Feasibility of using real-world data to emulate substance use disorder clinical trials: a cross-sectional study.

INTRODUCTION: Real-world evidence is receiving considerable attention as a way to evaluate the efficacy and safety of medical products for substance use disorders (SUDs). However, the feasibility of using real-world data (RWD) to emulate clinical trials evaluating treatments for SUDs is uncertain. The aim of this study is to identify the number of clinical trials evaluating treatments for SUDs with reported results that could be feasibly emulated using observational data from contemporary insurance claims and/or electronic health record (EHR) data. METHODS: In this cross-sectional study, all phase 2-4 trials evaluating treatments for SUDs registered on ClinicalTrials.gov with reported results were identified. Each trial was evaluated to determine if the indications, interventions, at least 80% of eligibility criteria, comparators, and primary end points could be ascertained using contemporarily available administrative claims and/or structured EHR data. RESULTS: There were 272 SUD trials on ClinicalTrials.gov with reported results. Of these, when examining feasibility using contemporarily available administrative claims and/or structured EHR data, 262 (96.3%) had indications that were ascertainable; 194 (71.3%) had interventions that were ascertainable; 21 (7.7%) had at least 80% of eligibility criteria that were ascertainable; 17 (6.3%) had active comparators that were ascertainable; and 61 (22.4%) had primary end points that were ascertainable. In total, there were no trials for which all 5 characteristics were ascertainable using contemporarily available administrative claims and/or structured EHR data. When considering placebo comparators as ascertainable, there were 6 (2.2%) trials that had all 5 key characteristics classified as ascertainable from contemporarily available administrative claims and/or structured EHR data. CONCLUSIONS: No trials evaluating treatments for SUDs could be feasibly emulated using contemporarily available RWD, demonstrating a need for an increase in the resolution of data capture within a public health system to facilitate trial emulation.

A Nationwide Emergency Department Data Analysis to Predict Beers List Medications Use Among Older Adults.

BACKGROUND: The use of potentially inappropriate medications (PIMs) is considered an important quality indicator for older adults seen in the ambulatory care setting. STUDY OBJECTIVES: To evaluate the pattern of potentially inappropriate medication (PIMs) use as specified in the Beers Criteria, for older adults during emergency department (ED) visits in the United States. METHODS: Using data from the National Hospital Ambulatory Care Survey (NHAMCS) we identified older adults (age 65 or older) discharged home from an ED visit in 2019. We defined PIMs as those with an 'avoid' recommendation under the American Geriatrics Society (AGS) 2019 Beers Criteria in older adults. Logistic regression models were used to assess demographic, clinical, and hospital factors associated with the use of any PIMs upon ED discharge. RESULTS: Overall, 5.9% of visits by older adults discharged from the ED included administration or prescriptions for PIMs. Among those who received any PIMs, 25.5% received benzodiazepines, 42.5 % received anticholinergics, 1.4% received nonbenzodiazepine hypnotics, and 0.5% received barbiturates. A multivariable model showed statistically significant associations for age 65 to 74 (OR 1.91, 95% CI 1.39-2.62 vs. age >=75), dementia (OR 0.45, 95% CI 0.21-0.95), lower immediacy (OR 2.45, 95% CI 1.56-3.84 vs. higher immediacy), and Northeastern rural region (OR 0.34, 95% CI 0.21-0.55 vs. Midwestern rural). CONCLUSION: We found that younger age and lower immediacy were associated with increased prescriptions of PIMs for older adults seen, while dementia and Northeastern rural region was associated with reduced use of PIMs seen and discharged from EDs in United States.

Assessing the use of observational methods and real-world data to emulate ongoing randomized controlled trials.

BACKGROUND/AIMS: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. METHODS: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). RESULTS: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. CONCLUSION: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

Safety and effectiveness of benzodiazepines and antipsychotics for agitation in older adults in the emergency department.

PURPOSE: To examine the safety and effectiveness of benzodiazepines (BZD) as compared to antipsychotics for the management of acute agitation in older adults in the emergency department (ED). BASIC PROCEDURES: Retrospective observational cohort study of 21 EDs across four states in the US, including adults ≥60 years old who received either BZD or antipsychotics for acute agitation in the ED and subsequently were admitted to the hospital. Safety was measured as presence of adverse events: respiratory depression, cardiovascular effects, extrapyramidal side effects, or a fall during hospitalization. Effectiveness was measured as indicators of treatment failure: need for additional medication, one-to-one observation, or physical restraints following initial medication administration. Proportions and odds ratios with 95% confidence intervals (CI) were calculated. Univariable and multivariable logistic regression were used to assess the association between potential risk factors and for efficacy and safety endpoints. MAIN FINDINGS: A total of 684 patients were included (63.9% received a BZD and 36.1% an antipsychotic). There was no difference in the incidence of adverse events between groups (20.6% vs 14.6%, difference 6.0%, 95% CI -0.2% to 11.8%), but there was a higher intubation rate in the BZD group (2.7% vs 0.4%, difference 2.3%). There were more treatment failures in the antipsychotic group for the composite primary efficacy endpoint (94.3% vs 87.6%, difference 6.7%, 95% CI 2.5% to 10.9%). This appears to have been driven by the need for 1:1 observation; sensitivity analysis excluding 1:1 observation in the composite outcome demonstrated no significant difference with a failure rate of 38.5% in the antipsychotic group and 35.2% in the benzodiazepine group. PRINCIPAL CONCLUSIONS: Overall there are high rates of treatment failure among agitated older adults receiving pharmacological treatment for agitation in the emergency department. The optimal selection of pharmacological treatment for agitation in older adults should be made considering patient-specific factors that could increase the risk of adverse effects or treatment failure.

Use of Potentially Nephrotoxic Medications by U.S. Adults with Chronic Kidney Disease: NHANES, 2011-2016.

BACKGROUND: People with chronic kidney disease (CKD) are at risk for adverse events and/or CKD progression with use of renally eliminated or nephrotoxic medications. OBJECTIVE: To examine the prevalence of potentially inappropriate medication (PIM) use by U.S. adults by CKD stage and self-reported CKD awareness. DESIGN: Cross-sectional analysis of National Health and Nutrition Examination Surveys, 2011-2016 PARTICIPANTS: Non-pregnant adults with stages 3a (eGFR 45-59 mL/min/1.73 m2), 3b (eGFR 30-44), or 4-5 (eGFR < 30) CKD, stratified as CKD-aware/unaware. MAIN MEASURES: PIMs were identified on the basis of KDIGO guidelines, label information, and literature review. We calculated proportions using any and individual PIMs, assessing for differences over CKD awareness within each CKD stage. Analyses were adjusted for age, sex, race/ethnicity, education, comorbidities, and insurance type. KEY RESULTS: Adjusted proportions of U.S. adults taking any PIM(s) exceeded 50% for all CKD stages and awareness categories, and were highest among CKD-unaware patients with stages 4-5 CKD: 66.6% (95% CI, 55.5-77.8). Proton pump inhibitors, opioids, metformin, sulfonylureas, and non-steroidal anti-inflammatory drugs (NSAIDs) were all used frequently across CKD stages. NSAIDs were used less frequently when CKD-aware by patients with stage 3a CKD (2.2% [95% CI, - 0.3 to 4.7] vs. 10.7% [95% CI, 7.6 to 13.8]) and stages 4-5 CKD (0.8% [95% CI, - 0.9 to 2.5] vs. 16.5% [95% CI, 4.0 to 29.0]). Metformin was used less frequently when CKD-aware by patients with stage 3b CKD (8.1% [95% CI, 0.3-15.9] vs. 26.5% [95% CI, 17.4-35.7]) and stages 4-5 CKD (none vs. 20.8% [95% CI, 1.8-39.8]). The impact of CKD awareness was statistically significant after correction for multiple comparisons only for NSAIDs in stage 3a CKD. CONCLUSIONS: PIMs are frequently used by people with CKD, with some impact of CKD awareness on NSAID and metformin use. This may lead to adverse outcomes or hasten CKD progression, reinforcing the need for improved medication management among people with CKD.

Opioid Prescribing for Opioid-Naive Patients in Emergency Departments and Other Settings: Characteristics of Prescriptions and Association With Long-Term Use.

STUDY OBJECTIVE: We explore the emergency department (ED) contribution to prescription opioid use for opioid-naive patients by comparing the guideline concordance of ED prescriptions with those attributed to other settings and the risk of patients' continuing long-term opioid use. METHODS: We used analysis of administrative claims data (OptumLabs Data Warehouse 2009 to 2015) of opioid-naive privately insured and Medicare Advantage (aged and disabled) beneficiaries to compare characteristics of opioid prescriptions attributed to the ED with those attributed to other settings. Concordance with Centers for Disease Control and Prevention (CDC) guidelines and rate of progression to long-term opioid use are reported. RESULTS: We identified 5.2 million opioid prescription fills that met inclusion criteria. Opioid prescriptions from the ED were more likely to adhere to CDC guidelines for dose, days' supply, and formulation than those attributed to non-ED settings. Disabled Medicare beneficiaries were the most likely to progress to long-term use, with 13.4% of their fills resulting in long-term use compared with 6.2% of aged Medicare and 1.8% of commercial beneficiaries' fills. Compared with patients in non-ED settings, commercial beneficiaries receiving opioid prescriptions in the ED were 46% less likely, aged Medicare patients 56% less likely, and disabled Medicare patients 58% less likely to progress to long-term opioid use. CONCLUSION: Compared with non-ED settings, opioid prescriptions provided to opioid-naive patients in the ED were more likely to align with CDC recommendations. They were shorter, written for lower daily doses, and less likely to be for long-acting formulations. Prescriptions from the ED are associated with a lower risk of progression to long-term use.

Integrating 4 methods to evaluate physical function in patients with cancer (In4M): protocol for a prospective cohort study.

INTRODUCTION: Accurate, patient-centred evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterise the longitudinal measurement characteristics of physical function assessments, including clinician-reported outcome, patient-reported ported outcome (PRO), performance outcome tests and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice. METHODS AND ANALYSIS: In this prospective study, we are enrolling 200 English-speaking and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centred health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multimodal physical function data collection in real-world patients with breast cancer or lymphoma will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform and PROs. ETHICS AND DISSEMINATION: This study has received approval from IRBs at Mayo Clinic, Yale University and the US Food and Drug Administration. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT05214144; Pre-results.

Association Between New 340B Program Participation and Commercial Insurance Spending on Outpatient Biologic Oncology Drugs.

Importance: Previous studies have found that hospitals participating in the 340B Drug Pricing Program have higher Medicare Part B spending and expansion into affluent neighborhoods. Less is known about the association of 340B participation with spending by commercial insurance, where reimbursements are higher than Medicare. Objective: To use the Affordable Care Act expansion of eligibility for the 340B Drug Pricing Program to study the association between participation and spending on outpatient-administered oncological drugs for commercially insured patients. Design, Setting, and Participants: This cohort study included a balanced panel hospital cohort containing new and never 340B program participants between 2007 and 2019; more recent data were not included to avoid the effect of disruptions in care due to the COVID-19 pandemic. Descriptive analyses documented spending trends for patients receiving common outpatient-administered biologics used in cancer treatments (bevacizumab, filgrastim, pegfilgrastim, rituximab, and trastuzumab) at 340B (treated) and non-340B (control) hospitals. A difference-in-differences model assessed changes in episode drug spending. Analyses were conducted between December 2021 and June 2022. Exposure: New 340B program participation between 2010 and 2016. Main Outcome and Measures: Total drug episode spending, with control variables including total billed units, drug, calendar-year fixed effects, and hospital fixed effects. Results: Of 95 127 included episodes (56 917 [59.8%] episodes in female patients) across 478 hospitals, patients seen in 340B and non-340B hospitals were similar in sex and drug used, and 340B hospital patients were older than non-340B patients (median [IQR] age for all patients, 61 [51-71] years). New 340B participating hospitals were more likely to be small (<50 beds) and more likely to be in rural settings. In the difference-in-differences analysis, total episode drug spending increased by $4074.69 (95% CI, $1592.84-$6556.70; P = .001) in the year following start of 340B program participation relative to nonparticipants. Heterogeneous group time effects were seen, with earlier participants less likely to have increased episode spending. Conclusions and Relevance: In this cohort study, new 340B participation was associated with statistically significant higher oncological drug episode spending compared with nonparticipants after changes in 340B inclusion rules in 2010. These findings raise questions about unintended consequences of the 340B program on drug spending from the commercially insured population.

Provider barriers in uptake of biosimilars: case study on filgrastim.

In this article, we used administrative claims data from the OptumLabs Data Warehouse and American Hospital Association Annual Survey data to examine associations between hospital characteristics and uptake of biosimilar granulocyte colony-stimulating factor treatments. We found that 340B-participating hospitals and non-rural referral center (RRC) hospitals that reported owning rural health clinics were less likely to administer the lower-cost biosimilars, whereas the opposite was true for hospitals that are RRCs. To our knowledge, our study offers a first look at an underappreciated source of disparities in access to lower-cost medications such as biosimilars. Results from our study reveal opportunities for targeted policies to encourage adoption of lower-cost treatments, particularly among hospitals that serve rural communities where patients often have fewer choices in care site.

National trends in emergency conditions through the Omicron COVID-19 wave in commercial and Medicare Advantage enrollees.

Objective: To evaluate trends in emergency care sensitive conditions (ECSCs) from pre-COVID (March 2018-February 2020) through Omicron (December 2021-February 2022). Methods: This cross-sectional analysis evaluated trends in ECSCs using claims (OptumLabs Data Warehouse) from commercial and Medicare Advantage enrollees. Emergency department (ED) visits for ECSCs (acute appendicitis, aortic aneurysm/dissection, cardiac arrest/severe arrhythmia, cerebral infarction, myocardial infarction, pulmonary embolism, opioid overdose, pre-eclampsia) were reported per 100,000 person months from March 2018 to February 2022 by pandemic wave. We calculated the percent change for each pandemic wave compared to the pre-pandemic period. Results: There were 10,268,554 ED visits (March 2018-February 2022). The greatest increases in ECSCs were seen for pulmonary embolism, cardiac arrest/severe arrhythmia, myocardial infarction, and pre-eclampsia. For commercial enrollees, pulmonary embolism visit rates increased 22.7% (95% confidence interval [CI], 18.6%-26.9%) during Waves 2-3, 37.2% (95% CI, 29.1%-45.8%] during Delta, and 27.9% (95% CI, 20.3%-36.1%) during Omicron, relative to pre-pandemic rates. Cardiac arrest/severe arrhythmia visit rates increased 4.0% (95% CI, 0.2%-8.0%) during Waves 2-3; myocardial infarction rates increased 4.9% (95% CI, 2.1%-7.8%) during Waves 2-3. Similar patterns were seen in Medicare Advantage enrollees. Pre-eclampsia visit rates among reproductive-age female enrollees increased 31.1% (95% CI, 20.9%-42.2%), 23.7% (95% CI, 7.5%,-42.3%), and 34.7% (95% CI, 16.8%-55.2%) during Waves 2-3, Delta, and Omicron, respectively. ED visits for other ECSCs declined or exhibited smaller increases. Conclusions: ED visit rates for acute cardiovascular conditions, pulmonary embolism and pre-eclampsia increased despite declines or stable rates for all-cause ED visits and ED visits for other conditions. Given the changing landscape of ECSCs, studies should identify drivers for these changes and interventions to mitigate them.

Integrating 4 Measures to Evaluate Physical Function in Patients with Cancer (In4M): Protocol for a prospective study.

Introduction: Accurate, patient-centered evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterize the longitudinal measurement characteristics of physical function assessments, including clinician-reported physical function (ClinRo), patient-reported physical function (PRO), performance outcome tests (PerfO) and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice. Methods and analysis: In this prospective study, we are enrolling 200 English- and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive standard of care intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centered health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity, and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multi-modal physical function data collection in real-world patients with cancer will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform, and PROs. Ethics and dissemination: This study has received approval from IRBs at Mayo Clinic, Yale University, and the U.S. Food & Drug Administration. Results will be made available to participants, funders, the research community, and the public. Registration Details: The trial registration number for this study is NCT05214144. Strengths & Limitations: This study addresses an important unmet need by characterizing the performance characteristics of multiple patient-centered physical function measures in patients with cancerPhysical function is an important and undermeasured clinical outcome. Scientifically rigorous capture and measurement of physical function constitutes a key component of cancer treatment tolerability assessment both from a regulatory and clinical perspective.This study will include patients with lymphoma or breast cancer receiving a broad range of cytotoxic chemotherapy regimens. While recruitment will occur at two academic sites, patients who ultimately receive treatment at local community sites will be included.A patient-centered health data aggregating platform facilitates the delivery of patient-reported outcome measures and collection of wearable data to researchers, while reducing patient burden compared to traditional patient-generated data collection and aggregation methodsHeterogeneity in patient willingness or comfort engaging with mobile products including smartphones and wearables, enrollment primarily at large academic centers, and the modest sample size are potential limitations to the external validity of the study.

The effectiveness of a health promotion program after 3 years: evidence from the University of Minnesota.

BACKGROUND: Health promotion programs for the workplace are often sold to employers with the promise that they will pay for themselves with lowered health care expenditures and reduced absenteeism. In a recent review of the literature, it was noted that analysts often caution not to expect a positive return on investment until the third year of operation. OBJECTIVE: This study investigates whether a positive return on investment was generated in the third year for the health promotion program used by the University of Minnesota. It further investigates what it is about the third year that would explain such a phenomenon. MEASURES: The study uses health care expenditure data and absenteeism data from 2004 to 2008 to investigate the effect of the University's lifestyle and disease management programs. It also investigates the effectiveness of participation in Minnesota's 10,000 Steps walking program and Miavita self-help programs. RESEARCH DESIGN: A differences-in-differences equations approach is used to address potential selection bias. Possible regression to the mean is dealt with by using only those who were eligible to participate as control observations. Propensity score weighting was used to balance the sample on observable characteristics and reduce bias due to omitted variables. RESULTS: The study finds that a 1.76 return on investment occurs in the third year of operation that is generated solely by the effect of disease management program participation in reducing health care expenditures. However, neither of the explanations for a third-year effect we tested seemed to be able to explain this phenomenon.

Changes in opioid marketing practices after release of the CDC guidelines.

OBJECTIVES: After the release of the CDC guidelines in March 2016, the rate of opioid prescriptions decreased. How or whether pharmaceutical companies changed their opioid marketing practices post release of the CDC guidelines is unknown. Our objectives were to (1) evaluate whether the release of the guidelines was associated with changes in total monthly marketing spending received per physician, monthly marketing encounter frequency per physician, and spending per encounter during opioid marketing; and (2) evaluate whether such changes in marketing differed between specialist physicians and primary care physicians (PCPs) and between urban and rural primary care service areas (PCSAs). STUDY DESIGN: Retrospective observational cross-sectional study using opioid marketing spending data from the CMS Open Payments database between August 2013 and December 2017. METHODS: Single-group and multiple-group interrupted time series analyses were used to evaluate differences in the immediate changes in level and trend over time in opioid marketing practices post release of the CDC guidelines. RESULTS: Post release of the CDC guidelines, the monthly number of marketing encounters per physician and total monthly amount received per physician decreased. However, the amount spent at each marketing encounter increased. The release of the CDC guidelines was associated with an immediate increase in level of opioid marketing spending per encounter by $0.59 (95% CI, $0.51-$0.68; P < .001) and an over-time increase in rate of spending per encounter of $0.04 per month (95% CI, $0.03-$0.05; P < .001). These changes differed between specialists and PCPs and between urban and rural PCSAs. CONCLUSIONS: It is important to continue ongoing education for physicians on changes in pharmaceutical opioid marketing practices.

Association of opioid fills with centers for disease control and prevention opioid guidelines and payer coverage policies: physician, insurance and geographic factors.

Background The Centers for Disease Control and Prevention (CDC) issued guidelines and certain healthcare payers have made pharmacy coverage changes (PCC) focusing on regulating prescription opioids. Aim We evaluated differences in the rate of first-time opioid fills at doses ≥ 50 morphine milligram equivalents (MME)/day and first-time opioid fills with benzodiazepine fill overlap following the CDC guidelines and following a PCC between provider types, geographic locations, and insurance types. Method We used OptumLabs® Data Warehouse claims data between 2014 and 2018. Subjects were opioid naïve non-cancer care patients, 18 years and older who had an identified chronic pain condition ICD diagnosis within 2 weeks prior to their first-time opioid fill. We used multiple treatment period segmented regression analysis with interaction terms to test the differences between primary care providers (PCPs) and specialist providers (SPs), urban and rural primary care service areas (PCSAs), and Medicare Advantage (MA) and commercially insured patients (CIPs) in their first-time opioid fill patterns. Results Prescribing first-time opioid fills at doses ≥ 50MME/day declined following the CDC guidelines and PCC, the decline was greater among SPs than PCPs and in rural PCSAs than urban PCSAs. Also, following the CDC guidelines, the decline was greater among MA patients however following the PCC the decline was greater among CIPs. There were no differences in rate of first-time opioid fill with benzodiazepine overlap between groups. Conclusion Responses to the CDC opioid guidelines and a PCC differed between PCPs and SPs, urban and rural PCSAs, and when prescribing to MA and CIPs. Understanding these differences is important to help inform future guidelines.

Association of outpatient use of renin-angiotensin-aldosterone system blockers on outcomes of acute respiratory illness during the COVID-19 pandemic: a cohort study.

OBJECTIVES: Evaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19. DESIGN: Retrospective cohort. SETTING: The USA; 2017-2018 influenza season, 2018-2019 influenza season, and 2019-2020 influenza/COVID-19 season. PARTICIPANTS: People with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. MAIN OUTCOME MEASURES: Change in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons. RESULTS: The cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (-0.2 pp, 95% CI -0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)). CONCLUSIONS: People with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

PreScription DigitaL ThErapEutic for Patients with Insomnia (SLEEP-I): a protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Cognitive behavioural therapy for insomnia (CBT-I) is effective at treating chronic insomnia, yet in-person CBT-I can often be challenging to access. Prior studies have used technology to bridge barriers but have been unable to extensively assess the impact of the digital therapeutic on real-world patient experience and multidimensional outcomes. Among patients with insomnia, our aim is to determine the impact of a prescription digital therapeutic (PDT) (PEAR-003b, FDA-authorised as Somryst; herein called PDT) that provides mobile-delivered CBT-I on patient-reported outcomes (PROs) and healthcare utilisation. METHODS AND ANALYSIS: We are conducting a pragmatically designed, prospective, multicentre randomised controlled trial that leverages Hugo, a unique patient-centred health data-aggregating platform for data collection and patient follow-up from Hugo Health. A total of 100 participants with insomnia from two health centres will be enrolled onto the Hugo Health platform, provided with a linked Fitbit (Inspire 2) to track activity and then randomised 1:1 to receive (or not) the PDT for mobile-delivered CBT-I (Somryst). The primary outcome is a change in the insomnia severity index score from baseline to 9-week postrandomisation. Secondary outcomes include healthcare utilisation, health utility scores and clinical outcomes; change in sleep outcomes as measured with sleep diaries and a change in individual PROs including depressive symptoms, daytime sleepiness, health status, stress and anxiety. For those allocated to the PDT, we will also assess engagement with the PDT. ETHICS AND DISSEMINATION: The Institutional Review Boards at Yale University and the Mayo Clinic have approved the trial protocol. This trial will provide important data to patients, clinicians and policymakers about the impact of the PDT device delivering CBT-I on PROs, clinical outcomes and healthcare utilisation. Findings will be disseminated to participants, presented at professional meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04909229.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Site of care potentially limits cost savings from biosimilars.

OBJECTIVES: The first FDA-approved biosimilar was launched in 2015: filgrastim-sndz (Zarxio), a biosimilar for the reference drug filgrastim (Neupogen). Filgrastim is a granulocyte colony-stimulating factor used to prevent and treat neutropenia. In this study, we examined the association between site of care and drug cost across reference filgrastim, tbo-filgrastim (Granix; a version of filgrastim approved as a biosimilar in Europe and as a new drug in the United States), and biosimilar filgrastim administrations among the commercially insured. STUDY DESIGN: Retrospective study using administrative claims data. METHODS: We used OptumLabs Data Warehouse to identify the site of care of each short-acting filgrastim administration among commercial enrollees between January 1, 2014, and December 31, 2019. RESULTS: For each filgrastim product, model-adjusted median drug costs were higher in the outpatient hospital setting than for the same drug administered in the office setting. Comparing drug costs within the same setting, in the office setting, costs of biosimilar and tbo-filgrastim were $103.61 and $94.07 lower than reference filgrastim, respectively (P < .001 for each comparison). In the outpatient hospital setting, adjusted median costs for tbo-filgrastim were lower than those for reference filgrastim (-$132.90; P < .001), but adjusted median costs of the biosimilar were slightly higher ($20.50; P = .025). CONCLUSIONS: Although previous work has found lower costs for biosimilar filgrastim compared with reference filgrastim, here we found that site of care can change this calculus, reducing savings. After adjusting for patient characteristics and geography, we found that drug cost savings for biosimilar filgrastim were limited to the office setting, with no savings in the outpatient hospital setting.

Epidemiology of paediatric pain-related visits to emergency departments in the USA: a cross-sectional study.

OBJECTIVE: To describe the epidemiology of paediatric pain-related visits to emergency departments (EDs) across the USA. DESIGN: Cross-sectional study. SETTING: A representative sample of US ED visits using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). PARTICIPANTS: Paediatric (age ≤18 years) ED visits in the 2017 NHAMCS data set. DATA ANALYSIS: Each visit was coded as pain-related or non-pain-related using the 'reason for visit' variable. Weighted proportions were calculated with 95% CIs. Logistic regression was used to compare odds of pain-related visits. OUTCOME MEASURES: Prevalence of pain-related visits among paediatric ED visits. RESULTS: There were an estimated 35 million paediatric ED visits in the USA in 2017, 55.6% (CI 53.3% to 57.8%) were pain related, which equates to 19.7 million annual visits. The prevalence of pain-related visits reached more than 50% of visits at age 6-7 and plateaued at relatively high proportions. Children of races other than white or black had lower odds of having a pain-related visit (OR 0.48, CI 0.29 to 0.81) than white children, as did children who were black, though the difference was not statistically significant (OR 0.88, CI 0.73 to 1.06). Relative to children covered by private insurance, children with Medicaid or CHIP (Children's Health Insurance Program) coverage had lower odds of a pain-related visit (OR 0.75, CI 0.60 to 0.93). Injuries represented 46.5% (CI 42.0% to 51.0%) of pain-related visits. Pain scores were reported in less than 50% of pain-related visits. CONCLUSION: Pain is the reason for visit in 55.6% of paediatric ED visits across the USA. The prevalence of pain-related visits peak before adolescence and it continues relatively high until the age 18. Injury, racial disparities in pain and poor pain score reporting should remain major topics of study in the paediatric population.