related history; concern about, knowledge of, and perceived risk of future fracture; beliefs about OP-RX; sources of information on OP; postfracture discussions with providers; and provider recommendations. RESULTS: The response rate was 73%. Of 634 eligible respondents, 84% did not undergo OP-RX during the 6 months after fracture. Fewer than 20% of women thought that OP caused their fracture, 52% did not think they were at risk of future fracture, and 75% did not think or know whether OP-RX reduces risk of fracture. Knowledge about OP and the benefits of treatment was higher in the 16% of women who underwent OP-RX after their fracture. Women reported low levels of engagement with their healthcare providers regarding OP and fracture risk management. CONCLUSION: These findings suggest low awareness about OP and its contribution to fracture risk, lack of understanding about the benefits of pharmacotherapy, and limited discussion about OP with primary care physicians. Information about individual's beliefs and knowledge gaps can help design targeted patient and provider education to improve treatment rates.

Evidence for Detection Bias by Medication Use in a Cohort Study of Breast Cancer Survivors.

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.

Facility-level CKD-MBD composite score and risk of adverse clinical outcomes among patients on hemodialysis.

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.

Geovariation in Fracture Risk among Patients Receiving Hemodialysis.

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.

Anticholinergic medication use and falls in postmenopausal women: findings from the women's health initiative cohort study.

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.