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.

Real-world utilization of SARS-CoV-2 serological testing in RNA positive patients across the United States.

BACKGROUND: As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. METHODS: Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. RESULTS: Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred <14 days from the RNA positive test. The proportion of people with a history of cardiovascular disease, obesity, chronic lung, or kidney disease; or presenting with shortness of breath or pneumonia appeared higher among those serotested compared to those who were not. Even in a population of people with active infection, race/ethnicity data were largely missing (>30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. CONCLUSION: Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Real world data (RWD) in pediatrics.

Unique challenges pertain when studying children, although many research principles are the same as those when studying adult populations. This truism extends to the use of real-world data (RWD). RWD are particularly relevant to pediatrics because they may potentially provide an additional source of data to inform pediatric labeling and practice patterns when clinical trials have not been or cannot be conducted. The purpose of this commentary is to provide a brief overview of the unique issues in using RWD to study the effectiveness or safety of medical therapies in children.

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.

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.

Methodologic approaches in studies using real-world data (RWD) to measure pediatric safety and effectiveness of vaccines administered to pregnant women: A scoping review.

OBJECTIVE: This scoping review mapped studies using real-world data (RWD) to measure pediatric safety and effectiveness of vaccines administered to pregnant women. INTRODUCTION: In the US, two vaccines are recommended for all pregnant women to prevent illness in the infant: inactivated influenza vaccine (recommended since 2004), and the combined tetanus-diphtheria-acellular pertussis (Tdap) vaccine (recommended since 2013). This scoping review maps the studies conducted to date that address questions about pediatric safety and effectiveness of vaccines administered during pregnancy and provides a knowledge base for evaluating the use of RWD to study this issue. METHODS: The scoping review was conducted following a published protocol. Methods included an electronic search of PubMed and Embase, screening of titles and abstracts by two reviewers, and double extraction of data for summary and synthesis. Studies that reported on pregnant women and the effectiveness or safety outcomes in their infants were included. RESULTS: Forty-eight studies met the inclusion criteria of the scoping review protocol using RWD to assess safety or effectiveness of influenza or pertussis vaccinations administered to pregnant women with respect to pregnancy, infant or child outcomes. Detailed information about data sources, linkage of maternal and infant data, and operational definitions for gestational age were largely absent from the majority of studies raising concerns about reproducibility and validity of study findings. CONCLUSIONS: A body of literature is available from which to plan and design future studies of vaccination in pregnant women using RWD. This is of intense importance as new vaccines, such as those for COVID-19, become available to the general population via approval or authorization without inclusion of pregnant women in the clinical trials.

Methodologic approaches in studies using real-world data to measure pediatric safety and effectiveness of vaccines administered to pregnant women: a scoping review protocol.

OBJECTIVE: This scoping review aims to map studies using real-world data (RWD) to measure pediatric safety and effectiveness of vaccines administered to pregnant women. INTRODUCTION: In the United States, two vaccines are recommended for all pregnant women to prevent illness in the infant: inactivated influenza vaccine (recommended since 2004) and the combined tetanus-diphtheria-acellular pertussis (Tdap) vaccine (recommended since 2013). Because of the ethical constraints in conducting randomized clinical trials to measure the effects on the infant, there is great interest in using electronic health care data or administrative claims data to study the effects of maternal immunization on the infant's health, and it is anticipated that such studies may be submitted to support regulatory decision-making. This scoping review will map the studies conducted to date that address these questions and provide a context for considering the regulatory issues that may arise in the future. INCLUSION CRITERIA: Studies that report on pregnant women receiving immunization and the effectiveness or safety outcomes in their infants will be included. Study participants may be from any population or country, of any reproductive age, and with any health status. Studies will be included if they use real-world data (from electronic health records, administrative claims, pharmacy benefit records, or registries). METHODS: An electronic search of PubMed and Embase will identify citations for screening. The search will be limited to studies published in English during the preceding 10 years. Two reviewers will screen citations in a two-step process (titles and abstracts, then full-text articles), and two reviewers will extract data for summary and synthesis.

Real-World Evidence to Assess Medication Safety or Effectiveness in Children: Systematic Review.

BACKGROUND: The promise of real-world evidence (RWE) is especially relevant to pediatrics, where medicines prescribed for children are often used without evidence derived from randomized clinical trials. OBJECTIVES: The aim of this systematic review was to describe the state of RWE in pediatrics by identifying observational studies published during 2016 that used RWE to assess medication safety or effectiveness in children. METHODS: An electronic search of PubMed was combined with an extended search of references within systematic reviews and expert suggestions. Studies were included if they reported on an infant or child under 18 years with exposure to medications; assessed safety or effectiveness; specified a comparison or control group, and were published in English in 2016. Data extraction was conducted by one team member using a standardized form and reviewed by a second team member. Study quality was assessed using the GRACE checklist for rating the quality of observational studies. RESULTS: After removing duplicates, 915 citations were screened and 29 studies met the eligibility criteria. Most of the eligible studies relied on primary data collection or chart review at a single institution and did not use the growing number of administrative or electronic health record databases available. One-quarter of the studies did not use well-established statistical methods to control for confounders. No single disease group or medication predominated, and age groups ranged from infants to adolescents. CONCLUSIONS: A small body of observational studies published in 2016 were categorized by the study team as using real-world data to assess medication safety or effectiveness in children. Studies varied in age groups, diseases or conditions, and methods, and may not have fully met the FDA definition of RWE. Our review indicates that the use of RWE is not fully developed in pediatrics, and suggests an opportunity to further develop capabilities and more fully leverage administrative and electronic health record databases to study medication safety and effectiveness in children. Our systematic review appears generalizable to pediatrics broadly, and documents that the high level of activity in RWE in general has had less of an impact on pediatrics.

In the Real-World, Kids Use Medications and Devices.

In the real world, we lack evidence guiding the use of medications and devices in children. This lack of evidence arose out of the challenges of conducting clinical trials in children and other vulnerable populations and the historical decision (reversed in recent decades) to exclude children from clinical trials. The recent focus on the potential of real-world evidence (RWE) to guide approval and use of new treatments may provide a much-needed solution. A broad definition of RWE includes prospective observational data and data from electronic health records and claims, as well as other sources. For the most part, it is reasonable to expect that considerations around the use of RWE in adult populations will apply to its use in children. However, a number of issues around the use of RWE are unique to studying children. These fall into at least four categories: (1) identification of databases with adequate numbers of children in the age sub-groups of interest, (2) access to critical variables such as birth date, birth weight, and gestational age, (3) linkage to parental records for information about pre-natal exposures, family history, and socio-economic status, and (4) linkage to school records for information about outcomes such as missed school days, academic progress, and behavioral issues. Addressing the needs of children in developing methodologies for use of RWE ensures that ongoing efforts will benefit children as well as other sectors of the population.

Current needs in pediatric pharmacoepidemiology.

PURPOSE: We report on a needs assessment conducted by the International Society of Pharmacoepidemiology (ISPE) Pediatric Special Interest Group (SIG) to identify critical needs in pediatric pharmacoepidemiology and directions for future activities. METHODS: A mixed methods survey using a structured interview was conducted in the SIG and ISPE membership to elicit information about current activities in pediatric pharmacoepidemiology and identify critical methodologic issues. The interviews were conducted in two phases over 2013 and 2014, beginning with interviews of SIG members and expanding to the wider ISPE membership. Members of the SIG conducted the interviews and summarized the responses. RESULTS: Twenty-nine ISPE members participated in the needs assessment The respondents reported working with a total of 59 distinct databases, with only eight databases used by more than one respondent. Seventeen respondents (57%) reported issues of limited sample sizes, noting that the problem intensifies when studying age sub-groups or specific genetic populations. Missing data elements were a problem in three main areas: lack of detailed medication information, inability to link to parental data, and lack of detailed information about age. Respondents reported the need for data elements not typically required in studies of adults, such as birthweight and current height and weight, as well as school performance and mental health status. CONCLUSIONS: Our needs assessment describes a preliminary picture of the emerging sub-specialty of pediatric pharmacoepidemiology encompassing a range of age sub-groups, disease areas, and medical specialties. The assessment also documents a body of methodologic challenges unique to pharmacoepidemiologic research in children. Copyright © 2016 John Wiley & Sons, Ltd.

Pediatric vancomycin use in 421 hospitals in the United States, 2008.

BACKGROUND: Recommendations to prevent the spread of vancomycin resistance have been in place since 1995 and include guidelines for inpatient pediatric use of vancomycin. The emergence of large databases allows us to describe variation in pediatric vancomycin across hospitals. We analyzed a database with hospitalizations for children under 18 at 421 hospitals in 2008. METHODOLOGY/PRINCIPAL FINDINGS: The Premier hospital 2008 database, consisting of records for 877,201 pediatric hospitalizations in 421 hospitals, was analyzed. Stratified analyses and logistic mixed effects models were used to calculate the probability of vancomycin use while considering random effects of hospital variation, hospital fixed effects and patient effects, and the hierarchical structure of the data. Most hospitals (221) had fewer than 10 hospitalizations with vancomycin use in the study period, and 47 hospitals reported no vancomycin use in 17,271 pediatric hospitalizations. At the other end of the continuum, 21 hospitals (5.6% of hospitals) each had over 200 hospitalizations with vancomycin use, and together, accounted for more than 50% of the pediatric hospitalizations with vancomycin use. The mixed effects modeling showed hospital variation in the probability of vancomycin use that was statistically significant after controlling for teaching status, urban or rural location, size, region of the country, patient ethnic group, payor status, and APR-mortality and severity codes. CONCLUSIONS/SIGNIFICANCE: The number and percentage of pediatric hospitalizations with vancomycin use varied greatly across hospitals and was not explained by hospital or patient characteristics in our logistic models. Public health efforts to reduce vancomycin use should be intensified at hospitals with highest use.

Use of analgesic, anesthetic, and sedative medications during pediatric hospitalizations in the United States 2008.

BACKGROUND: The wide need for analgesia, anesthesia, and sedation in children and the lack of pediatric labeling leads to widespread off-label use of medications for pain and sedation in children. Any attempt to address the lack of labeling will require national estimates of the numbers of children using each medication, their ages, and other factors, to understand the overall use of these medications. We describe use of analgesics, anesthetics, and sedatives in pediatric inpatients by result of conducting a statistical analysis of medication data from >800,000 pediatric hospitalizations in the United States. The purpose was to provide national estimates for the percentage of hospitalized children receiving specific analgesics, anesthetics, and sedatives and their use by age group. METHODS: Data from the Premier Database, the largest hospital-based, service-level comparative database in the country, were used. We identified all uses of a given medication, selected the first use for each child, and calculated the prevalence of use of specific medications among hospitalized children in 2008 as the number of hospitalizations in which the drug was used per 100 hospitalizations. Dose and number of doses were not considered in these analyses. RESULTS: The dataset contained records for 877,201 hospitalizations of children younger than 18 years of age at the time of admission. Thirty-three medications and an additional 11 combinations were administered in this population, including nonsteroidal antiinflammatory drugs, local and regional anesthetics, opioids, benzodiazepines, sedative-hypnotics, barbiturates, and others. The 10 most frequently administered analgesic, anesthetic, or sedative medications used in this population were acetaminophen (14.7%), lidocaine (11.0%), fentanyl (6.6%), ibuprofen (6.3%), morphine (6.2%), midazolam (4.5%), propofol (4.1%), lidocaine/prilocaine (2.5%), hydrocodone/acetaminophen (2.1%), and acetaminophen/codeine (2.0%). Use changed with age, and the direction of change (increases and decreases) and the type of change (linear, u-shaped, or other) appeared to be specific to each drug. CONCLUSIONS: A variety of drug classes and individual medications were used to manage pain and sedation in hospitalized children. The variation in patterns of use reflects the heterogeneity of the dataset, comprising a wide range of ages and conditions in which analgesia, anesthesia, and sedation might be required. It was not possible to assess whether use of a specific medication was clinically appropriate, except to note use of medications in age subgroups without pediatric labeling.

Morphine use in hospitalized children in the United States: a descriptive analysis of data from pediatric hospitalizations in 2008.

BACKGROUND: Morphine is among the top 10 medications given to children in the inpatient setting. It is not labeled for any pediatric indication, making it one of the drugs most widely used off-label in pediatrics. OBJECTIVES: The aims of this study were to describe the epidemiology of morphine use in pediatric inpatients in the United States and to describe the characteristics of patients and hospitals in hospitalizations with morphine use. METHODS: Deidentified data from the Premier Perspective Database (2008) were analyzed. Morphine use was defined as any morphine administration during the hospital stay and estimated by patient age in years, sex, race, and type of insurance; and hospital bedsize, teaching status, setting (urban or rural), and geographic location. Proportions (95% CI) were calculated for the entire population and for individual strata. The estimate was applied to national data to calculate the number of pediatric hospitalizations with morphine use in the United States in 2008. Logistic mixed-effects modeling was used to calculate the probability of morphine use by hospital after controlling for hospital and patient effects. RESULTS: The database contained records from 877,201 pediatric hospitalizations and 423 hospitals in the United States. Morphine was administered in 54,613 of pediatric hospitalizations (6.2%). Use was higher in boys than girls (6.4% and 6.1%, respectively) and in blacks compared with whites or other racial groups (7.5%, 6.7%, and 5.0%). Use increased from 1.6% in children aged <2 years to 27.4% in those aged 12 to 17 years. Based on these data, morphine may have been administered in 476,205 pediatric hospitalizations in the United States in 2008. The 2 diagnoses most frequently associated with morphine use were appendicitis (14.4%) and fracture (11.1%). On logistic mixed-effects modeling for patients with appendicitis and for patients with fractures, there was hospital variation in morphine use after controlling for variables in the model. CONCLUSIONS: Based on the data from this analysis, morphine was used in hospitalized children in all age groups, despite the lack of pediatric labeling. Common conditions such as appendicitis and fracture were leading diagnoses associated with morphine use.

Dopamine and dobutamine use in preterm or low birth weight neonates in the premier 2008 database.

BACKGROUND: Dobutamine and dopamine are off-patent drugs prioritized by the National Institute of Child Health and Human Development and US Food and Drug Administration for further study under the Best Pharmaceuticals for Children Act. Both agents are used to manage cardiac insufficiency in preterm neonates and are subject to controversy among neonatologists. Among the controversies are outcome measures (blood pressure vs end organ perfusion) and long-term effects. OBJECTIVES: We analyzed retrospective hospitalization data to (1) describe the use of dopamine and dobutamine in low birth weight (LBW) or preterm infants in a large sample and (2) explore the potential of using observational data to describe outcomes in LBW or preterm infants treated with dopamine or dobutamine. METHODS: Inpatient data were extracted from the Premier database to calculate the prevalence of use of dopamine and dobutamine among neonates in 2008. Prevalence of use was calculated by categorizing patients as ever or never having received dopamine or dobutamine. We compared mortality in the neonates by using Cox proportional hazards models to identify variables associated with survival and to control for their effects. RESULTS: Out of 877,201 pediatric hospitalizations in 2008, 65,216 were neonates and had data available about dopamine and dobutamine use. Of these, 7459 were preterm or LBW and included 1143 very LBW (VLBW) neonates. Dopamine alone was given to 194 VLBW neonates, dobutamine alone was given to 14, and both dopamine and dobutamine were given to 79 neonates. For the VLBW neonates, probability of treatment with dopamine or dobutamine varied almost 10-fold from 4.4% to 38.4% at 11 hospitals and did not differ by 3M APR-DRG (all patient refined diagnosis related group) severity of illness or 3M APR-DRG risk of mortality. CONCLUSIONS: Our data suggest the prevalence of dopamine or dobutamine use was 4.9% in preterm or LBW neonates and 25.1% in VLBW neonates. Treatment with dopamine alone was more common than treatment with dobutamine alone. There was no difference in mortality between neonates treated with dopamine compared with treatment with dobutamine, but access to charts and clinical details are required to conduct a comparative effectiveness study.

Children's hospitalizations with a mood disorder diagnosis in general hospitals in the united states 2000-2006.

BACKGROUND: Mood disorders including depression and bipolar disorders are a major cause of morbidity in childhood and adolescence, and hospitalizations for mood disorders are the leading diagnosis for all hospitalizations in general hospitals for children age 13 to 17. We describe characteristics of these hospitalizations in the U.S. focusing on duration of stay, charges, and geographic variation. METHODS: The Kids' Inpatient Database was analyzed to calculate hospitalization rates for 2000, 2003, and 2006. For each year, information was available for over 2 million hospitalizations, representing 6.3 to 6.5 million hospital stays annually in acute care, non-psychiatric hospitals. RESULTS: The rate of pediatric hospitalizations with a principal diagnosis of a mood disorder was 12.4/10,000 in 2000, 13.0 in 2003, and 12.1 in 2006. In the same period, the incidence of hospitalizations for depressive disorders decreased from 9.1 to 6.4/10,000 children while the incidence of hospitalizations for bipolar disorders increased from 3.3 to 5.7/10,000 children. The mean length of stay increased from 7.1 to 7.7 days, while inflation-adjusted hospital charges increased from $10,600 in 2000, to $13,700 in 2003, to $16,300 in 2006. The proportion of mood disorder stays paid by government increased from 35.3% to 45.2%. The Western region experienced the lowest rates (9.9/10,000, 11.6 and 10.2 in 2000, 2003 and 2006) while the Midwest had the highest rates (26.4, 27.6, and 25.4). CONCLUSIONS: Mood disorders are a major reason for hospitalization during development, especially in adolescence. Mood disorder hospitalizations remained relatively constant from 2000-2006, but diagnoses of depressive disorders decreased while diagnoses of bipolar disorders increased. Hospitalization rates vary widely by region of the country.