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Leah L Zullig,1,2 Walid F Gellad,3,4 Jivan Moaddeb,2,5 Matthew J Crowley,1,2 William Shrank,6 Bradi B Granger,7 Christopher B Granger,8 Troy Trygstad,9 Larry Z Liu,10 Hayden B Bosworth1,2,7,11 1Center for Health Services Research in Primary Care, Durham Veterans Affairs Medical Center, Durham, NC, USA; 2Department of Medicine, Duke University, Durham, NC, USA; 3Center for Health Equity Research and Promotion, Pittsburgh Veterans Affairs Medical Center, Pittsburgh, PA, USA; 4Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 5Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; 6CVS Caremark Corporation; 7School of Nursing, Duke University, Durham, NC, USA; 8Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA; 9North Carolina Community Care Networks, Raleigh, NC, USA; 10Pfizer, Inc., and Weill Medical College of Cornell University, New York, NY, USA; 11Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA Abstract: Effective medications are a cornerstone of prevention and disease treatment, yet only about half of patients take their medications as prescribed, resulting in a common and costly public health challenge for the US healthcare system. Since poor medication adherence is a complex problem with many contributing causes, there is no one universal solution. This paper describes interventions that were not only effective in improving medication adherence among patients with diabetes, but were also potentially scalable (ie, easy to implement to a large population). We identify key characteristics that make these interventions effective and scalable. This information is intended to inform healthcare systems seeking proven, low resource, cost-effective solutions to improve medication adherence. Keywords: medication adherence, diabetes mellitus, chronic disease, dissemination research, implementation research, review

Background: Although four-dollar programs ($4 per 30-day supply for selected generic drugs) have become important options for seniors to obtain affordable medications, little is known about access to these programs and the characteristics of those who use them.Objectives: We quantify access to $4 programs based on driving distance; evaluate factors affecting the program use and potential cost-savings associated with switching to $4 programs in Medicare.Design: Observational study.Setting: US Medicare Part D data, 5% random sample, 2007Participants: 347,653 elderly beneficiaries without Medicaid coverage or low-income subsidies.Main Measures: We evaluated how use of $4 programs was affected by driving distance to the store and the beneficiary's demographic and socioeconomic status, insurance coverage, health status, comorbidities, and medication use. For those who did not use the $4 programs, we calculated potential savings from switching to $4 generics.Key Results: Eighty percent of seniors in Medicare Part D filled prescriptions for generic drugs that were commonly available at $4 programs. Among them, only 16.3% filled drugs through $4 programs. Beneficiaries who lived in poor areas, had less insurance, more co-morbidities, and used more drugs and lived closer to $4 generic retail pharmacies, were more likely to use these programs. Blacks were less likely to use the program relative to Whites (15.0% vs. 16.4%; OR=0.75, 95% CI 0.71-0.80). While 53.2% of nonusers would save by switching to $4 program after incorporating travelling costs, 58% of those who could save would have net annual out-of-pocket savings of less than $20.Conclusions: The take-up rate of $4 programs was low in 2007 among Medicare beneficiaries. As more stores offer $4 programs and increasing numbers of drugs become generic, more beneficiaries could potentially benefit, as could the Medicare program. [ABSTRACT FROM AUTHOR]

BACKGROUND: Medication nonadherence is a common problem among the elderly. OBJECTIVE: To conduct a systematic review of the published literature describing potential nonfinancial barriers to medication adherence among the elderly. METHODS: The PubMed and PsychINFO databases were searched for articles published in English between January 1998 and January 2010 that (1) described 'predictors,' 'facilitators,' or 'determinants' of medication adherence or that (2) examined the 'relationship' between a specific barrier and adherence for elderly patients (ie, >=65 years of age) in the United States. A manual search of the reference lists of identified articles and the authors' files and recent review articles was conducted. The search included articles that (1) reviewed specific barriers to medication adherence and did not solely describe nonmodifiable predictors of adherence (eg, demographics, marital status), (2) were not interventions designed to address adherence, (3) defined adherence or compliance and specified its method of measurement, and (4) involved US participants only. Nonsystematic reviews were excluded, as were studies that focused specifically on people who were homeless or substance abusers, or patients with psychotic disorders, tuberculosis, or HIV infection, because of the unique circumstances that surround medication adherence for each of these populations. RESULTS: Nine studies met inclusion criteria for this review. Four studies used pharmacy records or claims data to assess adherence, 2 studies used pill count or electronic monitoring, and 3 studies used other methods to assess adherence. Substantial heterogeneity existed among the populations studied as well as among the measures of adherence, barriers addressed, and significant findings. Some potential barriers (ie, factors associated with nonadherence) were identified from the studies, including patient-related factors such as disease-related knowledge, health literacy, and cognitive function; drug-related factors such as adverse effects and polypharmacy; and other factors including the patient-provider relationship and various logistical barriers to obtaining medications. None of the reviewed studies examined primary nonadherence or nonpersistence. CONCLUSION: Medication nonadherence in the elderly is not well described in the literature, despite being a major cause of morbidity, and thus it is difficult to draw a systematic conclusion on potential barriers based on the current literature. Future research should focus on standardizing medication adherence measurements among the elderly to gain a better understanding of this important issue. [ABSTRACT FROM AUTHOR]

This study estimates how out-of-pocket drug costs could change for vulnerable populations (racial and ethnic minorities, the near-poor, and seniors with a greater burden of chronic conditions) who qualify for the standard Medicare drug benefit. Although the new benefit might be associated with modest-to-moderate declines in out-of-pocket spending for seniors who do not qualify for subsidies, the savings might not be shared equitably and therefore might not reduce financial barriers to medication use for these populations. [ABSTRACT FROM AUTHOR]

Importance: Drug shortages are a persistent public health issue that increased during the COVID-19 pandemic. Both the US and Canada follow similar regulatory standards and require reporting of drug-related supply chain issues that may result in shortages. However, it is unknown what proportion are associated with meaningful shortages (defined by a significant decrease in drug supply) and whether differences exist between Canada and the US., Objective: To compare how frequently reports of drug-related supply chain issues in the US vs Canada were associated with drug shortages., Design, Setting, and Participants: Longitudinal cross-sectional study conducted from January 2023 to March 2024 using drug-related reports of supply chain issues from 2017 to 2021 that were less than 180 days apart in Canada and the US. Shortages were assessed using data from the IQVIA Multinational Integrated Data Analysis database, comprising 89% of US and 100% of Canadian drug purchases., Exposure: Country (Canada vs US), timing of report issuance (before vs after the COVID-19 pandemic), and characteristics of the supply chain prior to the reports of drug-related supply chain issues (including World Health Organization essential medicine status, Health Canada tier 3 medicine [moderate risk classification], whether there was sole-source manufacturing of the drug, the formulation, the price per unit, ≥20 years since drug approval, and the number of therapeutic alternatives)., Main Outcomes and Measures: A drug shortage (a decrease of ≥33% in monthly purchased standardized drug units) within 12 months, relative to the average units purchased during the 6 months prior to the report of supply chain issues to a US or Canadian reporting system., Results: Among the 104 drug-related reports of supply chain issues in both countries, 49.0% (95% CI, 39.3%-59.7%) were associated with drug shortages in the US vs 34.0% (95% CI, 25.0%-45.0%) in Canada (adjusted hazard ratio [HR], 0.53 [95% CI, 0.36-0.79]). The lower risk of drug shortages in Canada vs the US was consistent before the COVID-19 pandemic (adjusted HR, 0.47 [95% CI, 0.30-0.75]) and after the pandemic (adjusted HR, 0.31 [95% CI, 0.15-0.66]). After combining reports of supply chain issues in both countries, the shortage risk was double for sole-sourced drugs (adjusted HR, 2.58 [95% CI, 1.57-4.24]) and nearly half for Canadian tier 3 medicines (moderate risk) (adjusted HR, 0.56 [95% CI, 0.32-0.98])., Conclusions and Relevance: Drug-related reports of supply chain issues were 40% less likely to result in meaningful drug shortages in Canada compared with the US. These findings highlight the need for international cooperation between countries to curb the effects of drug shortages and improve resiliency of the supply chain for drugs.

Background: Integrating advanced machine-learning (ML) algorithms into clinical practice is challenging and requires interdisciplinary collaboration to develop transparent, interpretable, and ethically sound clinical decision support (CDS) tools. We aimed to design a ML-driven CDS tool to predict opioid overdose risk and gather feedback for its integration into the University of Florida Health (UFHealth) electronic health record (EHR) system., Methods: We used user-centered design methods to integrate the ML algorithm into the EHR system. The backend and UI design sub-teams collaborated closely, both informed by user feedback sessions. We conducted seven user feedback sessions with five UF Health primary care physicians (PCPs) to explore aspects of CDS tools, including workflow, risk display, and risk mitigation strategies. After customizing the tool based on PCPs' feedback, we held two rounds of one-on-one usability testing sessions with 8 additional PCPs to gather feedback on prototype alerts. These sessions informed iterative UI design and backend processes, including alert frequency and reappearance circumstances., Results: The backend process development identified needs and requirements from our team, information technology, UFHealth, and PCPs. Thirteen PCPs (male = 62%, White = 85%) participated across 7 user feedback sessions and 8 usability testing sessions. During the user feedback sessions, PCPs (n = 5) identified flaws such as the term "high risk" of overdose potentially leading to unintended consequences (e.g., immediate addiction services referrals), offered suggestions, and expressed trust in the tool. In the first usability testing session, PCPs (n = 4) emphasized the need for natural risk presentation (e.g., 1 in 200) and suggested displaying the alert multiple times yearly for at-risk patients. Another 4 PCPs in the second usability testing session valued the UFHealth-specific alert for managing new or unfamiliar patients, expressed concerns about PCPs' workload when prescribing to high-risk patients, and recommended incorporating the details page into training sessions to enhance usability., Conclusions: The final backend process for our CDS alert aligns with PCP needs and UFHealth standards. Integrating feedback from PCPs in the early development phase of our ML-driven CDS tool helped identify barriers and facilitators in the CDS integration process. This collaborative approach yielded a refined prototype aimed at minimizing unintended consequences and enhancing usability., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Prior research documented racial and ethnic disparities in health care experiences within the Veterans Health Administration (VA). Little is known about such differences in VA-funded community care programs, through which a growing number of Veterans receive health care. Community care is available to Veterans when care is not available through the VA, nearby, or in a timely manner., Objective: To examine differences in Veterans' experiences with VA-funded community care by race and ethnicity and assess changes in these experiences from 2016 to 2021., Design: Observational analyses of Veterans' ratings of community care experiences by self-reported race and ethnicity. We used linear and logistic regressions to estimate racial and ethnic differences in community care experiences, sequentially adjusting for demographic, health, insurance, and socioeconomic factors., Participants: Respondents to the 2016-2021 VA Survey of Healthcare Experiences of Patients-Community Care Survey., Measures: Care ratings in nine domains., Key Results: The sample of 231,869 respondents included 24,306 Black Veterans (mean [SD] age 56.5 [12.9] years, 77.5% male) and 16,490 Hispanic Veterans (mean [SD] age 54.6 [15.9] years, 85.3% male). In adjusted analyses pooled across study years, Black and Hispanic Veterans reported significantly lower ratings than their White and non-Hispanic counterparts in five of nine domains (overall rating of community providers, scheduling a recent appointment, provider communication, non-appointment access, and billing), with adjusted differences ranging from - 0.04 to - 0.13 standard deviations (SDs) of domain scores. Black and Hispanic Veterans reported higher ratings with eligibility determination and scheduling initial appointments than their White and non-Hispanic counterparts, and Black Veterans reported higher ratings of care coordination, with adjusted differences of 0.05 to 0.21 SDs. Care ratings improved from 2016 to 2021, but differences between racial and ethnic groups persisted., Conclusions: This study identified small but persistent racial and ethnic differences in Veterans' experiences with VA-funded community care, with Black and Hispanic Veterans reporting lower ratings in five domains and, respectively, higher ratings in three and two domains. Interventions to improve Black and Hispanic Veterans' patient experience could advance equity in VA community care., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Coronavirus disease 2019 (COVID-19) has been associated with an increased risk of stroke. It remains unclear whether the risk of stroke associated with a diagnosis of COVID-19 differed with oral anticoagulation (OAC) use. The aim of this study was to evaluate the association between COVID-19 infection, OAC use, and stroke in patients with atrial fibrillation (AF)., Methods: A retrospective cohort study was conducted in individuals with established AF using data from Optum's deidentified Clinformatics ® Data Mart Database. Cox proportional hazard models with time-dependent variables were employed to assess the association between possession of OAC, COVID-19 diagnosis in both inpatient and outpatient setting, and time to ischemic stroke., Results: A total of 561,758 individuals aged 77 ± 10 were included in the study, with a mean follow up time of 1.3 years. OAC use was associated with a reduced stroke risk [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.82-0.88]. COVID-19 infection was associated with an increased risk of stroke (HR 2.11, 95% CI 1.87-2.38); this increased risk was particularly pronounced for patients diagnosed with an inpatient diagnosis of COVID-19 (HR 3.95, 95% CI 3.33-4.68). There was no significant interaction between OAC use and COVID-19 diagnosis (p value = 0.96). As a result, the relative increase in stroke risk associated with COVID-19 did not differ between patients on OAC (HR 2.12; 95% CI 1.71-2.62) and those not on OAC (HR 2.11; 95% CI 1.83-2.43)., Conclusion: In a nationwide sample of patients with established AF, we found the relative increase in stroke risk associated with COVID-19 was independent of OAC use., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Over half of veterans enrolled in the Veterans Health Administration (VA) are also enrolled in Medicare, potentially increasing their opportunity to receive low-value health services within and outside VA., Objectives: To characterize the use and cost of low-value services delivered to dually enrolled veterans from VA and Medicare., Design: Retrospective cross-sectional., Participants: Veterans enrolled in VA and fee-for-service Medicare (FY 2017-2018)., Main Measures: We used VA and Medicare administrative data to identify 29 low-value services across 6 established domains: cancer screening, diagnostic/preventive testing, preoperative testing, imaging, cardiovascular testing, and surgery. We determined the count of low-value services per 100 veterans delivered in VA and Medicare in FY 2018 overall, by domain, and by individual service. We applied standardized estimates to determine each service's cost., Key Results: Among 1.6 million dually enrolled veterans, the mean age was 73, 97% were men, and 77% were non-Hispanic White. Overall, 63.2 low-value services per 100 veterans were delivered, affecting 32% of veterans; 22.9 services per 100 veterans were delivered in VA and 40.3 services per 100 veterans were delivered in Medicare. The total cost was $226.3 million (M), of which $62.6 M was spent in VA and $163.7 M in Medicare. The most common low-value service was prostate-specific antigen testing at 17.3 per 100 veterans (VA 55.9%, Medicare 44.1%). The costliest low-value service was percutaneous coronary intervention (VA $10.1 M, Medicare $32.8 M)., Conclusions: Nearly 1 in 3 dually enrolled veterans received a low-value service in FY18, with twice as many low-value services delivered in Medicare vs VA. Interventions to reduce low-value services for veterans should consider their substantial use of such services in Medicare., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Veterans dually enrolled in the Veterans Health Administration (VA) and Medicare commonly experience downstream services as part of a care cascade after an initial low-value service. Our objective was to characterize the frequency and cost of low-value cervical cancer screening and subsequent care cascades among Veterans dually enrolled in VA and Medicare., Methods: This retrospective cohort study used VA and Medicare administrative data from fiscal years 2015 to 2019. The study cohort was comprised of female Veterans aged >65 years and at low risk of cervical cancer who were dually enrolled in VA and Medicare. Within this cohort, we compared differences in the rates and costs of cascade services related to low-value cervical cancer screening for Veterans who received and did not receive screening in FY2018, adjusting for baseline patient- and facility-level covariates using inverse probability of treatment weighting., Results: Among 20,972 cohort-eligible Veterans, 494 (2.4%) underwent low-value cervical cancer screening with 301 (60.9%) initial screens occurring in VA and 193 (39%) occurring in Medicare. Veterans who were screened experienced an additional 26.7 (95% CI, 16.4-37.0) cascade services per 100 Veterans compared to those who were not screened, contributing to $2919.4 (95% CI, -265 to 6104.7) per 100 Veterans in excess costs. Care cascades consisted predominantly of subsequent cervical cancer screening procedures and related outpatient visits with low rates of invasive procedures and occurred in both VA and Medicare., Conclusions: Veterans dually enrolled in VA and Medicare commonly receive related downstream tests and visits as part of care cascades following low-value cervical cancer screening. Our findings demonstrate that to fully capture the extent to which individuals are subject to low-value care, it is important to examine downstream care stemming from initial low-value services across all systems from which individuals receive care., (© 2024 The American Geriatrics Society.)

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Importance: Racial and ethnic disparities exist in anticoagulation therapy for atrial fibrillation (AF). Whether medical center racial and ethnic composition is associated with these disparities is unclear., Objective: To determine whether medical center racial and ethnic composition is associated with overall anticoagulation and disparities in anticoagulation for AF., Design, Setting, and Participants: Retrospective cohort study of Black, White, and Hispanic patients with incident AF from 2018 to 2021 at 140 Veterans Health Administration medical centers (VAMCs). Data were analyzed from March to November 2023., Exposure: VAMC racial and ethnic composition, defined as the proportion of patients from minoritized racial and ethnic groups treated at a VAMC, categorized into quartiles. VAMCs in quartile 1 (Q1) had the lowest percentage of patients from minoritized groups (ie, the reference group)., Main Outcomes and Measures: The odds of initiating any anticoagulant, direct-acting oral anticoagulant (DOAC), or warfarin therapy within 90 days of an index AF diagnosis, adjusting for sociodemographics, medical comorbidities, and facility factors., Results: The cohort comprised 89 791 patients with a mean (SD) age of 73.0 (10.1) years; 87 647 (97.6%) were male, 9063 (10.1%) were Black, 3355 (3.7%) were Hispanic, and 77 373 (86.2%) were White. Overall, 64 770 individuals (72.1%) initiated any anticoagulant, 60 362 (67.2%) initiated DOAC therapy, and 4408 (4.9%) initiated warfarin. Compared with White patients, Black and Hispanic patients had lower rates of any anticoagulant and DOAC therapy initiation but higher rates of warfarin initiation across all quartiles of VAMC racial and ethnic composition. Any anticoagulant therapy initiation was lower in Q4 than Q1 (69.8% vs 74.9%; adjusted odds ratio [aOR], 0.80; 95% CI, 0.69-0.92; P < .001). DOAC and warfarin initiation were also lower in Q4 than in Q1 (DOAC, 69.4% vs 65.3%; aOR, 0.85; 95% CI, 0.74-0.97; P < .001; warfarin, 5.4% vs 4.5%; aOR, 0.82; 95% CI, 0.67-1.00; P < .001). In adjusted models, patients in Q4 were significantly less likely to initiate any anticoagulant therapy than those in Q1 (aOR, 0.88; 95% CI, 0.78-0.99). Patients in Q3 (aOR, 0.75; 95% CI, 0.60-0.93) and Q4 (aOR, 0.69; 95% CI, 0.55-0.87) were significantly less likely to initiate warfarin therapy than those in Q1. There was no significant difference in the adjusted odds of initiating DOAC therapy across racial and ethnic composition quartiles. Although significant Black-White and Hispanic-White differences in initiation of any anticoagulant, DOAC, and warfarin therapy were observed, interactions between patient race and ethnicity and VAMC racial composition were not significant., Conclusions and Relevance: In a national cohort of VA patients with AF, initiation of any anticoagulant and warfarin, but not DOAC therapy, was lower in VAMCs serving more minoritized patients.

Importance: Accurately predicting major bleeding events in non-valvular atrial fibrillation (AF) patients on direct oral anticoagulants (DOACs) is crucial for personalized treatment and improving patient outcomes, especially with emerging alternatives like left atrial appendage closure devices. The left atrial appendage closure devices reduce stroke risk comparably but with significantly fewer non-procedural bleeding events., Objective: To evaluate the performance of machine learning (ML) risk models in predicting clinically significant bleeding events requiring hospitalization and hemorrhagic stroke in non-valvular AF patients on DOACs compared to conventional bleeding risk scores (HAS-BLED, ORBIT, and ATRIA) at the index visit to a cardiologist for AF management., Design: Prognostic modeling with retrospective cohort study design using electronic health record (EHR) data, with clinical follow-up at one-, two-, and five-years., Setting: University of Pittsburgh Medical Center (UPMC) system., Participants: 24,468 non-valvular AF patients aged ≥18 years treated with DOACs, excluding those with prior history of significant bleeding, other indications for DOACs, on warfarin or contraindicated to DOACs., Exposures: DOAC therapy for non-valvular AF., Main Outcomes and Measures: The primary endpoint was clinically significant bleeding requiring hospitalization within one year of index visit. The models incorporated demographic, clinical, and laboratory variables available in the EHR at the index visit., Results: Among 24,468 patients, 553 (2.3%) had bleeding events within one year, 829 (3.5%) within two years, and 1,292 (5.8%) within five years of index visit. We evaluated multivariate logistic regression and ML models including random forest, classification trees, k-nearest neighbor, naive Bayes, and extreme gradient boosting (XGBoost) which modestly outperformed HAS-BLED, ATRIA, and ORBIT scores in predicting clinically significant bleeding at 1-year follow-up. The best performing model (random forest) showed area under the curve (AUC-ROC) 0.76 (0.70-0.81), G-Mean score of 0.67, net reclassification index 0.14 compared to 0.57 (0.50-0.63), G-Mean score of 0.57 for HASBLED score, p-value for difference <0.001. The ML models had improved performance compared to conventional risk across time-points of 2-year and 5-years and within the subgroup of hemorrhagic stroke. SHAP analysis identified novel risk factors including measures from body mass index, cholesterol profile, and insurance type beyond those used in conventional risk scores., Conclusions and Relevance: Our findings demonstrate the superior performance of ML models compared to conventional bleeding risk scores and identify novel risk factors highlighting the potential for personalized bleeding risk assessment in AF patients on DOACs.

Background: Active surveillance pharmacovigilance is an emerging approach to identify medications with unanticipated effects. We previously developed a framework called pharmacopeia-wide association studies (PharmWAS) that limits false positive medication associations through high-dimensional confounding adjustment and set enrichment. We aimed to assess the transportability and generalizability of the PharmWAS framework by using medical claims data to reproduce known medication associations with Clostridioides difficile infection (CDI) or gastrointestinal bleeding (GIB)., Methods: We conducted case-control studies using Optum's de-identified Clinformatics Data Mart Database of individuals enrolled in large commercial and Medicare Advantage health plans in the United States. Individuals with CDI (from 2010 to 2015) or GIB (from 2010 to 2021) were matched to controls by age and sex. We identified all medications utilized prior to diagnosis and analysed the association of each with CDI or GIB using conditional logistic regression adjusted for risk factors for the outcome and a high-dimensional propensity score., Findings: For the CDI study, we identified 55,137 cases, 220,543 controls, and 290 medications to analyse. Antibiotics with Gram-negative spectrum, including ciprofloxacin (aOR 2.83), ceftriaxone (aOR 2.65), and levofloxacin (aOR 1.60), were strongly associated. For the GIB study, we identified 450,315 cases, 1,801,260 controls, and 354 medications to analyse. Antiplatelets, anticoagulants, and non-steroidal anti-inflammatory drugs, including ticagrelor (aOR 2.81), naproxen (aOR 1.87), and rivaroxaban (aOR 1.31), were strongly associated., Interpretation: These studies demonstrate the generalizability and transportability of the PharmWAS pharmacovigilance framework. With additional validation, PharmWAS could complement traditional passive surveillance systems to identify medications that unexpectedly provoke or prevent high-impact conditions., Funding: U.S. National Institute of Diabetes and Digestive and Kidney Diseases., Competing Interests: Declaration of interests RKV and WFG are employees of the Department of Veterans Affairs in the United States. This research does not necessarily represent the views of Department of Veterans Affairs or the United States Government. ARB, RF: No relevant disclosures. SDR: Co-Investigator on NIH grant R01-HS027985 from the National Institutes of Health (the funder of this research). RES: Research support from Exact Sciences, Immunovia, and Freenome not related to this research. JDL: Consulted for AbbVie, Merck, Scipher Medicine, Eli Lilly. Served on advisory board for Amgen, Arena Pharmaceuticals, Galapagos, Gilead, Janssen Pharmaceuticals, Pfizer, Protagonist Therapeutics, and Sanofi. He has had research funding from Nestle Health Science, Takeda, Janssen Pharmaceuticals, and AbbVie. He has performed legal work on behalf of generic manufacturers of ranitidine, including L. Perrigo Company, Glenmark Pharmaceuticals Inc., Amneal Pharmaceuticals LLC, Aurobindo Pharma USA, Inc., Dr. Reddy’s Laboratories, Inc., Novitium Pharma, Ranbaxy Inc. and Sun Pharmaceutical Industries, Inc., Strides Pharma, Inc., and Wockhardt USA LLC. He owns stock in Dark Canyon Labs. He has received honoraria from Nestle Health Science, and Celgene., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Oral anticoagulation reduces stroke risk for patients with atrial fibrillation (AF). Prior research demonstrates lower anticoagulant prescribing in Black than in White individuals but few studies have examined racial differences in facility-level anticoagulant prescribing for AF., Objective: To assess variation in anticoagulant initiation by race within Veterans Health Administration (VA) facilities., Design: Retrospective cohort study., Participants: Black and White patients enrolled in the VA with incident AF from 2020 through 2021., Main Measures: The primary outcome was rate of any anticoagulant initiation (i.e., warfarin or direct oral anticoagulant [DOAC]) or any DOAC therapy within 90 days of an AF diagnosis, overall and for Black and White patients at each facility. We also estimated the adjusted Black-White risk difference., Key Results: In 82 VA facilities serving 26,832 Black and White patients, overall unadjusted rates of any anticoagulant therapy ranged from 56.8 to 87.1% across facilities; the corresponding ranges for Black and White patients were 47.6 to 91.3% and 58.2 to 87.1%, respectively. Overall unadjusted rates of DOAC therapy ranged from 55.1 to 85.5% by facility; ranges for Black and White patients were 42.8 to 86.9% and 56.4 to 85.5%, respectively. The adjusted risk difference between Black and White patients ranged from - 29.9 (95% CI, - 54.9 to - 4.8) to 14.2 (95% CI, - 9.1 to 25.0) across facilities for any anticoagulant therapy and from - 28.8 (95% CI, - 58.3 to 0.8) to 15.0 (95% CI, - 8.0 to 38.1) for DOAC therapy. For any anticoagulant therapy there were 3 facilities where prescribing was statistically higher in White than Black patients; for DOAC therapy there were 5 such facilities., Conclusions: In a national cohort of patients with AF, we observed large facility-level variation and adjusted risk differences in any anticoagulant and DOAC initiation, overall and by race. These findings represent a target for local quality improvement in AF care., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Study Objective: The COVID-19 pandemic disrupted multiple aspects of the health care system, including the diagnosis and control of chronic conditions. This study aimed to quantify pandemic-related changes in the rates of clinical events among patients with atrial fibrillation (AF)., Design/setting/participants: In this retrospective cohort study, we identified individuals with established AF at any time before 2019 using de-identified Optum's Clinformatics® Data Mart, and followed them from 3/18/2019 to death, or disenrollment, or the end of the study (09/30/2021)., Main Outcome: Rates of clinical event, including all-cause hospitalization, ischemic stroke, and bleeding. We constructed interrupted time series to test changes in outcomes after the onset of the COVID-19 pandemic (3/11/2020, date of pandemic declaration). We then identified the first month after the start of the pandemic in which outcomes returned to pre-pandemic levels., Results: A total of 561,758 patients, with a mean age of 77 ± 9.9 years, were included in the study. The monthly incidence rate of all-cause hospitalization decreased from 2.8 % in the period immediately before the pandemic declaration to 1.7 % in the period immediately after, with p -value for level change<0.001. The rate of new ischemic stroke diagnoses decreased from 0.28 % in the period immediately before pandemic declaration to 0.20 % in the period immediately after, and the rate of major bleeding diagnoses from 0.81 % to 0.59 %, both p -values for level change<0.01. The incidence rate of ischemic stroke and bleeding events returned to pre-pandemic levels in October and November 2020, respectively., Conclusions: The COVID-19 pandemic was associated with a decrease in health care visits for ischemic stroke and bleeding in a nationwide cohort of patients with established AF., Competing Interests: Inmaculada Hernandez reports financial support was provided by National Heart Lung and Blood Institute (grants K01HL142847 and R01HL15705). Dr. Magnani is funded by R33HL144669 and R01HL143010. Dr. Guo is funded by NIDDK R01DK133465 and PhRMA Foundation Research Starter Award. The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Hernandez has received consulting fees from Pfizer and Bristol Myers Squibb, outside of the submitted work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives., Methods: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups., Results: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12)., Conclusions: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system., (© 2024 John Wiley & Sons Ltd.)

Importance: Drug shortages are a chronic and worsening issue that compromises patient safety. Despite the destabilizing impact of the COVID-19 pandemic on pharmaceutical production, it remains unclear whether issues affecting the drug supply chain were more likely to result in meaningful shortages during the pandemic., Objective: To estimate the proportion of supply chain issue reports associated with drug shortages overall and with the COVID-19 pandemic., Design, Setting, and Participants: This longitudinal cross-sectional study used data from the IQVIA Multinational Integrated Data Analysis database, comprising more than 85% of drug purchases by US pharmacies from wholesalers and manufacturers, from 2017 to 2021. Data were analyzed from January to May 2023., Exposure: Presence of a supply chain issue report to the US Food and Drug Administration or the American Society of Health-Systems Pharmacists (ASHP)., Main Outcomes and Measures: The main outcome was drug shortage, defined as at least 33% decrease in units purchased within 6 months of a supply chain issue report. Random-effects logistic regression models compared the marginal odds of shortages for drugs with vs without reports. Interaction terms assessed heterogeneity prior to vs during the COVID-19 pandemic and by drug characteristics (formulation, age, essential medicine status, clinician- vs self-administered, sales volume, and number of manufacturers)., Results: A total of 571 drugs exposed to 731 supply chain issue reports were matched to 7296 comparison medications with no reports. After adjusting for drug characteristics, 13.7% (95% CI, 10.4%-17.8%) of supply chain issue reports were associated with subsequent drug shortages vs 4.1% (95% CI, 3.6%-4.8%) of comparators (marginal odds ratio [mOR], 3.7 [95% CI, 2.6-5.1]). Shortages increased among both drugs with and without reports in February to April 2020 (34.2% of drugs with supply chain issue reports and 9.5% of comparison drugs; mOR, 4.9 [95% CI, 2.1-11.6]), and then decreased after May 2020 (9.8% of drugs with reports and 3.6% of comparison drugs; mOR, 2.9 [95% CI, 1.6-5.3]). Significant associations were identified by formulation (parenteral mOR, 1.9 [95% CI, 1.1-3.2] vs oral mOR, 5.4 [95% CI, 3.3-8.8]; P for interaction = .008), WHO essential medicine status (essential mOR, 2.2 [95% CI, 1.3-5.2] vs nonessential mOR, 4.6 [95% CI, 3.2-6.7]; P = .02), and for brand-name vs generic status (brand-name mOR, 8.1 [95% CI, 4.0-16.0] vs generic mOR, 2.4 [95% CI, 1.7-3.6]; P = .002)., Conclusions and Relevance: In this national cross-sectional study, supply chain issues associated with drug shortages increased at the beginning of the COVID-19 pandemic. Ongoing policy work is needed to protect US drug supplies from future shocks and to prioritize clinically valuable drugs at greatest shortage risk.

Background: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans., Methods: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects., Results: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1)., Conclusions: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits., Competing Interests: Potential conflicts of interest. K. W. M., S. G., and A. R. Z. report investigator-initiated support from Sanofi, Seqirus, and Pfizer for other non–coronavirus disease 2019 (COVID-19) vaccine-related work. I. J. D. is principal investigator of a research agreement between Sanofi and Harvard University to develop methods for transportability analyses for use of influenza vaccination trials and reports consulting fees from ModernaTX for work unrelated to COVID-19. S.G. reports vaccine related consulting or speaker fees from GlaxoSmithKline, Janssen, Moderna, Novavax, Pfizer, Sanofi, Seqirus. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Valsartan was recalled by the US Food and Drug Administration in July 2018 for carcinogenic impurities, resulting in a drug shortage and management challenges for valsartan users. The influence of the valsartan recall on clinical outcomes is unknown. We compared the risk of adverse events between hypertensive patients using valsartan and a propensity score-matched group using nonrecalled angiotensin receptor blockers and angiotensin-converting enzyme inhibitors., Methods and Results: We used Optum's deidentified Clinformatics Datamart (July 2017-January 2019). Hypertensive patients who received valsartan or nonrecalled angiotensin receptor blockers/angiotensin-converting enzyme inhibitors for 1 year before and on the recall date were compared. Primary outcomes were measured in the 6 months following the recall and included: (1) a composite measure of all-cause hospitalization, all-cause emergency department visit, and all-cause urgent care visit, and (2) a composite cardiac event measure of hospitalizations for acute myocardial infarction and hospitalizations/emergency department visits/urgent care visits for stroke/transient ischemic attack, heart failure, or hypertension. We compared the risk of outcomes between treatment groups using Cox proportional hazard models. Of the hypertensive patients, 76 934 received valsartan, and 509 472 received a nonrecalled angiotensin receptor blocker/angiotensin-converting enzyme inhibitor. Valsartan use at the time of recall was associated with a higher risk of all-cause hospitalization, emergency department use, or urgent care use (hazard ratio [HR], 1.02 [95% CI, 1.00-1.04]) and the composite of cardiac events (HR, 1.22 [95% CI, 1.15-1.29]) within 6 months after the recall., Conclusions: The valsartan recall and shortage affected hypertensive patients. Local- and national-level systems need to be enhanced to protect patients from drug shortages by providing safe and reliable medication alternatives.

Background: The COVID-19 pandemic profoundly disrupted the delivery of medical care. It remains unclear whether individuals diagnosed with new onset disease during the pandemic were less likely to initiate treatments after diagnosis. We sought to evaluate changes in the treatment initiation of patients newly diagnosed with atrial fibrillation (AF) after the onset of the COVID-19 pandemic., Methods: In this retrospective cohort study, we identified individuals with incident AF from 01/01/2016-09/30/2021 using Optum's de-identified Clinformatics® Data Mart Database. The primary outcome was initiation of oral anticoagulation (OAC) within 30 days of AF diagnosis. Secondary outcomes included initiation of OAC within 180 days of diagnosis, initiation of warfarin, direct oral anticoagulants (DOACs), rhythm control medications and electrical cardioversion within 30 days of diagnosis. We constructed interrupted time series analyses to examine changes in the outcomes following the onset of the pandemic., Results: A total of 573,524 patients (age 73.0 ± 10.9 years) were included in the study. There were no significant changes in the initiation of OAC, DOAC, and rhythm control medications associated with the onset of the pandemic. There was a significant decrease in initiation of electrical cardioversion associated with the onset of the pandemic. The rate of electronic cardioversion within 30 days of diagnosis decreased by 4.9% per 1,000 patients after the onset of the pandemic and decreased by about 35% in April 2020, compared to April 2019, from 5.53% to 3.58%., Conclusion: The COVID-19 pandemic did not affect the OAC initiation within 30 days of AF diagnosis but was associated with a decline in the provision of procedures for patients newly diagnosed with AF., (© 2023. The Author(s).)

Introduction: The opioid epidemic has exacted a significant toll in rural areas, yet adoption of medications for opioid use disorder (MOUD) lags. The Rural Access to Medication Assisted Treatment in Pennsylvania (RAMP) Project facilitated adoption of MOUD in rural primary care clinics. The purpose of this study was to gain a better understanding of the barriers and facilitators operating at multiple levels to access or provide MOUD in rural Pennsylvania., Methods: In total, the study conducted 35 semi-structured interviews with MOUD patients and MOUD providers participating in RAMP. Qualitative analysis incorporated both deductive and inductive approaches. The study team coded interviews and performed thematic analysis. Using a modified social-ecological framework, themes from the qualitative interviews are organized in five nested levels: individual, interpersonal, health care setting, community, and public policy., Results: Patients and providers agreed on many barriers (e.g., lack of providers, lack of transportation, insufficient rapport and trust in patient-provider relationship, and cost, etc.); however, their interpretation of the barrier, or indicated solution, diverged in meaningful ways. Patients described their experiences in broad terms pointing to the social determinants of health, as they highlighted their lives outside of the therapeutic encounter in the clinic. Providers focused on their professional roles, responsibilities, and operations within the primary care setting., Conclusions: Providers may want to discuss barriers to treatment related to social determinants of health with patients, and pursue partnerships with organizations that seek to address those barriers. The findings from these interviews point to potential opportunities to enhance patient experience, increase access to and optimize processes for MOUD in rural areas, and reduce stigma against people with opioid use disorder (OUD) in the wider community., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In the United States, dentists frequently prescribe hydrocodone. In October 2014, the US Drug Enforcement Administration rescheduled hydrocodone from controlled substance schedule III to II, introducing more restricted prescribing and dispensing regulations, which may have changed dental prescribing of opioids., Objective: The study aim was to evaluate the impact of the hydrocodone rescheduling on dental prescribing of opioids in the United States., Methods: This was a cross-sectional study of opioids prescribed by dentists between October 2012 and October 2016, using the IQVIA Longitudinal Prescription Dataset. Monthly dentist-based opioid prescribing rate (opioid prescription [Rx]/1,000 dentists) and monthly average opioid dosages per prescription (mean morphine milligram equivalent per day [MME/d]) were measured in the 24 mo before and after hydrocodone rescheduling in October 2014 (index or interruption). An interrupted time-series analysis was conducted using segmented ordinary least square regression models, with Newey-West standard errors to handle autocorrelation., Results: Dentists prescribed 50,412,942 opioid prescriptions across the 49 mo. Hydrocodone was the most commonly prescribed opioid pre- and postindex (74.9% and 63.8%, respectively), followed by codeine (13.8% and 21.6%), oxycodone (8.1% and 9.5%), and tramadol (2.9% and 4.8%). At index, hydrocodone prescribing immediately decreased by -834.8 Rx/1,000 dentists (95% confidence interval [CI], -1,040.2 to -629.4), with increased prescribing of codeine (421.9; 95% CI, 369.7-474.0), oxycodone (85.3; 95% CI, 45.4-125.2), and tramadol (111.8; 95% CI, 101.4-122.3). The mean MME increased at index for all opioids except for hydrocodone, and dosages subsequently decreased during the postindex period., Conclusion: Following the rescheduling, dentist prescribing of hydrocodone declined while prescribing of nonhydrocodone opioids increased. Understanding the impact of this regulation informs strategies to ensure appropriate prescribing of opioids for dental pain., Knowledge Transfer Statement: The study findings can be used by policy makers to make informed decisions in developing future risk mitigation strategies aimed to regulate opioid prescribing behaviors. Furthermore, dentist-specific resources and guidelines are needed subsequent to these policies in order to meet the dental population needs.

Background: Although statins are a class I recommendation for prevention of atherosclerotic cardiovascular disease and its complications, their use is suboptimal. Differential underuse may mediate disparities in cardiovascular health for systematically marginalized persons., Objective: To estimate disparities in statin use by race-ethnicity-gender and to determine whether these potential disparities are explained by medical appropriateness of therapy and structural factors., Design: Cross-sectional analysis., Setting: National Health and Nutrition Examination Survey from 2015 to 2020., Participants: Persons eligible for statin therapy based on 2013 and 2018 American College of Cardiology/American Heart Association blood cholesterol guidelines., Measurements: The independent variable was race-ethnicity-gender. The outcome of interest was use of a statin. Using the Institute of Medicine framework for examining unequal treatment, we calculated adjusted prevalence ratios (aPRs) to estimate disparities in statin use adjusted for age, disease severity, access to health care, and socioeconomic status relative to non-Hispanic White men., Results: For primary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors among non-Hispanic Black men (aPR, 0.73 [95% CI, 0.59 to 0.88]) and non-Mexican Hispanic women (aPR, 0.74 [CI, 0.53 to 0.95]). For secondary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors for non-Hispanic Black men (aPR, 0.81 [CI, 0.64 to 0.97]), other/multiracial men (aPR, 0.58 [CI, 0.20 to 0.97]), Mexican American women (aPR, 0.36 [CI, 0.10 to 0.61]), non-Mexican Hispanic women (aPR, 0.57 [CI, 0.33 to 0.82), non-Hispanic White women (aPR, 0.69 [CI, 0.56 to 0.83]), and non-Hispanic Black women (aPR, 0.75 [CI, 0.57 to 0.92])., Limitation: Cross-sectional data; lack of geographic, language, or statin-dose data., Conclusion: Statin use disparities for several race-ethnicity-gender groups are not explained by measurable differences in medical appropriateness of therapy, access to health care, and socioeconomic status. These residual disparities may be partially mediated by unobserved processes that contribute to health inequity, including bias, stereotyping, and mistrust., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0720.

Importance: Despite the political salience of insulin prices, no study to date has quantified trends in insulin prices that account for manufacturer discounts (net prices)., Objective: To describe trends in insulin list prices and net prices faced by payers from 2012 to 2019 and estimate changes in net prices after the 2015 to 2017 entry of new insulin products., Design, Setting, and Participants: This longitudinal study included an analysis of Medicare, Medicaid, and SSR Health drug pricing data from January 1, 2012, to December 31, 2019. Data analyses were performed from June 1, 2022, to October 31, 2022., Exposures: US sales of insulin products., Main Outcomes and Measures: Net prices faced by payers were estimated for insulin products as list prices minus manufacturer discounts negotiated in commercial and Medicare Part D markets (ie, commercial discounts). Trends in net prices were evaluated before and after the entry of new insulin products., Results: Net prices of long-acting insulin products increased at an annual rate of 23.6% from 2012 to 2014 but decreased at an annual rate of 8.3% after the introduction of insulin glargine (Toujeo and Basaglar) and degludec (Tresiba) in 2015. Net prices of short-acting insulin increased at an annual rate of 5.6% from 2012 to 2017 but then decreased from 2018 to 2019 after the introduction of insulin aspart (Fiasp) and lispro (Admelog). For human insulin products, which did not experience entry of new products, net prices increased at an annual rate of 9.2% from 2012 to 2019. From 2012 to 2019, commercial discounts increased from 22.7% to 64.8% for long-acting insulin products, from 37.9% to 66.1% for short-acting insulin products, and from 54.9% to 63.1% for human insulin products., Conclusions and Relevance: In this longitudinal study of US insulin products, results suggest that insulin prices substantially increased from 2012 to 2015, even after accounting for discounts. The introduction of new insulin products was followed by substantial discounting practices that lowered net prices faced by payers.

Importance: The latest guidelines continue to recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). Despite this, overall use of these 2 drug classes has been suboptimal., Objective: To assess the association of high out-of-pocket (OOP) costs and the initiation of an SGLT2 inhibitor or GLP-1 RA among adults with T2D and established CVD who are treated with metformin-treated., Design, Setting, and Participants: This retrospective cohort study used 2017 to 2021 data from the Optum deidentified Clinformatics Data Mart Database. Each individual in the cohort was categorized into quartiles of OOP costs for a 1-month supply of SGLT2 inhibitor and GLP-1 RA based on their health plan assignment. Data were analyzed from April 2021 to October 2022., Exposures: OOP cost for SGLT2 inhibitors and GLP-1 RA., Main Outcomes and Measures: The primary outcome was treatment intensification, defined as a new dispensing (ie, initiation) of either an SGLT2 inhibitor or GLP-1 RA, among patients with T2D previously treated with metformin monotherapy. For each drug class separately, Cox proportional hazards models were used to adjust for demographic, clinical, plan, clinician, and laboratory characteristics to estimate the hazard ratios of treatment intensification comparing the highest vs the lowest quartile of OOP costs., Results: Our cohort included 80 807 adult patients (mean [SD] age, 72 [9.5] years, 45 129 [55.8%] male; 71 128 [88%] were insured with Medicare Advantage) with T2D and established CVD on metformin monotherapy. Patients were followed for a median (IQR) of 1080 days (528 to 1337). The mean (SD) of OOP costs in the highest vs lowest quartile was $118 [32] vs $25 [12] for GLP-1 RA, and $91 [25] vs $23 [9] for SGLT2 inhibitors. Compared with patients in plans with the lowest quartile (Q1) of OOP costs, patients in plans with the highest quartile (Q4) of costs were less likely to initiate a GLP-1 RA (adjusted HR, 0.87 [95% CI, 0.78 to 0.97]) or an SGLT2 inhibitor (adjusted HR, 0.80 [95% CI, 0.73 to 0.88]). The median (IQR) number of days to initiating a GLP-1 RA was 481 (207-820) days in Q1 and 556 (237-917) days in Q4 of OOP costs and 520 (193-876) days in Q1 vs 685 (309-1017) days in Q4 for SGLT2 inhibitors., Conclusions and Relevance: In this cohort study of more than 80 000 older adults with T2D and established CVD covered by Medicare Advantage and commercial plans, those in the highest quartile of OOP cost were 13% and 20% less likely to initiate a GLP-1 RA or SGLT2 inhibitor, respectively, when compared with those in the lowest quartile of OOP costs.

Purpose: Opioids, benzodiazepines and sedatives can manage dental pain, fear and anxiety but have a narrow margin of safety in children. General dentists may inappropriately prescribe gabapentin and stimulants. National evidence on dispensing rates of these high-alert medicines by dentists to children is limited., Methods: We utilize join-point regression to identify changes in fills for opioids, sedatives, benzodiazepines, gabapentin, and stimulants to children <18 years from 2012 to 2019 in a national dataset comprising 92% of dispensed outpatient prescriptions by dentists., Results: From 2012 to 2019, 3.8 million children filled prescriptions for high-alert drugs from general dentists. National quarterly dispensing of high-alert drugs decreased 63.1%, from 10456.0 to 3858.8 days per million. Opioids accounted for 69.4% of high-alert prescriptions. From 2012 to 2019, fills for opioids, sedatives, benzodiazepines, and stimulants decreased by 65.2% (7651.8 to 2662.7), 43.4% (810.9 to 458.7), 43.6% (785.7 to 442.7) and 89.3% (825.6 to 88.6 days per million), respectively. Gabapentin increased 8.1% (121.8 to 131.7 days per million). A significant decrease in high-alert fills occurred in 2016, (-6.0% per quarter vs. -1.6% pre-2016, P-value<0.001), especially for opioids (-7.0% vs. -1.2%, P-value<0.001). Older teenagers (15-17 years) received 42.5% of high-alert prescriptions. Low-income counties in the South were overrepresented among top-prescribing areas in 2019., Conclusions: We found promising national decreases in fills for high-alert medicines to children by general dentists from 2012 to 2019. However, older teenagers and children in some counties continued to receive dental opioids at high rates. Future efforts should address non-evidence-based pain management in these groups., (© 2022 John Wiley & Sons Ltd.)

Importance: Insulin list prices have grown substantially since 2010, but net prices have declined since 2015 because of manufacturer discounts, leading to an increasingly large difference between list and net prices of drugs often called the gross-to-net bubble. It remains unclear to what extent the gross-to-net bubble represents voluntary manufacturer discounts negotiated in commercial and Medicare Part D markets (hereafter called commercial discounts) vs mandatory discounts under the Medicare Part D coverage gap, Medicaid, and the 340B program., Objective: To decompose the overall gross-to-net bubble of leading insulin products into discount types., Design, Setting, and Participants: This economic evaluation obtained data from Medicare and Medicaid claims and spending dashboards, Medicare Part D Prescriber Public Use File, and SSR Health for the top 4 commonly used insulin products: Lantus, Levemir, Humalog, and Novolog. The gross-to-net bubble, which represents total discounts, was estimated for each insulin product and year (from 2012 to 2019). Analyses were conducted in June to December 2022., Main Outcomes and Measures: The gross-to-net bubble was decomposed into 4 discount types: (1) Medicare Part D coverage gap discounts, (2) Medicaid discounts, (3) 340B discounts, and (4) commercial discounts. Coverage gap discounts were estimated using Medicare Part D claims data. Medicaid and 340B discounts were estimated using a novel algorithm that accounted for best prices set by commercial discounts., Results: Total discounts for the 4 insulin products increased from $4.9 billion to $22.0 billion. Commercial discounts represented a majority of all discounts, increasing from 71.7% of the gross-to-net bubble in 2012 ($3.5 billion) to 74.3% ($16.4 billion) in 2019. Among mandatory discounts, coverage gap discounts remained relatively consistent as a proportion of discounts (5.4% in 2012 vs 5.3% in 2019). Medicaid rebates decreased as a proportion of total discounts, from 19.7% in 2012 to 10.6% in 2019. The 340B discounts increased as a proportion of total discounts from 3.3% in 2012 to 9.8% in 2019. Results for the contribution of discount types to the gross-to-net bubble were consistent across insulin products., Conclusions and Relevance: Results of a decomposition of the gross-to-net bubble for leading insulin products suggest that commercial discounts play a growing role in lowering net sales compared with mandatory discounts.

Objectives: To develop and validate a machine-learning algorithm to predict fatal overdose using Pennsylvania Prescription Drug Monitoring Program (PDMP) data., Methods: The training/testing (n = 3020,748) and validation (n = 2237,701) cohorts included Pennsylvania residents with a prescription dispensing from February 2018-September 2021. Potential predictors (n = 222) were measured in the 6 months prior to a random index date. Using a gradient boosting machine, we developed a 20-variable model to predict risk of fatal drug overdose in the 6 months after the index date., Results: Beneficiaries in the training (n = 1,812,448), testing (n = 1,208,300), and validation (n = 2,237,701) samples had similar age, with low rates of fatal overdose during 6-month follow up (0.12%, 0.12%, 0.04%, respectively). The validation c-statistic was 0.86 for predicting fatal overdose using 20 PDMP variables. When ranking individuals based on risk score, the prediction model more accurately identified fatal overdose at 6 months compared to using opioid dosage or opioid/benzodiazepine overlap, although the percentage of individuals in the highest risk percentile who died at 6 months was less than 1%., Conclusions and Policy Implications: A gradient boosting machine algorithm predicting fatal overdose derived from twenty variables performed well in discriminating risk across testing and validation samples, improving on single factor risk measures like opioid dosage., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) is a common arrhythmia, the management of which includes anticoagulation for stroke prevention. Although disparities in anticoagulant prescribing have been well documented for individual socioeconomic factors, less is known about the association of neighborhood-level disadvantage and anticoagulation for AF., Objective: To assess the association between neighborhood disadvantage and anticoagulant initiation for patients with incident AF., Design: Retrospective cohort study., Participants: A cohort of patients enrolled in the Veterans Health Administration (VA) with incident AF from January 2014 through December 2020 from the Race, Ethnicity, and Anticoagulant CHoice in Atrial Fibrillation (REACH-AF) Study., Main Measures: The primary exposure was neighborhood disadvantage quantified using area deprivation index (ADI), classified by quintiles (Q). The outcomes were initiation of any anticoagulant therapy (warfarin or direct oral anticoagulant, DOAC) within 90 days of AF diagnosis and DOAC use among initiators. We used mixed effects logistic regression to assess the association between ADI and anticoagulant therapy, incorporating a fixed effect for treatment site and baseline patient, provider, and facility covariates., Key Results: Among 161,089 patients, 105,489 (65.5%) initiated any anticoagulant therapy, and 78,903 (74.8%) used DOACs. Any anticoagulant therapy increased 3.2 percentage points (63.0% to 66.2%; p<.001) from Q1 to Q5, whereas DOAC use decreased 8.2 percentage points (79.4% to 71.2%; p<.0001) across quintiles. The adjusted odd ratios of any anticoagulant therapy were non-significantly different for Q2-Q5 than Q1. The adjusted odds of DOAC use decreased progressively from 0.89 (95% CI, 0.84-0.94) in Q2 to 0.77 (95% CI, 0.73-0.83) in Q5 compared to Q1 (p<.0001)., Conclusions: Among Veterans with incident AF, we observed similar initiation of any anticoagulant, though neighborhood deprivation was associated with decreased DOAC use among anticoagulant initiators. Future interventions to improve pharmacoequity in anticoagulant prescribing for AF should consider the role of neighborhood-level determinants of health inequities., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Atrial fibrillation (AF) is associated with a five-fold increased risk of stroke and a two-fold increased risk of death. We aimed to quantify changes in new diagnoses of AF following the onset of the COVID-19 pandemic. Investigating changes in new diagnoses of AF is of relevance because delayed diagnosis interferes with timely treatment to prevent stroke, heart failure, and death., Methods: Using De-identified Optum's Clinformatics® Data Mart, we identified 19,500,401 beneficiaries continuously enrolled for 12 months in 2016-Q3 2020 with no history of AF. The primary outcome was new AF diagnoses per 30-day interval. Secondary outcomes included AF diagnosis in the inpatient setting, AF diagnosis in the outpatient setting, and ischemic stroke as initial manifestation of AF. We constructed seasonal autoregressive integrated moving average models to quantify changes in new AF diagnoses after the onset of the COVID-19 pandemic (3/11/2020, date of pandemic declaration). We tested whether changes in the new AF diagnoses differed by race and ethnicity., Results: The average age of study participants was 51.0±18.5 years, and 52% of the sample was female. During the study period, 2.7% of the study sample had newly-diagnosed AF. New AF diagnoses decreased by 35% (95% CI, 21%-48%) after the onset of the COVID-19 pandemic, from 1.14 per 1000 individuals (95% CI, 1.05-1.24) to 0.74 per 1000 (95% CI, 0.64 to 0.83, p-value<0.001). New AF diagnoses decreased by 37% (95% CI, 13%- 55%) in the outpatient setting and by 29% (95% CI, 14%-43%) in the inpatient setting. The decrease in new AF diagnoses was similar across racial and ethnic subgroups., Conclusion: In a nationwide cohort of 19.5 million individuals, new diagnoses of AF decreased substantially following the onset of the COVID-19 pandemic. Our findings evidence pandemic disruptions in access to care for AF, which are concerning because delayed diagnosis interferes with timely treatment to prevent complications., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Hernandez has received consulting fees from Pfizer and Bristol Myers Squibb, outside of the submitted work. Our conflicts do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Hernandez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Low-value care cascades, defined as the receipt of downstream health services potentially related to a low-value service, can result in harm to patients and wasteful healthcare spending, yet have not been characterized within the Veterans Health Administration (VHA)., Objective: To examine if the receipt of low-value preoperative testing is associated with greater utilization and costs of potentially related downstream health services in Veterans undergoing low or intermediate-risk surgery., Design: Retrospective cohort study using VHA administrative data from fiscal years 2017-2018 comparing Veterans who underwent low-value preoperative electrocardiogram (EKG) or chest radiograph (CXR) with those who did not., Participants: National cohort of Veterans at low risk of cardiopulmonary disease undergoing low- or intermediate-risk surgery., Main Measures: Difference in rate of receipt and attributed cost of potential cascade services in Veterans who underwent low-value preoperative testing compared to those who did not KEY RESULTS: Among 635,824 Veterans undergoing low-risk procedures, 7.8% underwent preoperative EKG. Veterans who underwent a preoperative EKG experienced an additional 52.4 (95% CI 47.7-57.2) cascade services per 100 Veterans, resulting in $138.28 (95% CI 126.19-150.37) per Veteran in excess costs. Among 739,005 Veterans undergoing low- or intermediate-risk surgery, 3.9% underwent preoperative CXR. These Veterans experienced an additional 61.9 (95% CI 57.8-66.1) cascade services per 100 Veterans, resulting in $152.08 (95% CI $146.66-157.51) per Veteran in excess costs. For both cohorts, care cascades consisted largely of repeat tests, follow-up imaging, and follow-up visits, with low rates invasive services., Conclusions: Among a national cohort of Veterans undergoing low- or intermediate-risk surgeries, low-value care cascades following two routine low-value preoperative tests are common, resulting in greater unnecessary care and costs beyond the initial low-value service. These findings may guide de-implementation policies within VHA and other integrated healthcare systems that target those services whose downstream effects are most prevalent and costly., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: Opioids are overprescribed in the outpatient dental setting. Therefore, opportunities exist for opioid stewardship., Objectives: The purpose of this pilot study was to test the feasibility of an academic detailing (AD) intervention to promote appropriate prescribing of opioids in outpatient dentistry., Methods: We implemented an AD intervention targeting management of acute oral pain in a Midwestern Veterans Affairs outpatient dental facility. The intervention targeted dentists who actively prescribed opioids at the time of the study. The pilot study tested feasibility, adoption, and acceptance of the AD campaign. Visit-based prescribing rates were obtained from the Veterans Health Administration's Corporate Data Warehouse for baseline and postintervention using difference-in-differences analyses to detect potential changes in health service outcomes., Results: Results indicate moderate levels of feasibility through participation rates (n = 5, 55.5%) and high levels of organizational readiness for change (average of 88.6% agree to strongly agree). Furthermore, fidelity of the AD intervention was high. Adoption measures show moderate indication of motivation to change, and trends suggest that participating dentists decreased their visit-based opioid prescribing rates (P > 0.05)., Conclusion: The intervention demonstrated feasibility with some indications of adoption of intervention techniques and decrease in opioid prescribing. We further recommend working closely with frontline providers to gather feedback and buy-in before scaling and implementing the AD campaign., (Published by Elsevier Inc.)

BACKGROUND: Oral anticoagulants (OAC) is indicated for stroke prevention in patients with atrial fibrillation (AF) with a moderate or high risk of stroke. Despite the benefits of stroke prevention, only 50%-60% of Americans with nonvalvular AF and a moderate or high risk of stroke receive OAC medication. OBJECTIVE: To understand the extent to which low OAC use by patients with AF is attributed to underprescribing or underfilling once the medication is prescribed. METHODS: This is a retrospective cohort study that used linked claims data and electronic health records from Optum Integrated data. Participants were adults (aged ≥ 18 years) with first AF between January 2013 and June 2017. The outcomes included (1) being prescribed OACs within 180 days of AF diagnosis or not and (2) filling an OAC prescription or not among patients with AF who were prescribed an OAC within 150 days of AF diagnosis. Multivariable logistic regression models were constructed to determine factors associated with underprescribing and underfilling. RESULTS: Of the 6,141 individuals in the study cohort, 51% were not prescribed OACs within 6 months of their AF diagnosis. Of the 2,956 patients who were prescribed, 19% did not fill it at the pharmacy. In the final adjusted model, younger age, location (Northeast and South), a low CHA 2 DS 2 -VASc score, and a high HAS-BLED score were associated with a lower likelihood of being prescribed OACs. Among patients who were prescribed, Medicare enrollment (odds ratio [OR] [95% CI] = 2.2 [1.3-3.7]) and having a direct oral anticoagulant prescription (1.5 [1.2-1.9]) were associated with a lower likelihood of filling the prescription. CONCLUSIONS: Both underprescribing and underfilling are major drivers of low OAC use among patients with AF, and solutions to increase OAC use must address both prescribing and filling. DISCLOSURES: Research reported in this study was supported by the National Heart, Lung and Blood Institute (K01HL142847 and R01HL157051). Dr Guo is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465), PhMRA Foundation Research Starter Award, and the University of Florida Research Opportunity Seed Fund. Dr Hernandez reports scientific advisory board fees from Pfizer and Bristol Myers Squibb, outside of the submitted work.

Importance: Older US veterans commonly receive health care outside of the US Veterans Health Administration (VHA) through Medicare, which may increase receipt of low-value care and subsequent care cascades., Objective: To characterize the frequency, cost, and source of low-value prostate-specific antigen (PSA) testing and subsequent care cascades among veterans dually enrolled in the VHA and Medicare and to determine whether receiving a PSA test through the VHA vs Medicare is associated with more downstream services., Design, Setting, and Participants: This retrospective cohort study used VHA and Medicare administrative data from fiscal years (FYs) 2017 to 2018. The study cohort consisted of male US veterans dually enrolled in the VHA and Medicare who were aged 75 years or older without a history of prostate cancer, elevated PSA, prostatectomy, radiation therapy, androgen deprivation therapy, or a urology visit. Data were analyzed from December 15, 2020, to October 20, 2022., Exposures: Receipt of low-value PSA testing., Main Outcomes and Measures: Differences in the use and cost of cascade services occurring 6 months after receipt of a low-value PSA test were assessed for veterans who underwent low-value PSA testing in the VHA and Medicare compared with those who did not, adjusted for patient- and facility-level covariates., Results: This study included 300 393 male US veterans at risk of undergoing low-value PSA testing. They had a mean (SD) age of 82.6 (5.6) years, and the majority (264 411 [88.0%]) were non-Hispanic White. Of these veterans, 36 459 (12.1%) received a low-value PSA test through the VHA, which was associated with 31.2 (95% CI, 29.2 to 33.2) additional cascade services per 100 veterans and an additional $24.5 (95% CI, $20.8 to $28.1) per veteran compared with the control group. In the same cohort, 17 981 veterans (5.9%) received a PSA test through Medicare, which was associated with 39.3 (95% CI, 37.2 to 41.3) additional cascade services per 100 veterans and an additional $35.9 (95% CI, $31.7 to $40.1) per veteran compared with the control group. When compared directly, veterans who received a PSA test through Medicare experienced 9.9 (95% CI, 9.7 to 10.1) additional cascade services per 100 veterans compared with those who underwent testing within the VHA., Conclusions and Relevance: The findings of this cohort study suggest that US veterans dually enrolled in the VHA and Medicare commonly experienced low-value PSA testing and subsequent care cascades through both systems in FYs 2017 and 2018. Care cascades occurred more frequently through Medicare compared with the VHA. These findings suggest that low-value PSA testing has substantial downstream implications for patients and may be especially challenging to measure when care occurs in multiple health care systems.