Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Characteristics and outcomes of pregnancies in the Maternal Outcomes Masterset real-world database.

PURPOSE: Describe patient characteristics and pregnancy outcomes among all pregnant patients, and additionally describe infant outcomes among the subset with linked infants in the Maternal Outcomes Masterset (MOM). METHODS: We used closed claims within the MOM data to identify publicly and privately insured patients at the first record of pregnancy January 1, 2018-December 1, 2021, with ≥180 days baseline enrollment. We described characteristics during baseline and follow-up (until an observed pregnancy endpoint, disenrollment, or 42-week maximum). We described maternal and infant characteristics overall and by infant linkage and contextualized them within national statistics. RESULTS: Among the 1 438 861 pregnant patients meeting the study criteria, the most common pregnancy endpoint recorded was live birth (42%) followed by spontaneous abortion (14%). Among 602 721 patients with a live birth, 99% had a week-specific gestational age recorded and 35% had at least one linked infant. Patients with infant linkage and sufficient follow-up (N = 155 621) had similar baseline comorbidities, pregnancy complications, and gestational age at delivery as those without any linkage. However, more patients with linkage had commercial coverage (70% vs. 31%), and were therefore older (50% vs. 31% aged ≥30 years) and more likely to have an unknown race (57% vs. 34%). CONCLUSIONS: In this large sample of pregnant patients, maternal and infant characteristics generally align with national statistics, providing confidence in the use of this data source for pregnancy research. Further, confirmation that the subset of patients with infant linkage is similar to the overall pregnancy cohort provides assurance that this subset can be considered representative.

A Descriptive Cohort Study of Drug Utilization Patterns Among Patients Hospitalized With Coronavirus Disease 2019 in the United States, January 2021-February 2022.

Background: There is a dearth of drug utilization studies for coronavirus disease 2019 (COVID-19) treatments in 2021 and beyond after the introduction of vaccines and updated guidelines; such studies are needed to contextualize ongoing COVID-19 treatment effectiveness studies during these time periods. This study describes utilization patterns for corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase inhibitors, and remdesivir among hospitalized adults with COVID-19, over the entire hospitalization, and within hospitalization periods categorized by respiratory support requirements. Methods: This descriptive cohort study included United States adults hospitalized with COVID-19 admitted from 1 January 2021 through 1 February 2022; data included HealthVerity claims and hospital chargemaster. The number and distribution of patients were reported for the first 3 drug regimen lines initiated. Results: The cohort included 51 066 patients; the most common initial drug regimens were corticosteroids (23.4%), corticosteroids plus remdesivir (25.1%), and remdesivir (4.4%). IL-6 inhibitors and Janus kinase inhibitors were included in later drug regimens and were more commonly administered with both corticosteroids and remdesivir than with corticosteroids alone. IL-6 inhibitors were more commonly administered than Janus kinase inhibitors when patients received high-flow oxygen or ventilation. Conclusions: These findings provide important context for comparative studies of COVID-19 treatments with study periods extending into 2021 and later. While prescribing generally aligned with National Institutes of Health COVID-19 treatment guidelines during this period, these findings suggest that prescribing preference, potential confounding by indication, and confounding by prior/concomitant use of other therapeutics should be considered in the design and interpretation of comparative studies.

Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses: Results of 32 Clinical Trials.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates. Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs. Design, Setting, and Participants: New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022. Exposures: Therapies for multiple clinical conditions were included. Main Outcomes and Measures: Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference. Results: In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement). Conclusions and Relevance: Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.

Describing characteristics and treatment patterns of patients hospitalized with COVID-19 by race and ethnicity in a national RWD during the early months of the pandemic.

OBJECTIVE: To describe differences by race and ethnicity in treatment patterns among hospitalized COVID-19 patients in the US from March-August 2020. METHODS: Among patients in de-identified Optum electronic health record data hospitalized with COVID-19 (March-August 2020), we estimated odds ratios of receiving COVID-19 treatments of interest (azithromycin, dexamethasone, hydroxychloroquine, remdesivir, and other steroids) at hospital admission, by race and ethnicity, after adjusting for key covariates of interest. RESULTS: After adjusting for key covariates, Black/African American patients were less likely to receive dexamethasone (adj. OR [95% CI]: 0.83 [0.71, 0.96]) and more likely to receive other steroids corticosteroids (adj. OR [95% CI]: 2.13 [1.90, 2.39]), relative to White patients. Hispanic/Latino patients were less likely to receive dexamethasone than Not Hispanic/Latino patients (adj. OR [95% CI]: 0.69 [0.58, 0.82]). CONCLUSIONS: Our findings suggest that COVID-19 treatments patients received in Optum varied by race and ethnicity after adjustment for other possible explanatory factors. In the face of rapidly evolving treatment landscapes, policies are needed to ensure equitable access to novel and repurposed therapeutics to avoid disparities in care by race and ethnicity.

Treatment effectiveness in a rare oncology indication: Lessons from an external control cohort study.

Real-world data (RWD) reflecting patient treatment in routine clinical practice can be used to develop external control groups for single-arm trials. External controls can provide valuable benchmark results on potential comparator drug effectiveness, particularly in rare indications when randomized controlled trials are either infeasible or unethical. This paper describes lessons learned from a descriptive real-world external control cohort study conducted to provide benchmark data for a single-arm clinical trial in a rare oncology biomarker driven disease. Conducting external control cohort studies to evaluate treatment effectiveness in rare indications likely will present data and analysis challenges as seen in the example study. However, there are mitigating measures that can be applied in the study design, identification of RWD sources, and data analysis. The lessons learned and reported here with a proposal of an external control study framework can provide guidance for future research in this area, and may be applicable as well in other rare indications. Taking these learnings into consideration, the use of real-world external controls to contextualize treatment effectiveness in rare indications is a valuable approach and warrants further application in the future.

Alternative analytic and matching approaches for the prevalent new-user design: A simulation study.

PURPOSE: To describe the creation of prevalent new user (PNU) cohorts and compare the relative bias and computational efficiency of several alternative analytic and matching approaches in PNU studies. METHODS: In a simulated cohort, we estimated the effect of a treatment of interest vs a comparator among those who switched to the treatment of interest using the originally proposed time-conditional propensity score (TCPS) matching, standardized morbidity ratio weighting (SMRW), disease risk scores (DRS), and several alternative propensity score matching approaches. For each analytic method, we compared the average RR (across 2000 replicates) to the known risk ratio (RR) of 1.00. RESULTS: SMRW and DRS yielded unbiased results (RR = 0.998 and 0.997, respectively). TCPS matching with replacement was also unbiased (RR = 0.999). TCPS matching without replacement was unbiased when matches were identified starting with patients with the shortest treatment history as initially proposed (RR = 0.999), but it resulted in very slight bias (RR = 0.983) when starting with patients with the longest treatment history. Similarly, creating a match pool without replacement starting with patients with the shortest treatment history yielded an unbiased estimate (RR = 0.997), but matching with the longest treatment history first resulted in substantial bias (RR = 0.903). The most biased strategy was matching after selecting one random comparator observation per individual that continued on the comparator (RR = 0.802). CONCLUSIONS: Multiple analytic methods can estimate treatment effects without bias in a PNU cohort. Still, researchers should be wary of introducing bias when selecting controls for complex matching strategies beyond the initially proposed TCPS.

Categorization of COVID-19 severity to determine mortality risk.

PURPOSE: Algorithms for classification of inpatient COVID-19 severity are necessary for confounding control in studies using real-world data. METHODS: Using Healthverity chargemaster and claims data, we selected patients hospitalized with COVID-19 between April 2020 and February 2021, and classified them by severity at admission using an algorithm we developed based on respiratory support requirements (supplemental oxygen or non-invasive ventilation, O2/NIV, invasive mechanical ventilation, IMV, or NEITHER). To evaluate the utility of the algorithm, patients were followed from admission until death, discharge, or a 28-day maximum to report mortality risks and rates overall and by stratified by severity. Trends for heterogeneity in mortality risk and rate across severity classifications were evaluated using Cochran-Armitage and Logrank trend tests, respectively. RESULTS: Among 118 117 patients, the algorithm categorized patients in increasing severity as NEITHER (36.7%), O2/NIV (54.3%), and IMV (9.0%). Associated mortality risk (and 95% CI) was 11.8% (11.6-12.0%) overall and increased with severity [3.4% (3.2-3.5%), 11.5% (11.3-11.8%), 47.3% (46.3-48.2%); p < 0.001]. Mortality rate per 1000 person-days (and 95% CI) was 15.1 (14.9-15.4) overall and increased with severity [5.7 (5.4-6.0), 14.5 (14.2-14.9), 32.7 (31.8-33.6); p < 0.001]. CONCLUSION: As expected, we observed a positive association between the algorithm-defined severity on admission and 28-day mortality risk and rate. Although performance remains to be validated, this provides some assurance that this algorithm may be used for confounding control or stratification in treatment effect studies.

Healthcare Resource Utilization and Related Costs in Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype: A US Claims Database Analysis.

INTRODUCTION: We aimed to describe healthcare resource utilization (HCRU) patterns and costs in patients with fibrosing interstitial lung disease (ILD) and those with a progressive phenotype of fibrosing ILD in a US claims database. METHODS: Data from the IBM® MarketScan® databases (1 October 2011-30 September 2015) were used. Diagnosis codes documented on medical claims on two occasions (without any claims during the 12 months prior) identified patients with incident fibrosing ILD. Patients with chronic fibrosing ILD with a progressive phenotype were identified by proxies for progression. Patients aged ≥ 18 years with 365 days of continuous coverage before the index date were eligible for inclusion. Data were analyzed for 12 months prior to identification of fibrosing ILD/progressive phenotype (baseline) and 12 months after (follow-up). Outcomes included treatment patterns, outpatient and inpatient claims, and costs. RESULTS: We identified 23,577 patients with incident fibrosing ILD and 14,722 with the progressive phenotype. Follow-up data were available for 9986 and 5840 patients, respectively. The most frequent ILD-related medications during baseline were corticosteroids (49.4% and 56.6%). Mean (± standard deviation [SD]) annualized number of outpatient claims was 30.0 (± 26.4) and 34.1 (± 27.7) in the baseline period and 36.2 (± 28.6) and 41.9 (± 30.2) in the follow-up in fibrosing ILD and with a progressive phenotype, respectively. Mean (SD) number of all-cause hospitalizations was 0.5 (± 1.1) and 0.7 (± 1.2) during baseline and 0.6 (± 1.1) and 0.7 (± 1.2) during follow-up. Mean (SD) total costs were $40,907 (± 92,496) and $49,561 (± 98,647) during baseline and $46,157 (± 102,858) and $54,215 (± 116,833) during follow-up. Inpatient mortality during follow-up was 53.50 and 77.44 per 1000 patient-years. CONCLUSION: HCRU and costs were high in patients with chronic fibrosing ILD with a progressive phenotype, likely reflecting the disease severity and the need for close monitoring and acute care. Outpatient claims accounted for a substantial proportion of the total costs.

Some patients with lung diseases have inflammation or scarring of the lung tissues (interstitial lung diseases, or ILDs). In some patients with lung scarring, the scarring may become progressive (i.e., it worsens over time). In this study, we looked at these patients identified in US health insurance records. We counted how many times patients visited a doctor, were admitted to hospital, or needed medications or tests. We also looked at the total cost of all this medical care. Overall, we concluded that patients with ILDs with progressive lung scarring had a high number of visits to the doctor, and the total costs of their medical care were high.

Treatment Transitions in Chronic Obstructive Pulmonary Disease: Retrospective Analyses of US and UK Healthcare Databases.

INTRODUCTION: Previous studies have reported that more patients receive inhaled corticosteroid (ICS)-containing therapies than would be expected based on exacerbation history, suggesting overprescribing. We aimed to describe patterns of treatment switching from first (1MT) to second maintenance therapy (2MT) among COPD patients in the US and UK. METHODS: We used healthcare data from the US IBM® MarketScan® and UK Clinical Practice Research Datalink databases (2015 - 2018) to assess transitions between 1MT and 2MT among COPD patients. Patients with a recorded asthma diagnosis prior to 1MT were excluded. We assessed whether prescribed treatments (long-acting muscarinic antagonists [LAMA], long-acting ß2-agonists [LABA], inhaled corticosteroids [ICS], as monotherapy or in combination) were consistent with global and national recommendations for COPD, identified patient characteristics associated with treatment transitions, and evaluated treatment duration. RESULTS: Overall, 7028 patients in the US and 2461 in the UK initiated 2MT within a median (IQR) 160.0 (76.0; 335.0) and 218.0 (86.0; 428.0) days after 1MT, respectively. In the US, 33.6% of patients initiating 2MT had no recorded exacerbations in the previous year, whereas 23.1% had one and 43.3% had ≥ 2. In the UK, 54.9% of patients had no recorded exacerbations in the previous year, whereas 20.9% had one and 24.2% had ≥ 2. At 2MT, most patients switched to LAMA/LABA/ICS (26.1%) or LABA/ICS (25.8%) in the US, and LAMA/LABA (39.4%) or LAMA/LABA/ICS (27.8%) in the UK; 62.2% (US) and 47.5% of patients (UK) were prescribed ICS-containing regimens. The most common treatment transition from 1MT to 2MT was LABA/ICS to LAMA/LABA/ICS (13.0%) in the US; and LAMA to LAMA/LABA (32.5%) and LAMA to LAMA/LABA/ICS (14.3%) in the UK. CONCLUSIONS: At 2MT, the proportion of patients on LAMA/LABA/ICS was similar between the US and UK, but treatment pathways were different.

People with chronic obstructive pulmonary disease (COPD) take inhaled medication to control symptoms such as breathlessness and cough. There are two types of inhaler: 'reliever' inhalers for immediate symptom relief, and 'maintenance' inhalers for long-term disease control. Maintenance inhalers can be used on their own or together, and treatment is often escalated based on the persistence of symptoms or exacerbations (flare-ups), for which inhaled corticosteroids (ICS) are often prescribed. We wanted to see whether doctors' prescribing habits are in line with clinical guidelines, so we looked at data from COPD patients who switched from their first maintenance therapy (1MT) to a second, different maintenance therapy (2MT) between 2015 and 2018. Our data sources were a US health claims database (~ 7000 patients) and a UK general practice database (~ 2500 patients). We excluded people with a diagnosis of both COPD and asthma, as similar inhalers are used to treat these two conditions, although the clinical decisions for when to prescribe them differ. On average, the time between 1MT and 2MT was 160 days (US) and 218 days (UK). Overall, 50% (UK) and 60% of patients (US) were prescribed ICS as part of their treatment regimen at 2MT, and ICS use in both countries was higher than expected based on the guidelines, which recommend ICS only for patients with severe COPD who meet certain criteria. This means that some patients are being given medication without a known clinical benefit, which puts them at risk of side effects, possibly increasing unnecessary healthcare costs.

First Maintenance Therapy for Chronic Obstructive Pulmonary Disease: Retrospective Analyses of US and UK Healthcare Databases.

INTRODUCTION: Inhaled corticosteroids (ICS) are often prescribed inappropriately alongside long-acting bronchodilators for chronic obstructive pulmonary disease (COPD). We aimed to investigate if prescribing habits in the US and UK differ from recommendations for initiation of COPD maintenance therapy. METHODS: We used healthcare data from the US IBM® MarketScan® and UK Clinical Practice Research Datalink databases to assess exacerbations and comorbidities in patients with COPD initiating first maintenance therapy (1MT) between 2015 and 2018. Patients with a recorded asthma diagnosis prior to initiation of 1MT were excluded. We evaluated time from recorded diagnosis of COPD until initiation of 1MT, and treatment regimen at 1MT (long-acting muscarinic antagonist [LAMA], long-acting ß2-agonist [LABA], ICS, as monotherapy or in combination). RESULTS: In the US and UK, median (IQR) time between recorded COPD diagnosis and 1MT was 158 (12; 839) and 29 (1; 521) days, respectively. Among the 53,473 US patients and 8786 UK patients who initiated 1MT, 50.9% and 32.4% had ≥ 1 exacerbation in the previous year. In the US, 20% of patients initiated LAMA, 1% LABA, 13% LAMA/LABA, and 66% an ICS-containing regimen (49% LABA/ICS, 13% ICS, and 4% LAMA/LABA/ICS). In the UK, 53% of patients initiated LAMA, 4% LABA, 16% LAMA/LABA, and 27% an ICS-containing regimen (14% LABA/ICS, 9% ICS, and 4% LAMA/LABA/ICS). CONCLUSIONS: At 1MT, two-thirds of patients in the US received ICS-containing therapies, with almost half on LABA/ICS. In contrast, less than one-third received ICS-containing therapy in the UK and more than half of patients received LAMA. In both countries, more patients received ICS-containing therapies at initiation of 1MT than would be expected based on their exacerbation history, suggesting overprescribing.

Chronic obstructive pulmonary disease (COPD), a smoking-related lung disease, restricts airflow in the lungs, causing symptoms such as breathlessness and coughing. To control symptoms, patients use one or more types of inhaled 'maintenance' medication, which can be prescribed alone or together. When patients have a short-term worsening of symptoms, doctors often prescribe inhaled corticosteroids (ICS). We wanted to see whether doctors' prescribing habits for maintenance inhalers are in line with clinical guidelines, so we analyzed data from a US health insurance database (~ 50,000 patients) and UK primary care medical records (~ 8000 patients). We focused on patients with a diagnosis of COPD who were prescribed their first maintenance therapy (1MT) between 2015 and 2018. We excluded people with a diagnosis of both COPD and asthma, as similar inhalers are used to treat these conditions, although the clinical decisions for when to prescribe them differ. The average time between COPD diagnosis and 1MT was longer in the US (158 days) than in the UK (29 days). A higher percentage of patients in the US (~ 65%) versus UK (~ 25%) were prescribed ICS as part of their treatment, and ICS use in both countries was higher than expected based on the guidelines, which recommend ICS only for patients with severe COPD who meet certain criteria. Our findings suggest overprescribing of ICS in both countries (particularly the US), meaning that some patients are being given medication without a known clinical benefit, which puts them at risk of side effects, possibly increasing unnecessary healthcare costs.

The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications.

The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis.

Prescription opioid fills following surgical abortion.

OBJECTIVE: To characterize opioid fills after surgical abortion among US commercially-insured women. STUDY DESIGN: We identified women aged 15-50 years with an outpatient claim for dilation and curettage or evacuation surgical abortion (D&C/D&E) in IBM MarketScan 2015-2018 and excluded patients with > 1 opioid fill in the prior 90 days, evidence of opioid dependence or abuse in the prior 180 days (baseline), miscarriage in 7 days prior, or mifepristone use in 3 to 7 days prior. We describe the frequency of an oral opioid fill within 7 days after abortion, refill within 42 days of initial fill, and chronic use (≥ 6 fills) in 1 year after abortion. We used multivariable logistic regression to evaluate predictors of opioid fill including patient and procedure characteristics. RESULTS: Among 28,252 patients who underwent induced surgical abortion, 2,340 (8.3%) filled an opioid prescription within 7 days. The strongest predictors of opioid fill were non-Northeast region, use of moderate sedation for the procedure, and baseline depression. Among 2,250 patients with an initial fill and sufficient follow-up, 10.0% had a refill within 42 days of initial fill. Among 15,353 patients with sufficient follow-up, patients with an opioid fill after abortion had a higher percentage of subsequent chronic use than those without (2.1% and 0.4%, respectively). CONCLUSION: The frequency of an opioid fill after surgical abortion among commercially-insured women was notable given it is not recommended for post-procedural analgesia. Opioid prescribing contrary to recommendations may be associated with subsequent chronic use or abuse. IMPLICATIONS STATEMENT: Despite public health efforts to decrease opioid prescribing, these findings suggest opioid prescribing after surgical abortion as a potential source of overprescribing among commercially insured patients in the United States. As surgical abortion is a minimally-invasive procedure, prescribing opioids for use in this setting may contribute to chronic use.

Prevalence and Incidence of Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype in the United States Estimated in a Large Claims Database Analysis.

INTRODUCTION: Many fibrosing interstitial lung diseases (ILDs) develop a chronic progressive phenotype. While idiopathic pulmonary fibrosis, which is always progressive, is well characterized with established treatment options, the epidemiology of other chronic fibrosing ILDs with a progressive phenotype has not been widely investigated. Treatment options are limited, with a high unmet need. This claims database study estimates the incidence and prevalence of these diseases in the USA. METHODS: Diagnosis, procedure and resource utilization codes from insurance claims were used to identify patients with fibrosing ILD and those with a chronic progressive phenotype among 37,565,644 adult patients in the IBM® MarketScan® Research Database 2012-2015. Two eligible ILD claims were required for a fibrosing ILD diagnosis. Progression was defined using a novel algorithm constituted by criteria considered proxies for progression. Patients were defined as having incident (new) or existing diagnoses based on claims during a 365-day period before study entry. RESULTS: The estimated age- and sex-adjusted prevalence per 100,000 persons of fibrosing ILD (95% confidence interval) was 117.82 (116.56, 119.08) and of chronic fibrosing ILDs with a progressive phenotype was 70.30 (69.32, 71.27). The estimated adjusted incidence per 100,000 patient-years of fibrosing ILD was 51.56 (50.88, 52.24) and of chronic fibrosing ILDs with a progressive phenotype was 32.55 (32.01, 33.09). Among incident fibrosing ILD patients, 57.3% experienced progression over a median of 117 days (interquartile range 63-224), with largely comparable rates of progression among different diseases. CONCLUSIONS: Chronic fibrosing ILDs with a progressive phenotype comprise a relatively new disease construct requiring varied approaches to obtain reliable estimates of prevalence and incidence. This is the first large claims database study using real-world data to provide estimates of the prevalence and incidence of these diseases among a very large segment of the US population and could form the groundwork for future studies.

Progressive lung fibrosis occurs in idiopathic pulmonary fibrosis; however, interstitial lung fibrosis may occur in other diseases such as rheumatoid arthritis, chronic hypersensitivity pneumonitis and sarcoidosis, and may or may not be progressive in these diseases. Little is known about the frequency of lung fibrosis among patients with these diseases or how often such fibrosis is progressive. This study used information from a large insurance claims database (IBM^® MarketScan^®) to estimate the frequency and progression of lung fibrosis associated with different diseases.

Real-world effectiveness of early intervention with fixed-dose tiotropium/olodaterol vs tiotropium in Japanese patients with COPD: a high-dimensional propensity score-matched cohort analysis.

BACKGROUND: Escalation to triple therapy (long-acting muscarinic antagonist/ß2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma. METHODS: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy. RESULTS: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy. CONCLUSIONS: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.

BACKGROUND: Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. METHODS: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication. RESULTS: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. CONCLUSIONS: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

Disease frequency, patient characteristics, comorbidity outcomes and immunosuppressive therapy in systemic sclerosis and systemic sclerosis-associated interstitial lung disease: a US cohort study.

OBJECTIVES: To investigate prevalence estimates and incidence rates (IRs) for SSc and SSc-associated interstitial lung disease (SSc-ILD) cohorts and describe patient characteristics, immunosuppressive therapy (IST) and comorbid outcomes among incident SSc and SSc-ILD cohorts. METHODS: Data were obtained from the US IBM MarketScan (2008-2017) claims database using algorithms developed with expert consultation. For the SSc cohort, newly diagnosed patients (aged ≥18 years) had one or more diagnostic claim for SSc. For the SSc-ILD cohort, patients had an additional ILD claim. Sensitivity analyses using two or more claims or alternative ILD diagnostic codes were also conducted. RESULTS: When requiring one or more diagnostic claim, the prevalence of SSc and SSc-ILD per 100 000 persons was 72.1 and 19.0. The IR for SSc and SSc-ILD per 100 000 person-years was 18.3 and 4.3. Sensitivity analyses requiring two or more claims yielded much lower prevalence (SSc: 41.5; SSc-ILD: 13.3) and IR (SSc: 8.8; SSc-ILD: 1.6) estimates. Patients with SSc-ILD were older, with increased comorbidities and diagnostic procedures at baseline. MTX and MMF were the most common ISTs; 12.7% of the SSc-ILD cohort received therapy at baseline vs 8.2% for SSc. A total of 42.5% and 45.0% of the SSc and SSc-ILD cohorts, respectively, started a stable IST regimen and 21.7% and 19.4% of these had an escalation. Skin disorders were the most common comorbid outcome in both cohorts during follow-up. CONCLUSIONS: SSc, with or without associated ILD, is a rare disease in the US. Newly diagnosed patients with SSc-ILD had received more IST and had more comorbidities compared with newly diagnosed SSc.

Incidence of lower extremity amputations among patients with type 1 and type 2 diabetes in the United States from 2010 to 2014.

AIM: To compare the incidence of lower extremity amputation (LEA) among patients with type 1 diabetes (T1D) and patients with type 2 diabetes (T2D) with those without diabetes using US commercial claims and to assess the presence of key co-morbidities and precipitating factors at the time of the LEA. METHODS: Cohorts were defined via IBM MarketScan research databases for beneficiaries with T1D and T2D during 2010-2014. For each T1D and T2D patient, one patient without a prior diabetic claim matched on calendar time, sex and age, was randomly selected. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals. RESULTS: Among the matched cohorts of 120 129 T1D patients and 1.7 million T2D patients, the incidence of LEA was higher among patients with T1D than patients with T2D, with the most frequent cases being minor LEAs (4.85 and 1.53 per 1000 patient years [PY], respectively), largely toe amputations (4.49 and 1.43 per 1000 PY, respectively). Compared with non-diabetic patients matched on age, sex and calendar time, T1D and T2D patients had more co-morbidities and a higher incidence of LEA (6.02 vs. 0.14 per 1000 PY; aHR, 22.47 [16.42-30.73] and 1.90 vs. 0.23 per 1000 PY; aHR, 4.64 [4.32-4.98]). CONCLUSIONS: Our data showed a higher incidence of LEA, especially minor LEA, in patients with T1D and T2D compared with those without diabetes, with a greater risk among patients with T1D than patients with T2D. Accounting for known and measurable risk factors for LEA reduced the relative hazard by nearly 50%; the majority of LEA cases were minor LEAs and toe amputations.

Actionable Real-World Evidence to Improve Health Outcomes and Reduce Medical Spending Among Risk-Stratified Patients with Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic condition with a high economic burden as well as drug treatments that have not all demonstrated effects on longevity. Managed care organizations want to improve health outcomes in these complex patients but lack actionable evidence to make informed decisions on which therapies are most effective among their members and may also control total health care spending. OBJECTIVE: To produce actionable evidence by identifying antidiabetic treatments that are effective and may reduce total cost of care in various risk groups of patients with T2DM, using insurance claims data that includes medical claims and pharmacy dispensing data among members of Horizon Blue Cross Blue Shield of New Jersey with T2DM. METHODS: We identified patients with T2DM in longitudinal claims data from Horizon between 2014 and 2017 with demographic and enrollment information, inpatient and outpatient diagnoses and procedures, and pharmacy dispensing. Outcomes included myocardial infarction, heart failure (HF), stroke, percutaneous revascularization, health care services utilization, and plan costs (i.e., medical, pharmacy, and total cost of care). After propensity score decile adjustment on over 20 covariates, we evaluated the effectiveness and safety of second-line antidiabetic treatment that included sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas (SUs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. RESULTS: Among 115,308 members with T2DM, the most common comorbidities were cardiovascular risk factors, including hyperlipidemia (56%), hypertension (50%), and existing cardiovascular disease (CVD; 55%). Among members receiving dual antidiabetic treatment (n = 20,204), the most prevalent treatments were metformin plus the following second-line medications: SUs (42%), DPP-4 inhibitors (29%), SGLT-2 inhibitors (10%), or GLP-1 receptor agonists (3%). Approximately 20% of members accounted for 79% of total cost of care, with an average of $9,605 per member per year (PMPY). Compared with SU initiation and after propensity score decile adjustment, new users of SGLT-2 inhibitors had a reduced risk for HF hospitalization (HR = 0.35, 95% CI = 0.13-0.89), hypoglycemia, albuminuria, microvascular disease, and metabolic failure. Among SGLT-2 inhibitor initiators with established CVD, the savings in total cost of care compared with SU initiators was $5,520 per member over an average treatment duration of 6 months and an approximate savings of $11,000 PMPY if patients persisted on treatment for 12 months. CONCLUSIONS: In the Horizon membership, we confirmed that SGLT-2 inhibitors reduce HF hospitalizations, resulting in reduced medical spending and savings in total cost of care. Regulatory-grade analytics of local data provided the confidence to encourage increased SGLT-2 inhibitor use to produce better outcomes and save total cost of care despite higher pharmacy spending. DISCLOSURES: This research did not receive outside funding; however, Aetion has since begun a contractual relationship with Horizon Blue Cross Blue Shield of New Jersey. Garry, Petruski-Ivleva, Cheever, and Rajan are employees of and have stock options in Aetion, a company that makes software for the analysis of real-world data. Eapen was an employee of Aetion during the implementation of this study. Rassen is an employee of and has ownership interest in Aetion. Murk is a consultant to Aetion of which he owns equity. Schneeweiss is a consultant to WHISCON and to Aetion, of which he also owns equity. He is the principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, Boehringer Ingelheim, and Vertex. Gambino is an employee and officer at Horizon Blue Cross and Blue Shield of New Jersey. He was recently appointed to a board observer position at Aetion, as Horizon has small equity interest in Aetion. Jan is an employee of Rutgers State University and Horizon Blue Cross Blue Shield of New Jersey and has no conflict of interest or association with Aetion or any pharmaceutical company. Jang and Rubin are employees of Horizon Blue Cross and Blue Shield of New Jersey and have no conflict of interest or association with Aetion. This work was presented as a poster at AMCP Nexus 2018, October 22-25, 2018, in Orlando, FL; as part of a continuing education session at the AMCP Managed Care & Specialty Pharmacy 2019 Annual Meeting in San Diego, CA, March 25-28, 2019; as invited podium presenter at the Blue Cross Blue Shield 2019 National Summit conference in Grapevine, TX, April 29-May 2, 2019; and was accepted for a podium presentation at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 annual conference in New Orleans, LA, May 18-22, 2019, where it won an award for Best Podium Presentation.

Study design choices for evaluating the comparative safety of diabetes medications: An evaluation of pioglitazone use and risk of bladder cancer in older US adults with type-2 diabetes.

AIM: The aim of the study was to empirically demonstrate the effect of varying study designs when evaluating the safety of pioglitazone in treating bladder cancer. METHODS: We identified Medicare beneficiaries above 65 years of age with diabetes between 2008 and 2015 and with classified exposure (at least two claims within 180 days) to glucose-lowering drugs (GLD), pioglitazone or another drug. The effects of varying the following study design parameters on bladder cancer risk were assessed: use of a new vs existing drug, choice of referent (all non-users and users of GLDs, non-insulin GLDs and DPP-4s) and whether or not censoring accounted for treatment change. We used the Cox proportional hazards model to obtain adjusted HRs and 95% CIs. RESULTS: We included 1,510,212 patients classified as pioglitazone users (N = 135,188) or non-users (N = 1,375,024). Users had more diabetic complications than non-users, but fewer than insulin users. The HR ranged from 1.10 (1.01-1.20) to 1.13 (0.99-1.29) when censoring ignored treatment change, suggesting a weak association or none between pioglitazone and bladder cancer, probably under-estimating risk. However, the HR was 1.20 (1.01-1.42) when cohorts were restricted to new users, censored upon treatment change, and when DPP-4 was used as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone. CONCLUSIONS: The continued demand for new GLDs indicates the need for more robust observational methods to improve the value of generating real-world evidence in equipping clinicians to make informed prescribing decisions. Although there is no one-size-fits-all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates.