Sex Differences in Diagnosis and Treatment Timing of Comorbid Depression/Anxiety and Disease Subtypes in Patients With ADHD: A Database Study.

OBJECTIVE: Our study examined the impact of sex, ADHD subtype, and comorbid illnesses (depression/anxiety) on the timing of diagnosis and treatment for ADHD. METHOD: To analyze ADHD patients, four health databases were used to assess subtype, comorbid mood, and antidepressant or anxiolytic drug exposure. Analyses were stratified by sex and age. Standardized mean differences measured intergroup differences. RESULTS: Females with ADHD were identified at older ages and had higher rates of depression and anxiety diagnoses and treatments before and after their initial ADHD diagnosis. Predominantly inattentive ADHD patients were diagnosed later and more likely to receive mood disorder diagnosis and treatment than hyperactive impulsive ADHD patients. CONCLUSIONS: Results suggest a more complex ADHD presentation in females, potentially causing late diagnosis and delayed treatment.

Research Protocol for an Observational Health Data Analysis on the Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in "real-life" patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Cardiovascular outcomes among patients with castration-resistant prostate cancer: A comparative safety study using US administrative claims data.

BACKGROUND: Cardiovascular conditions are the most prevalent comorbidity among patients with prostate cancer, regardless of treatment. Additionally, cardiovascular risk has been shown to increase following exposure to certain treatments for advanced prostate cancer. There is conflicting evidence on risk of overall and specific cardiovascular outcomes among men treated for metastatic castrate resistant prostate cancer (CRPC). We, therefore, sought to compare incidence of serious cardiovascular events among CRPC patients treated with abiraterone acetate plus predniso(lo)ne (AAP) and enzalutamide (ENZ), the two most widely used CRPC therapies. METHODS: Using US administrative claims data, we selected CRPC patients newly exposed to either treatment after August 31, 2012, with prior androgen deprivation therapy (ADT). We assessed incidence of hospitalization for heart failure (HHF), ischemic stroke, and acute myocardial infarction (AMI) during the period 30-days after AAP or ENZ initiation to discontinuation, outcome occurrence, death, or disenrollment. We matched treatment groups on propensity-scores (PSs) to control for observed confounding to estimate the average treatment effect among the treated (AAP) using conditional Cox proportional hazards models. To account for residual bias, we calibrated our estimates against a distribution of effect estimates from 124 negative-control outcomes. RESULTS: The HHF analysis included 2322 (45.1%) AAP initiators and 2827 (54.9%) ENZ initiators. In this analysis, the median follow-up times among AAP and ENZ initiators (after PS matching) were 144 and 122 days, respectively. The empirically calibrated hazard ratio (HR) estimate for HHF was 2.56 (95% confidence interval [CI]: 1.32, 4.94). Corresponding HRs for AMI and ischemic stroke were 1.94 (95% CI: 0.90, 4.18) and 1.25 (95% CI: 0.54, 2.85), respectively. CONCLUSIONS: Our study sought to quantify risk of HHF, AMI and ischemic stroke among CRPC patients initiating AAP relative to ENZ within a national administrative claims database. Increased risk for HHF among AAP compared to ENZ users was observed. The difference in myocardial infarction did not attain statistical significance after controlling for residual bias, and no differences were noted in ischemic stroke between the two treatments. These findings confirm labeled warnings and precautions for AAP for HHF and contribute to the comparative real-world evidence on AAP relative to ENZ.

Reproducible variability: assessing investigator discordance across 9 research teams attempting to reproduce the same observational study.

OBJECTIVE: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics. MATERIALS AND METHODS: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics. RESULTS: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5. CONCLUSIONS: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices.

Comparing broad and narrow phenotype algorithms: differences in performance characteristics and immortal time incurred.

Introduction: When developing phenotype algorithms for observational research, there is usually a trade-off between definitions that are sensitive or specific. The objective of this study was to estimate the performance characteristics of phenotype algorithms designed for increasing specificity and to estimate the immortal time associated with each algorithm. Materials and methods: We examined algorithms for 11 chronic health conditions. The analyses were from data from five databases. For each health condition, we created five algorithms to examine performance (sensitivity and positive predictive value (PPV)) differences: one broad algorithm using a single code for the health condition and four narrow algorithms where a second diagnosis code was required 1-30 days, 1-90 days, 1-365 days, or 1- all days in a subject's continuous observation period after the first code. We also examined the proportion of immortal time relative to time-at-risk (TAR) for four outcomes. The TAR's were: 0-30 days after the first condition occurrence (the index date), 0-90 days post-index, 0-365 days post-index, and 0-1,095 days post-index. Performance of algorithms for chronic health conditions was estimated using PheValuator (V2.1.4) from the OHDSI toolstack. Immortal time was calculated as the time from the index date until the first of the following: 1) the outcome; 2) the end of the outcome TAR; 3) the occurrence of the second code for the chronic health condition. Results: In the first analysis, the narrow phenotype algorithms, i.e., those requiring a second condition code, produced higher estimates for PPV and lower estimates for sensitivity compared to the single code algorithm. In all conditions, increasing the time to the required second code increased the sensitivity of the algorithm. In the second analysis, the amount of immortal time increased as the window used to identify the second diagnosis code increased. The proportion of TAR that was immortal was highest in the 30 days TAR analyses compared to the 1,095 days TAR analyses. Conclusion: Attempting to increase the specificity of a health condition algorithm by adding a second code is a potentially valid approach to increase specificity, albeit at the cost of incurring immortal time.

International cohort study indicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients.

Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale healthcare databases to generate comprehensive evidence in a transparent and reproducible manner. Methods: In this international cohort study, we deployed electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We assessed association between alpha-1 blocker use and risks of three COVID-19 outcomes-diagnosis, hospitalization, and hospitalization requiring intensive services-using a prevalent-user active-comparator design. We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We pooled database-specific estimates through random effects meta-analysis. Results: Our study overall included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH medications. We observed no significant difference in their risks for any of the COVID-19 outcomes, with our meta-analytic HR estimates being 1.02 (95% CI: 0.92-1.13) for diagnosis, 1.00 (95% CI: 0.89-1.13) for hospitalization, and 1.15 (95% CI: 0.71-1.88) for hospitalization requiring intensive services. Conclusion: We found no evidence of the hypothesized reduction in risks of the COVID-19 outcomes from the prevalent-use of alpha-1 blockers-further research is needed to identify effective therapies for this novel disease.

Alpha-1 blockers and susceptibility to COVID-19 in benign prostate hyperplasia patients : an international cohort study.

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.

Propensity score trimming mitigates bias due to covariate measurement error in inverse probability of treatment weighted analyses: A plasmode simulation.

BACKGROUND: Inverse probability of treatment weighting (IPTW) may be biased by influential observations, which can occur from misclassification of strong exposure predictors. METHODS: We evaluated bias and precision of IPTW estimators in the presence of a misclassified confounder and assessed the effect of propensity score (PS) trimming. We generated 1000 plasmode cohorts of size N = 10 000, sampled with replacement from 6063 NHANES respondents (1999-2014) age 40 to 79 with labs and no statin use. We simulated statin exposure as a function of demographics and CVD risk factors; and outcomes as a function of 10-year CVD risk score and statin exposure (rate ratio [RR] = 0.5). For 5% of the people in selected populations (eg, all patients, exposed, those with outcomes), we randomly misclassified a confounder that strongly predicted exposure. We fit PS models and estimated RRs using IPTW and 1:1 PS matching, with and without asymmetric trimming. RESULTS: IPTW bias was substantial when misclassification was differential by outcome (RR range: 0.38-0.63) and otherwise minimal (RR range: 0.51-0.53). However, trimming reduced bias for IPTW, nearly eliminating it at 5% trimming (RR range: 0.49-0.52). In one scenario, when the confounder was misclassified for 5% of those with outcomes (0.3% of cohort), untrimmed IPTW was more biased and less precise (RR = 0.37 [SE(logRR) = 0.21]) than matching (RR = 0.50 [SE(logRR) = 0.13]). After 1% trimming, IPTW estimates were unbiased and more precise (RR = 0.49 [SE(logRR) = 0.12]) than matching (RR = 0.51 [SE(logRR) = 0.14]). CONCLUSIONS: Differential misclassification of a strong predictor of exposure resulted in biased and imprecise IPTW estimates. Asymmetric trimming reduced bias, with more precise estimates than matching.

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension. METHODS: In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296. FINDINGS: Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of >40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons. INTERPRETATION: No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19. FUNDING: Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

BACKGROUND: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. METHODS: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. FINDINGS: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). INTERPRETATION: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study.

INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results. METHODS: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) use to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments. RESULTS: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug- classes for COVID-19 hospitalization or pneumonia risk across all comparisons. CONCLUSION: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

"A secret club": focus groups about women's toileting behaviors.

BACKGROUND: Understanding reasons for and impact of women's toileting behaviors on bladder health is important to prevent and manage urinary incontinence (UI) and overactive bladder (OAB). METHODS: Women, regardless of urinary incontinence (UI) and overactive bladder (OAB) status, were recruited in Pennsylvania and North Carolina. Focus groups were conducted by trained female moderators and sessions were audiotaped. Participants completed an anonymous questionnaire containing validated items to determine the presence of UI and OAB. Audiotapes were transcribed and content was analyzed by two investigators to identify themes. RESULTS: Twenty-four women participated (mean age 68 ± 13.4 years); most had UI (75%) or OAB (87.5%). Many women had difficulty in describing bladder health, and talked about bladder function, diseases or conditions, and control over the bladder. Four themes about toileting emerged: 1) cues/triggers/alerts women used to find and use toilets, 2) toilet cleanliness away from and at home, 3) toileting as a nuisance, and 4) situational awareness. Women described internal (e.g., sensation of heaviness) and external cues/triggers/alerts (e.g., walking by restrooms), and the trade-off between their concerns about public toilet cleanliness and the need to urinate. Some women expressed being irritated or annoyed about having to stop activities to urinate. Most women reported sitting on their home toilets, whereas, many hovered or stood over the toilet in public places. CONCLUSIONS: The information gained from this study will facilitate the development of relevant public health messaging and interventions to raise public awareness about UI, OAB, and bladder health with the aim to encourage women to seek help when symptoms are present.

Classifying medical histories in US Medicare beneficiaries using fixed vs all-available look-back approaches.

PURPOSE: Evaluate use of fixed and all-available look-backs to identify eligibility criteria and confounders among Medicare beneficiaries. METHODS: We identified outpatient visits (2007-2012) with recently documented (≤180 days) cardiovascular risk and classified patients according to whether the exposure (statin) was initiated within 14 days. We selected each beneficiary's first eligible visit (in each treatment group) that met criteria during the respective look-backs: continuous enrollment (1 or 3 years for fixed look-back; 180 days for all-available), no cancer history, and no statin claims. We estimated crude and standardized mortality ratio weighted hazard ratios (HRs) for the effect of statin initiation on incident 6-month cancer (a known null effect) and 2-year mortality, separately, adjusting for covariates assessed by using each look-back. RESULTS: Analyzing short-term cancer, the estimated HR from the all-available approach (HR = 0.90, 95% CI: 0.83, 0.98) was less biased than the 1-year look-back (HR = 0.79, 95% CI: 0.73, 0.84), which included beneficiaries with prevalent cancer. The 3-year look-back (HR = 1.05, 95% CI: 0.90, 1.21) was somewhat less biased than the all-available estimate but less precise due the exclusion of a large proportion of observations without sufficient continuous enrollment (62.0% and 59.9% of initiators and non-initiators, respectively). All approaches produced similar estimates of the effect on all-cause mortality. Alternative look-backs did not differ in their ability to control confounding. CONCLUSIONS: The all-available look-back performed nearly as well as the 3-year fixed, which produced the least biased point estimate. If 3-year look-backs are infeasible (eg, due to power/sample), all-available look-backs may be preferable to short (1-year) fixed look-backs.

Medication Use in Women and Men With Sudden Unexpected Death.

BACKGROUND: In Wake County, NC, sudden unexpected death accounts for 10% to 15% of all natural deaths in individuals 18 to 64 years old. Medications such as aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and ß-blockers are recommended in guidelines to reduce cardiovascular events and even sudden death (ß-blockers). However, guidelines are often underpracticed, even in high-risk patients, with noted disparities in women. OBJECTIVE: We assessed the relation between prescription of evidence-based medications and sudden unexpected death in Wake County, NC. METHODS: We analyzed 399 cases of sudden unexpected death for the time period March 1, 2013 to February 28, 2015 in Wake County, NC. Medications were assessed from available medical examiner reports and medical records and grouped using the third level of the Anatomical Therapeutic Chemical Classification System (ATC) codes. This study was reviewed and exempt by the University of North Carolina's institutional review board. RESULTS: Among 126 female and 273 male victims, women were prescribed more medications overall than men (6.5 vs 4.3, P = 0.001); however, the use of guideline-directed therapies was not different between genders in the chronic conditions associated with sudden death. Overall, there was remarkably low use of evidence-based medications. CONCLUSIONS: Our findings highlight the need to improve prescribing of evidence-based medications and to further explore the relationship between undertreatment and sudden unexpected death.

Bias from restricting to live births when estimating effects of prescription drug use on pregnancy complications: A simulation.

PURPOSE: Administrative claim databases are increasingly being used to study the safety of medication exposures during pregnancy. These studies are restricted to live births due to a reliance on algorithms for estimating gestational age that are based on codes associated with live delivery. Conditioning on live birth may induce selection bias when studying the effect of a drug on a pregnancy complication if fetal death is a competing risk for the complication or is caused by the complication. METHODS: We simulated a population of 100,000 pregnancies and estimated the impact of selection bias on relative estimates for the effect of antidepressant exposure on the outcome of preeclampsia. We assumed that the exposure, outcome, and covariates increased the risk of fetal loss. RESULTS: A downward bias in the risk ratio was consistently observed when conditioning on live births. When an unmeasured covariate was assumed to be a common cause of fetal death, antidepressant use, and preeclampsia, the direction of bias varied depending on the strength of the confounding relationship coupled with the selection bias. Despite the very low prevalence of stillbirth, the strength of the relationship between antidepressant use and stillbirth had a substantial impact on bias. CONCLUSIONS: Conditioning on live birth can be problematic when studying pregnancy complications. Simple quantitative selection bias analysis in populations restricted to live births may not fully account for selection bias.

Measurement error and misclassification in electronic medical records: methods to mitigate bias.

PURPOSE OF REVIEW: We sought to: 1) examine common sources of measurement error in research using data from electronic medical records (EMR), 2) discuss methods to assess the extent and type of measurement error, and 3) describe recent developments in methods to address this source of bias. RECENT FINDINGS: We identified eight sources of measurement error frequently encountered in EMR studies, the most prominent being that EMR data usually reflect only the health services and medications delivered within the specific health facility/system contributing to the EMR data. Methods for assessing measurement error in EMR data usually require gold standard or validation data, which may be possible using data linkage. Recent methodological developments to address the impact of measurement error in EMR analyses were particularly rich in the multiple imputation literature. SUMMARY: Presently, sources of measurement error impacting EMR studies are still being elucidated, as are methods for assessing and addressing them. Given the magnitude of measurement error that has been reported, investigators are urged to carefully evaluate and rigorously address this potential source of bias in studies based in EMR data.

Impact of New Medications and $4 Generic Programs on Overactive Bladder Treatment Among Older Adults in the United States, 2000-2015.

BACKGROUND: Despite several new medications being Food and Drug Administration-approved for overactive bladder (OAB) and new prescription drug payment programs, there are limited population-based data regarding OAB medication use among older adults. OBJECTIVES: To examine: (1) impacts of new medications and $4 generic programs on time trends for OAB-related medication dispensing for older adults in the United States; (2) differences by age and sex; and (3) temporal changes in OAB-related medication payments. METHODS: Using Truven Health Analytics' Medicare Supplemental Database (2000-2015), we analyzed OAB-related medication claims for 9,477,061 Medigap beneficiaries age 65-104. We estimated dispensing rates (per 1000 person-months), assessed dispensing trends using interrupted time-series methods, compared dispensing rates by age and sex, and summarized payment trends. RESULTS: From 2000 to 2015, 771,609 individuals filled 13,863,998 OAB-related prescriptions. During 2000-2007, 3 new extended-release medications became available (tolterodine, darifenacin, solifenacin), leading to increases in overall OAB-related dispensing rates by 19.1 (99% confidence interval, 17.0-21.2), a 92% increase since 2000; overall rates remained stable during 2008-2015. By 2015, the most common medications were oxybutynin (38%), solifenacin (20%), tolterodine (19%), and mirabegron (12%). Dispensing rates peaked at age 90 (rate, 53.4; 99% confidence interval, 53.1-53.7). Women had higher rates than men at all ages (average ratewomen-ratemen, 22.0). The gap between upper and lower percentiles of medication payments widened between 2008-2015; by 2015, 25% of reimbursed dispensed prescriptions had total payments exceeding $250. CONCLUSIONS: Medication-specific dispensing rates for OAB changed when new alternatives became available. Recent changes in utilization and cost of OAB medications have implications for clinical guidelines, pharmacoepidemiologic studies, and payment policies.

Trends in Pharmacotherapy for Bladder Dysfunction Among Children in the United States, 2000 to 2013.

Bladder-related issues such as nocturnal enuresis and incontinence have long been a part of general pediatric practice. Increasingly, clinicians are prescribing medications directed at a variety of types of bladder dysfunction, but no prior population-based data exist. We used MarketScan health care claims data on 32 074 638 insured children to estimate utilization patterns by age, sex, year, and geographic region in the United States from 2000 to 2013, and to assess related diagnosis codes. Approximately 1 in 500 children filled an antimuscarinic prescription. The most common prescriptions were for oxybutynin (78%) and tolterodine (17%). Rates were highest at ages 6 to 10 years (65/100 000 person-months), 31% higher for girls versus boys, peaked in 2011 (44/100 000 person-months), and were highest in the Midwest (59/100 000 person-months). Seventy-three percent of children with prescriptions had diagnosis codes for genitourinary symptoms, and 13% had codes for congenital anomalies. Research is needed regarding the comparative effectiveness and safety of these drugs in children.

Trends and Patterns of Urodynamic Studies in U.S. Males, 2000-2012.

OBJECTIVE: To evaluate trends in urodynamic procedures in the U.S. males from 2000-2012 and determine if a 2010 decline in reimbursement was associated with decreased utilization. SUBJECTS AND METHODS: We analyzed 2000-2012 administrative healthcare claims from Truven Health's Marketscan Database and evaluated males ≥18 years of age. We identified cystometrograms and any concurrent procedures using procedure billing codes. Covariates included age, year of cystometrogram, region and associated diagnosis codes. We estimated standardized cystometrogram utilization rates per 10,000 person-years (PY). We used age, region, and calendar year adjusted Poisson regression models to estimate the independent effect of calendar year and region. RESULTS: During 127,558,186 PY of observation, we identified 153,168 cystometrograms for an overall utilization rate of 12.0 per 10,000 PY (95% CI 11.9-12.1). Cystometrogram utilization increased with age, peaking at age 85 with a rate of 77.7 per 10,000 PY (95% CI 74.7-80.7). Adjusted cystometrogram utilization rate ratios show that compared to a referent of 2000-2004, utilization was significantly higher in each year 2005 to 2011 among all patients and in 2012 among patients ≥ 65. Standardized utilization rates peaked in 2008 at 12.4 per 10,000 PY (95% CI 12.2-12.6), remained elevated until 2010, then decreased slightly in 2011 and substantially in 2012 to 8.5 per 10,000 PY (95% CI 8.4-8.7). CONCLUSIONS: Utilization of urodynamic procedures increased until 2010 and decreased thereafter. Utilization was greatest among men older than 65.

Incidence of opioid-managed pelvic pain after hysteroscopic sterilization versus laparoscopic sterilization, US 2005-2012.

OBJECTIVE: Compare incidence of opioid-managed pelvic pain within 12 months after hysteroscopic and laparoscopic sterilization. METHODS: Using administrative claims, we identified women aged 18-49 years without recent history of childbirth who underwent hysteroscopic or laparoscopic sterilization between 2005 and 2012. We defined the outcome as ≥2 diagnoses for pelvic pain and ≥2 prescription fills for opioids. We calculated adjusted hazard ratios (HR) using Cox models and propensity score methods (matching and inverse-probability-of-treatment-weighting [IPTW]). RESULTS: We identified 71,875 eligible women (hysteroscopic n = 26,927 [37.5%], laparoscopic n = 44,948 [62.5%]). Of those, 236 (0.88%) hysteroscopic patients and 420 (0.93%) laparoscopic patients experienced the outcome (crude HR = 0.97, 95%CI: [0.83, 1.14]). Adjusted analyses also yielded near-null results (matched HR = 1.08, 95%CI [0.90, 1.31]; IPTW HR = 0.97, 95%CI [0.80, 1.18]). While most sensitivity analyses generated results close to the null, hazard ratios estimated using propensity score matching ranged from 0.65 to 1.53. CONCLUSIONS: Among women without recent history of childbirth, we did not find compelling evidence of a clinically meaningful increase in the incidence of pelvic pain requiring opioids during the year after hysteroscopic sterilization. However, effects observed in sensitivity analyses may merit further investigation.