HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

PROBLEM: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. WHAT WE DID: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force.

OBJECTIVES: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. METHODS: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The over-arching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

At baseline patients treated with esketamine have higher burden of disease than other patients with treatment resistant depression: Learnings from a population based study.

INTRODUCTION: It is critical to assess who is being treated with a new marketed drug like esketamine to understand how it is used in the real-world setting and the effects of the medication. METHODS: Retrospective analysis using two large U.S. health care databases that included commercially insured and Medicaid patients. Patients treated with esketamine were identified and their baseline characteristics described and compared with the baseline characteristics of patients with treatment resistant depression (TRD) and with patients undergoing transcranial magnetic stimulation (TMS). To quantify the differences, standardized mean differences were calculated. RESULTS: In the commercially insured database, 418 patients were treated with esketamine and 830,047 patients were in the TRD group. Large differences in baseline characteristics were observed. Patients in the esketamine group were more likely to have severe depression, suicidal thoughts, and prior treatments with TMS or electroconvulsive therapy than the TRD control group. Patients in the esketamine group had more comorbid psychiatric conditions (anxiety disorder, posttraumatic stress disorders, substance use disorders) and higher exposure to antipsychotics, antiepileptics, hypnotics and sedatives. In terms of general health, patients in the esketamine group had many more outpatient visits, were more likely to have chronic pain and higher Charlson comorbidity scores, a predicator of mortality. Results were similar for both the Medicaid and TMS populations. CONCLUSION: Patients treated with esketamine have a higher burden of disease than other patients with TRD. In any real-world comparative effectiveness or safety study these differences need to be understood and accounted for to produce valid results.

Individuals who develop drug-resistant epilepsy within a year after initial diagnosis have higher burden of mental and physical diseases one-year prior to epilepsy diagnosis as compared to those whose seizures were controlled during the same interval.

INTRODUCTION: Epilepsy is a neurological disease characterized by recurrent, unprovoked seizures and its impact on biological, cognitive, psychological, and social outcomes. An unmet need for finding effective treatment options exists. Identifying medical diagnoses present prior to a diagnosis of epilepsy is an important step in increasing our understanding of how people with epilepsy may respond to therapy, help guide clinicians in managing associated comorbid conditions, and inform future research. METHODS: A population-based retrospective comparative cohort study was conducted using administrative claims data to explore differences in medical diagnoses prior to an initial diagnosis of epilepsy between patients with and without drug-resistant epilepsy (DRE) identified within one-year post diagnosis by evaluating standardized mean differences between the groups. RESULTS: A total of 205,183 patients with newly diagnosed epilepsy were identified. Of those, 4.1% (n = 8340) were considered drug resistant one-year post diagnosis. Pain and mood disorders were the common physical and psychiatric diagnoses in both cohorts. Differences between the newly diagnosed epilepsy and DRE cohorts were observed. Patients in the DRE cohort were younger, had more encounters with the healthcare system, and higher burden of disease for both physical (e.g., headache, neuropathy, muscular-skeletal disorders, and traumatic brain injury) and psychiatric diagnoses (e.g., depression, anxiety, bipolar disorder, suicidal thoughts, drug dependency, and sleep disorders). CONCLUSION: Physical and psychiatric diagnoses are common one year prior to first diagnosis of epilepsy in administrative claims data. Compared to patients without DRE, those who develop DRE within one-year post initial diagnosis demonstrated a higher burden of disease.

Treatment patterns of patients diagnosed with major depressive disorder and suicidal ideation or attempt: a U.S. population-based study utilizing real-world data.

BACKGROUND: There is a knowledge gap regarding the treatment patterns of patients with major depressive disorder (MDD) who experience suicidal ideation or a suicide attempt (SI/SA). METHODS: Patients with SI/SA were identified from a large US-based claims database covering 84 million lives, during 1/1/2014-3/31/2020. Patients with MDD were indexed at their first diagnosis for SI/SA and followed up to 365 days. Treatment patterns were captured at the class level and included procedures of electroconvulsive therapy and transcranial magnetic stimulation, and pharmacotherapy including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, antipsychotics, psychostimulants, and lithium. RESULTS: There were 42,204 MDD + SI/SA patients identified. In the year prior to the index event > 40% of individuals received an SSRI and more than one-third received an anxiolytic. Within 1 year following, 84.4% received ≥1 of the treatments of interest. Of those, 70.2% went on to a subsequent class-based regimen, 46.3% received a third, and 28.1% received ≥4. More than three-quarters of patients received multiple treatment classes simultaneously. SSRIs were the most common treatments during follow-up (61.9%), followed by other antidepressants (51.3%), anxiolytics (50.8%) and anticonvulsants (43.6%). CONCLUSIONS: There was a large amount of variability and polypharmacy in the treatments received by MDD patients with SI/SA, and is much more complex than what has been previously observed in the general MDD population. Within one-year, many patients received four or more unique class-based regimens and most patients received treatments from multiple classes simultaneously, indicating the high unmet medical need and therapy refractoriness of this patient population.

Treatment patterns and comorbid burden of patients newly diagnosed with multiple sclerosis in the United States.

BACKGROUND: The treatment landscape for multiple sclerosis (MS) is quickly evolving. Understanding real-world treatment patterns of patients is necessary to identifying potential gaps in care. METHODS: Patients with incident MS were identified from a large national claims database during 1/1/2014-6/30/2019. Patients had ≥2 diagnoses for MS or an inpatient hospitalization with a primary diagnosis of MS. Patients were required to have enrollment in the database ≥1 year prior to and ≥ 1 year following their first MS diagnosis. Treatment sequences were captured for all available disease modifying therapies (DMTs) during all available follow-up. Presence of comorbid conditions were captured during the one year prior to and following (and including) the index date; absolute change in prevalence from the pre- to post-index periods was calculated. RESULTS: We identified 5691 patients with incident MS. Common comorbidities included physical symptoms (e.g., pain, weakness, fatigue), mental health conditions (anxiety, depression), and cardiovascular/metabolic conditions (hypertension, hyperlipidemia, diabetes, obesity). Just 1994 (35.0%) of patients received a DMT at any time during follow-up. Of those receiving a DMT, 28.2% went on to receive a second line of therapy, 5.8% received a third, and just 0.9% went on to a fourth line. Use of more than one DMT concomitantly occurred in just 1.8% of all treated patients. Glatiramer and dimethyl fumarate were by far the most common first-line treatments received accounting for nearly 62% of patients receiving a DMT. CONCLUSION: Approximately two-thirds of patients newly diagnosed with MS did not receive a DMT and the disease is accompanied by a significant comorbid burden.

Oral Opioid Prescribing Trends in the United States, 2002-2018.

OBJECTIVE: To conduct a retrospective analysis of sequential cross-sectional data of opioid prescribing practices in patients with no prior history of opioid use. METHODS: Individuals filling an oral opioid prescription who had 1 year of prior observation were identified from four different administrative claims databases for the period between January 1, 2002, and December 31, 2018: IBM MarketScan® Commercial Database (CCAE), Multi-State Medicaid Database (MDCD), Medicare Supplemental Database (MDCR), and Optum©â€¯De-Identified Clinformatics® Data Mart Database. Outcomes included incidence of new opioid use and characteristics of patients' first opioid prescription, including dispensed morphine milligram equivalent (MME) per day, total MME dispensed, total MME ≥300, and days' supply of prescription for ≤3 or ≥30 days. RESULTS: There were 40,600,696 new opioid users identified. The incidence of new opioid use in the past 17 years ranged from 6% to 11% within the two commercially insured databases. Incidence decreased over time in MDCD and was consistently higher in MDCR. Total MME dispensed decreased in MDCD and increased in CCAE, with no major changes in the other databases. The proportion of patients receiving ≥30-day prescriptions decreased and the proportion of patients receiving ≤3-day prescriptions increased in MDCD, while ≥30-day prescriptions in the Optum database dramatically increased (low of 3.0% in 2003 to peak of 16.9% in 2017). CONCLUSIONS: Opioid prescribing practices varied across different populations of insured individuals during the past 17 years. The most substantial changes in opioid prescriptions over time have occurred in MDCD, with reductions in use across multiple metrics.

Frequency of Early Refills for Opioids in the United States.

OBJECTIVE: Refilling an opioid prescription early is an important risk factor of prescription opioid abuse and misuse; we aimed to understand the scope of this behavior. This study was conducted to quantify the prevalence and distribution of early refills among patients prescribed opioids. METHODS: We conducted a retrospective cohort study utilizing dispensed prescription records. Patients filling one or more prescription opioids were identified and followed for one year. Early refills were defined as having a second prescription filled ≥15% early relative to the days' supply of the previous prescription for the same opioid (according to the National Drug Code [NDC]). The distribution of the number of early refills and patient characteristics were assessed. RESULTS: A total of 60.6 million patients met the study criteria; 28.8% had two or more opioid prescriptions for the same opioid during follow-up. Less than 3% of all patients receiving an opioid had an early refill. Approximately 10% of those with two or more opioid prescriptions for the same drug had an early refill. For patients with multiple fills (N = 1.5 million with extended-release long-acting [ER/LA] opioids; N = 17.1 million with immediate-release short-acting [IR/SA] opioids), early refills were more common among patients with an ER/LA opioid (18.5%) compared with an IR/SA opioid (8.7%). Three-quarters of patients with an early refill had only one (70.9% and 78.4% for ER/LA and IR/SA, respectively). CONCLUSION: Refilling an opioid prescription with the same opioid early is an infrequent behavior within all opioid users, but more common in ER/LA users. Patients who refilled early tended to do so just once.

Treatment patterns and sequences of pharmacotherapy for patients diagnosed with depression in the United States: 2014 through 2019.

BACKGROUND: Understanding how patients are treated in the real-world is vital to identifying potential gaps in care. We describe the current pharmacologic treatment patterns for the treatment of depression. METHODS: Patients with depression were identified from four large national claims databases during 1/1/2014-1/31/2019. Patients had ≥2 diagnoses for depression or an inpatient hospitalization with a diagnosis of depression. Patients were required to have enrollment in the database ≥1 year prior to and 3 years following their first depression diagnosis. Treatment patterns were captured at the class level and included selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, and antipsychotics. Treatment patterns were captured during all available follow-up. RESULTS: We identified 269,668 patients diagnosed with depression. The proportion not receiving any pharmacological treatment during follow-up ranged from 29 to 52%. Of the treated, approximately half received ≥2 different classes of therapy, a quarter received ≥3 classes and more than 10% received 4 or more. SSRIs were the most common first-line treatment; however, many patients received an anxiolytic, hypnotic/sedative, or antipsychotic prior to any antidepressive treatment. Treatment with a combination of classes ranged from approximately 20% of first-line therapies to 40% of fourth-line. CONCLUSIONS: Many patients diagnosed with depression go untreated and many others receive a non-antidepressant medication class as their first treatment. More than half of patients received more than one type of treatment class during the study follow up, suggesting that the first treatment received may not be optimal for most patients.

Treatment resistant depression in women with peripartum depression.

BACKGROUND: Peripartum depression is a leading cause of disease burden for women and yet there is little evidence as to how often peripartum depression does not respond to treatment and becomes treatment resistant depression. We sought to determine the incidence of treatment resistant depression (TRD) in women with peripartum depression. METHODS: Population based retrospective cohort study using a large US claims database. Peripartum depression was defined as having a depression diagnosis during pregnancy or up to 6 months after the end of pregnancy. We included women with prevalent or incident depression. The outcome was the development of TRD within 1 year after the diagnosis of peripartum depression. TRD was defined as having 3 distinct antidepressants or 1 antidepressant and 1 antipsychotic in 1 year. Women with peripartum depression may not be exposed to pharmacological treatments early in pregnancy, therefore we created two groups: 1. women with peripartum depression, and 2. women with peripartum depression diagnosed 3 months before a live birth delivery or within 6 months after that delivery. RESULTS: There were 3,207,684 pregnant women, of whom 2.5% had peripartum depression. Of these women half had incident depression during pregnancy. Five percent of women with peripartum depression developed TRD within 1 year of the depression diagnosis. The risk of developing TRD was 50% higher in women with prevalent depression than in women with incident peripartum depression (P < 0.0001). Results were similar in women with peripartum depression diagnosed later in their pregnancy. Women who went on to develop TRD had more substance use disorders, anxiety, insomnia and painful conditions. CONCLUSIONS: TRD occurs in approximately 5% of women with peripartum depression. The risk of TRD is higher in pregnant women with a history of depression. Women who went on to develop TRD had more psychiatric comorbidities and painful conditions than women who did not.

Non-adherence to basal insulin among patients with type 2 diabetes in a US managed care population: Results from a patient survey.

The aim of this study was to assess insulin non-adherence among patients with type 2 diabetes (T2DM) to better understand relationships between adherence, basal insulin (BI) usage, and patient experiences. A cross-sectional survey of patients with T2DM using BI was conducted. Adherence was measured by the Morisky Medication Adherence Scale 8-Items (MMAS-8). Low adherence (LA) was defined as MMAS-8 score < 6, high adherence (HA) as MMAS-8 score = 8, and medium adherence as MMAS-8 score = 6 to < 8. Patients with MMAS-8 scores = 6 to < 8 were excluded from the analysis. Of 400 completed surveys, 395 patients (98.8%) completed all MMAS-8 items, 112 with LA, 134 with HA. Compared with HA patients, greater proportions of LA patients followed more complex BI dosing patterns (57.1% vs. 39.5%, P = 0.014), had some difficulty calculating their correct BI dose (40.2% vs. 6.8%, P < 0.001), reported having missed ≥1 dose per month (79.3% vs. 12.6%, P < 0.001), and temporarily stopped BI in the past year (23.2% vs. 0.7%, P < 0.001). In conclusion, understanding patients' experiences with BI therapy can help formulate strategies to improve adherence.

Neighborhood price of healthier food relative to unhealthy food and its association with type 2 diabetes and insulin resistance: The multi-ethnic study of atherosclerosis.

This study examined the association between the price of healthier food relative to unhealthy food and type 2 diabetes prevalence, incidence and insulin resistance (IR). Data came from the Multi-Ethnic Study of Atherosclerosis exam 5 administered 2010-2012 (exam 4, five years prior, was used only for diabetes incidence) and supermarket food/beverage prices derived from Information Resources Inc. For each individual, average price of a selection of healthier foods, unhealthy foods and their ratio was computed for supermarkets within 3miles of the person's residential address. Diabetes status was confirmed at each exam and IR was assessed via the homeostasis model assessment index. Multivariable-adjusted logistic, modified Poisson and linear regression models were used to model diabetes prevalence, incidence and IR, respectively as a function of price and covariates; 2353 to 3408 participants were included in analyses (depending on the outcome). A higher ratio of healthy-to-unhealthy neighborhood food price was associated with greater IR (4.8% higher HOMA-IR score for each standard deviation higher price ratio [95% CI -0.2% to 10.1%]) after adjusting for region, age, gender, race/ethnicity, family history of diabetes, income/wealth index, education, smoking status, physical activity, and neighborhood socioeconomic status. No association with diabetes incidence (relative risk=1.11, 95% CI 0.85 to 1.44) or prevalence (odds ratio=0.95, 95% CI 0.81 to 1.11) was observed. Higher neighborhood prices of healthier food relative to unhealthy food were positively associated with IR, but not with either diabetes outcome. This study provides new insight into the relationship between food prices with IR and diabetes.

Longitudinal Associations of Local Cigarette Prices and Smoking Bans with Smoking Behavior in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Few studies have examined associations of geographically proximal cigarette prices with within-person changes in smoking outcomes or assessed interactions between cigarette prices and smoking bans. METHODS: We linked neighborhood cigarette prices (inflation-adjusted) at chain supermarkets and drug stores and bar/restaurant smoking ban policies to cohort participants (632 smokers from the Multi-Ethnic Study of Atherosclerosis, 2001-2012, baseline mean age 58 years) using geocoded retailer and participant addresses. We used fixed-effects models to investigate associations of within-person changes in price and ban exposures with within-person changes in five smoking outcomes: current smoking, heavy (≥10 cigarettes) smoking, cessation, relapse, and intensity (average number of cigarettes smoked per day, natural log transformed). We assessed intensity associations among all smokers, and heavy (≥10 cigarettes per day) and light (<10) baseline smokers. Finally, we tested interactions between cigarette price and bans. RESULTS: A $1 increase in price was associated with a 3% reduction in risk of current smoking (adjusted risk ratio [aRR]: 0.97; 95% confidence interval [CI] = 0.93, 1.0), a 7% reduction in risk of heavy smoking (aRR: 0.93; CI = 0.87, 0.99), a 20% increase in risk of smoking cessation (aRR: 1.2; CI = 0.99, 1.4), and a 35% reduction in the average number of cigarettes smoked per day by heavy baseline smokers (ratio of geometric means: 0.65; CI = 0.45, 0.93). We found no association between smoking bans and outcomes, and no evidence that price effects were modified by the presence of bans. CONCLUSIONS: Results underscore the importance of local prices, but not hospitality smoking bans, in influencing older adults' smoking behaviors.

Healthy and Unhealthy Food Prices across Neighborhoods and Their Association with Neighborhood Socioeconomic Status and Proportion Black/Hispanic.

This paper evaluates variation in food prices within and between neighborhoods to improve our understanding of access to healthy foods in urbanized areas and potential economic incentives and barriers to consuming a higher-quality diet. Prices of a selection of healthier foods (dairy, fruit juice, and frozen vegetables) and unhealthy foods (soda, sweets, and salty snacks) were obtained from 1953 supermarkets across the USA during 2009-2012 and were linked to census block group socio-demographics. Analyses evaluated associations between neighborhood SES and proportion Black/Hispanic and the prices of healthier and unhealthy foods, and the relative price of healthier foods compared with unhealthy foods (healthy-to-unhealthy price ratio). Linear hierarchical regression models were used to explore geospatial variation and adjust for confounders. Overall, the price of healthier foods was nearly twice as high as the price of unhealthy foods ($0.590 vs $0.298 per serving; healthy-to-unhealthy price ratio of 1.99). This trend was consistent across all neighborhood characteristics. After adjusting for covariates, no association was found between food prices (healthy, unhealthy, or the healthy-to-unhealthy ratio) and neighborhood SES. Similarly, there was no association between the proportion Black/Hispanic and healthier food price, a very small positive association with unhealthy price, and a modest negative association with the healthy-to-unhealthy ratio. No major differences were seen in food prices across levels of neighborhood SES and proportion Black/Hispanic; however, the price of healthier food was twice as expensive as unhealthy food per serving on average.

Neighbourhood variation in the price of soda relative to milk and its association with neighbourhood socio-economic status and race.

OBJECTIVE: Soda consumption is high in the USA, especially among minorities and individuals of lower socio-economic status (SES); this may be due to its affordable price in relation to healthier alternatives. The objective of the present study was to examine geospatial variation in price of milk and soda, and the price of milk relative to soda, by neighbourhood SES and proportion of Hispanic and black individuals. DESIGN: Retailer soda and milk prices (n 2987; Information Resources, Inc. Academic Data Set 2004-2011) were linked to census block group sociodemographic characteristics (American Community Survey 2005-2009). Linear hierarchical regression models were used to adjust for confounders. SETTING: Large chain supermarkets and superstores (n 1743) in forty-one states and 1694 block groups (USA). RESULTS: For equivalent fluid ounces, price of soda on average was 62 % lower than milk ($US 0·23 v. $US 0·63 per serving) and there was high dispersion in milk price across geographic areas. After adjustment for confounding, neighbourhoods with a higher concentration of black and Hispanic individuals tended to have lower soda prices and higher milk prices (-$US 0·001 and +$US 0·007 in price per serving, respectively, for a one quintile increase in black/Hispanic population), while soda and milk both became less expensive as SES decreased (-$US 0·002 and -$US 0·015 in serving price per one sd decrease in SES index, respectively). CONCLUSIONS: Neighbourhoods with a higher concentration of blacks and Hispanics may be at greater risk of higher soda consumption due to more affordable prices, in absolute terms and relative to the price of milk.

Comparative effectiveness of budesonide/formoterol combination and fluticasone/salmeterol combination among chronic obstructive pulmonary disease patients new to controller treatment: a US administrative claims database study.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist combinations (ICS/LABA) have emerged as first line therapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical trial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and fluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared the real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large US managed care setting. METHODS: COPD patients (≥40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012 were identified in a geographically diverse US managed care database and followed for 12 months; index date was defined as first prescription fill date. Patients with a cancer diagnosis or chronic (≥180 days) oral corticosteroid (OCS) use within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation clinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD exacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource utilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare resource utilization. RESULTS: Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched patients were well balanced on age (mean=64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication use, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and FSC patients for number of COPD-related exacerbations overall (rate ratio [RR]=1.02, 95% CI=[0.96,1.09], p=0.56) or by event type: COPD-related hospitalizations (RR=0.96), COPD-related ED visits (RR=1.11), and COPD-related office/outpatient visits with OCS and/or antibiotic use (RR=1.01). The proportion of patients diagnosed with pneumonia during the post-index period was similar for patients in each group (BFC =17.3%, FSC =19.0%, odds ratio=0.92 [0.81,1.04], p=0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service. CONCLUSION: This study demonstrated no difference in COPD-related exacerbations or pneumonia events between BFC and FSC treatment groups for patients new to ICS/LABA treatment in a real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01921127 .

Asthma and Chronic Obstructive Pulmonary Disease Overlap Syndrome: Doubled Costs Compared with Patients with Asthma Alone.

BACKGROUND: Patients with asthma and chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) have more rapid disease progression and more exacerbations than do those with either condition alone. Little research has been performed, however, in these patients. OBJECTIVE: The objective was to summarize the health care utilization, costs, and comorbidities of patients with uncontrolled asthma and patients with ACOS. METHODS: This retrospective analysis used medical and pharmacy claims from large commercial health plans. The study included patients 6 years or older with a diagnosis of asthma and one or more asthma exacerbation (index event). Patients were classified as having asthma alone or ACOS, and the two groups were matched for age, sex, region, index year, index month, and health plan type. Outcomes included rates of comorbid disease, health care utilization, and costs during the 12 months before and after the index exacerbation. RESULTS: Among the matched patients with asthma (6,505 ACOS; 26,060 without COPD), mean annual all-cause health care costs were twice as high as for patients with ACOS ($22,393 vs. $11,716; P < 0.0001). Asthma-related costs, representing 29% of total costs, were nearly twice as high among patients with ACOS ($6,319 vs. 3,356; P < 0.0001). Cost differences were driven by large differences in the proportions of patients with an inpatient hospitalization (34.0% vs. 14.6%; P < 0.0001) or emergency department visit (29.6% vs. 19.9%; P < 0.0001). Nearly all prespecified comorbid conditions were more prevalent in the ACOS group. CONCLUSIONS: Patients with asthma and COPD had nearly double the health care costs as did patients with asthma without COPD. The overall disease profile of patients with asthma should be considered when managing patients, rather than treating asthma as a solitary condition.

Healthcare utilization and costs associated with S. aureus and P. aeruginosa pneumonia in the intensive care unit: a retrospective observational cohort study in a US claims database.

BACKGROUND: Staphylococcus aureus and Pseudomonas aeruginosa are major causes of pneumonia in intensive care unit (ICU) patients. Limited data exist regarding the health economic impact of S. aureus and P. aeruginosa pneumonias in the ICU setting. METHODS: We conducted a retrospective observational cohort study using a 29.6 million enrollee US medical and pharmacy administrative claims database. ICU patients with S. aureus or P. aeruginosa infection per International Classification of Diseases, 9th ed. coding between 01/01/2007-8/31/2012 were compared with ICU patients without any pneumonia or infections of interest. Primary outcomes were costs in 2012 US dollars, healthcare utilization and all-cause mortality associated with hospital-acquired S. aureus or P. aeruginosa pneumonia, and the relative odds of incurring higher costs due to a comorbid condition. RESULTS: Patients with S. aureus or P. aeruginosa pneumonia had longer mean hospital (37.9 or 55.4 vs 7.2 days, P < .001) and ICU stays (6.9 or 14.8 vs 1.1 days, P < .001), a higher rate of mechanical ventilation (62.6 % or 62.3 % vs 7.4 %, P < .001), higher mortality (16.0 % or 20.2 % vs 3.1 %, P < .001), and higher total mean hospitalization costs ($146,978 or $213,104 vs $33,851, P < .001) vs controls. Pneumonia survivors had significantly increased risk of rehospitalization within 30 days (27.2 % or 31.1 % vs 15.3 %, P < .001). Comorbid conditions were not associated with increased cost in the pneumonia cohorts. CONCLUSIONS: Healthcare costs and resource utilization were high among ICU patients with S. aureus or P. aeruginosa pneumonia. Reducing the incidence of these infections could lead to substantial cost savings in the United States.

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.

Association between prolactin increasing antipsychotic use and the risk of breast cancer: a retrospective observational cohort study in a United States Medicaid population.

Introduction: Results of retrospective studies examining the relationship between prolactin increasing antipsychotics and incident breast cancer have been inconsistent. This study assessed the association between use of high prolactin increasing antipsychotics (HPD) and the incidence of breast cancer using best practices in pharmacoepidemiology. Methods: Using administrative claims data from the MarketScan Medicaid database, schizophrenia patients initiating antipsychotics were identified. Those initiating HPD were compared with new users of non/low prolactin increasing drugs (NPD). Two definitions of breast cancer, two at-risk periods, and two large-scale propensity score (PS) adjustment methods were used in separate analyses. PS models included all previously diagnosed conditions, medication use, demographics, and other available medical history. Negative control outcomes were used for empirical calibration. Results: Five analysis variants passed all diagnostics for sufficient statistical power and balance across all covariates. Four of the five variants used an intent-to-treat (ITT) approach. Between 4,256 and 6,341 patients were included in each group for the ITT analyses, and patients contributed approximately four years of follow-up time on average. There was no statistically significant association between exposure to HPD and risk of incident breast cancer in any analysis, and hazard ratios remained close to 1.0, ranging from 0.96 (95% confidence interval 0.62 - 1.48) to 1.28 (0.40 - 4.07). Discussion: Using multiple PS methods, outcome definitions and at-risk periods provided robust and consistent results which found no evidence of an association between use of HPD and risk of breast cancer.