Search

Background: There is a plethora of real-world data on the safety and effectiveness of direct-acting oral anticoagulants (DOACs); however, study heterogeneity has contributed to inconsistent findings. We compared the effectiveness and safety of apixaban with those of other direct-acting oral anticoagulants (DOACs) and vitamin K antagonists (VKA e.g., warfarin)., Methods: A systematic review and meta-analysis was conducted retrieving data from PubMed, SCOPUS and Web of Science from January 2009 to December 2021. Studies that evaluated apixaban (intervention) prescribed for adults (aged 18 years or older) with AF for stroke prevention compared to other DOACs or VKAs were identified. Primary outcomes included stroke/systemic embolism (SE), all-cause mortality, and major bleeding. Secondary outcomes were intracranial haemorrhage (ICH) and ischaemic stroke. Randomised controlled trials and non-randomised trials were considered for inclusion., Results: In total, 67 studies were included, and 38 studies were meta-analysed. Participants taking apixaban had significantly lower stroke/SE compared to patients taking VKAs (relative risk (RR) 0.77, 95% confidence interval (CI) 0.64-0.93, I 2 = 94%) and dabigatran (RR 0.84, 95% CI 0.74-0.95, I 2 = 66%), but not to patients administered rivaroxaban. There was no statistical difference in mortality between apixaban and VKAs or apixaban and dabigatran. Compared to patients administered rivaroxaban, participants taking apixaban had lower mortality rates (RR 0.83, 95% CI 0.71-0.96, I 2 = 96%). Apixaban was associated with a significantly lower risk of major bleeding compared to VKAs (RR 0.58, 95% CI 0.52-0.65, I 2 = 90%), dabigatran (RR 0.79, 95% CI 0.70-0.88, I 2 = 78%) and rivaroxaban (RR 0.61, 95% CI 0.53-0.70, I 2 = 87%)., Conclusions: Apixaban was associated with a better overall safety and effectiveness profile compared to VKAs and other DOACs.

Purpose: To compare the predictive ability of mapping algorithms derived using cross-sectional and longitudinal data., Methods: This methodological assessment used data from a randomized controlled noninferiority trial of patients with low-risk prostate cancer, conducted by NRG Oncology (ClinicalTrials.gov identifier: NCT00331773), which examined the efficacy of conventional schedule versus hypofractionated radiation therapy (three-dimensional conformal external beam radiation therapy/IMRT). Health-related quality-of-life data were collected using the Expanded Prostate Cancer Index Composite (EPIC), and health utilities were obtained using EuroQOL-5D-3L (EQ-5D) at baseline and 6, 12, 24, and 60 months postintervention. Mapping algorithms were estimated using ordinary least squares regression models through five-fold cross-validation in baseline cross-sectional data and combined longitudinal data from all assessment periods; random effects specifications were also estimated in longitudinal data. Predictive performance was compared using root mean square error. Longitudinal predictive ability of models obtained using baseline data was examined using mean absolute differences in the reported and predicted utilities., Results: A total of 267 (and 199) patients in the estimation sample had complete EQ-5D and EPIC domain (and subdomain) data at baseline and at all subsequent assessments. Ordinary least squares models using combined data showed better predictive ability (lowest root mean square error) in the validation phase for algorithms with EPIC domain/subdomain data alone, whereas models using baseline data outperformed other specifications in the validation phase when patient covariates were also modeled. The mean absolute differences were lower for models using EPIC subdomain data compared with EPIC domain data and generally decreased as the time of assessment increased., Conclusion: Overall, mapping algorithms obtained using baseline cross-sectional data showed the best predictive performance. Furthermore, these models demonstrated satisfactory longitudinal predictive ability.

The field of implementation science has devoted increasing attention to optimizing the fit of evidence-based interventions to the organizational settings in which they are delivered. Institutionalization of health promotion into routine organizational operations is one way to achieve this. However, less is known about how to maximize fit and achieve institutionalization, particularly in settings outside of the healthcare system. This paper reports on findings from a parallel cluster-randomized trial that compared an organizationally tailored with a standard (core components only) approach for institutionalizing ("integrating") an evidence-based cancer control intervention into African American churches. Churches randomized to the organizationally tailored condition identified three or more implementation strategies from a menu of 20, with an implementation time frame for each. The primary study outcome was assessed through the Faith-Based Organization Health Integration Inventory, a measure of institutionalization of health promotion activities in church settings, completed by pastors at baseline and 12-month follow-up. Seventeen churches were randomized and 14 were analyzed as 3 did not implement the study protocol. Though the percent increase in total integration score was greater in the tailored condition (N = 9; 18%) than in the standard condition (N = 5; 12%), linear mixed-effect models did not detect a statistically significant group × time interaction. Despite the challenges of integrating health promotion activities outside of healthcare organizations, the current approach shows promise for fostering sustainable health promotion in community settings and merits further study., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adjuvant therapy for most sentinel-node-positive (stage IIIA) melanoma may have limited clinical benefit for older patients given the competing risk of non-cancer death. The objective of this study is to model the clinical effect and cost of adjuvant therapy in stage IIIA melanoma across age groups., Study Design: A Markov decision analysis model simulated the overall survival of patients with resected stage IIIA melanoma treated with adjuvant therapy vs observation. In the adjuvant approach, patients are modeled to receive adjuvant pembrolizumab (BRAF wild type) or dabrafenib/trametinib (BRAF mutant). In the observation approach, treatment is deferred until recurrence. Transition variables were derived from landmark randomized trials in adjuvant and salvage therapy. The model was analyzed for age groups spanning 40 to 89 years. The primary outcome was the number needed to treat (NNT) to prevent one melanoma-related death at 10 years. Cost per mortality avoided was estimated using Medicare reimbursement rates., Results: Projections for NNT among BRAF wild type patients increased by age from 14.71 (age 40 to 44) to 142.86 (age 85 to 89), with patients in cohorts over the age of 75 having an NNT over 25. The cost per mortality avoided ranged from $2.75 million (M) (age 40 to 44) to $27.57M (age 85 to 89). Corresponding values for BRAF mutant patients were as follows: NNT 18.18 to 333.33; cost per mortality avoided ranged from $2.75M to $54.70M., Conclusion: Universal adjuvant therapy for stage IIIA melanoma is costly and provides limited clinical benefit in patients older than 75 years., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Standard opioid tapers tend to be associated with increased patient anxiety and higher pain ratings. Pre-authorized concealed opioid reductions may minimize expectations such as fear of increased pain due to the reduction of opioids and, prolong analgesic benefits in experimental settings. We recently observed that patients and clinicians are open to concealed opioid tapering. However, little is known about the "why" behind their attitudes. Based on this lack of data, we analyzed qualitative responses to survey questions on patients' and clinicians' acceptance of a concealed opioid reduction for chronic pain. Seventy-four patients with a history of high dose opioid therapy and 49 clinicians completed a web-based questionnaire with open-ended questions examining responses to two hypothetical clinical trials comparing a concealed opioid reduction pre-authorized by patients vs. standard tapering. We used content analysis based on qualitative descriptive methodology to analyze comments from the patients and clinicians. Five themes were identified: informed consent; anxiety; safety; support; and ignorance is bliss, or not. These themes highlight the overall positive attitudes toward concealed opioid tapers. Our findings reinforce the importance of patient-centered care and are expected to inform the design of clinical trials from both the patient and clinician perspective. This qualitative study presents patients' and clinicians' attitudes toward hypothetical scenarios for a trial of pre-authorized reduction of opioids. The findings indicate positive attitudes and the relevance of engaging patients with effective decision-making processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bedford, Kisaalita, Haycock, Mullins, Wright, Curatolo, Hamlin and Colloca.)

Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces the previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, and the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as healthcare, public health, education, and social care). This Explanation and Elaboration Report presents the new CHEERS 2022 28-item checklist with recommendations and explanation and examples for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer-reviewed journals and the peer reviewers and editors assessing them for publication. Nevertheless, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, given that there is an increasing emphasis on transparency in decision making., (Copyright © 2022 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. Published by Elsevier Inc. All rights reserved.)

The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)-based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: There have been ongoing efforts to understand when and how data from observational studies can be applied to clinical and regulatory decision making. The objective of this review was to assess the comparability of relative treatment effects of pharmaceuticals from observational studies and randomized controlled trials (RCTs)., Methods: We searched PubMed and Embase for systematic literature reviews published between January 1, 1990, and January 31, 2020, that reported relative treatment effects of pharmaceuticals from both observational studies and RCTs. We extracted pooled relative effect estimates from observational studies and RCTs for each outcome, intervention-comparator, or indication assessed in the reviews. We calculated the ratio of the relative effect estimate from observational studies over that from RCTs, along with the corresponding 95% confidence interval (CI) for each pair of pooled RCT and observational study estimates, and we evaluated the consistency in relative treatment effects., Results: Thirty systematic reviews across 7 therapeutic areas were identified from the literature. We analyzed 74 pairs of pooled relative effect estimates from RCTs and observational studies from 29 reviews. There was no statistically significant difference (based on the 95% CI) in relative effect estimates between RCTs and observational studies in 79.7% of pairs. There was an extreme difference (ratio < 0.7 or > 1.43) in 43.2% of pairs, and, in 17.6% of pairs, there was a significant difference and the estimates pointed in opposite directions., Conclusions: Overall, our review shows that while there is no significant difference in the relative risk ratios between the majority of RCTs and observational studies compared, there is significant variation in about 20% of comparisons. The source of this variation should be the subject of further inquiry to elucidate how much of the variation is due to differences in patient populations versus biased estimates arising from issues with study design or analytical/statistical methods., (© 2021. The Author(s).)

Oncology trials are the cornerstone of effective and safe therapeutic discoveries. However, there is increasing demand for pragmatism and patient engagement in the design, implementation and dissemination of oncology trials. Many researchers are uncertain about making trials more practical and even less knowledgeable about how to meaningfully engage patients without compromising scientific rigor to meet regulatory requirements. The present work provides practical guidance for addressing both pragmaticism and meaningful patient engagement. Applying evidence-based approaches like PRECIS-2-tool and the 10-Step Engagement Framework offer practical guidance to make future trials in oncology truly pragmatic and patient-centered. Consequently, such patient-centered trials have improved participation, faster recruitment and greater retention, and uptake of innovative technologies in community-based care.

Purpose: Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes., Methods: Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity., Results: A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( P < .0001) and 19 months versus not reached ( P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion., Conclusion: Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials., Competing Interests: Matthew J. FrankEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/Genentech Ilan KirschEmployment: Adaptive BiotechnologiesStock and Other Ownership Interests: Adaptive Biotechnologies Allison P. JacobEmployment: Adaptive BiotechnologiesStock and Other Ownership Interests: Adaptive Biotechnologies Chelsea D. MullinsEmployment: Adaptive BiotechnologiesStock and Other Ownership Interests: Adaptive Biotechnologies Lik Wee LeeEmployment: Adaptive Biotechnologies Crystal L. MackallStock and Other Ownership Interests: Lyell Immunopharma, Alimera Sciences, Vor Pharmaceuticals, Apricity Health, Syncopation Life SciencesConsulting or Advisory Role: Bryology, Vor Biopharma, Apricity Health, TPG, Alimera Sciences, PACT Pharma, Nektar, Lyell Immunopharma, NeoImmuneTech, Syncopation Life Sciences, NeoImmuneTech, Bristol Myers Squibb, ImmaticsResearch Funding: Lyell ImmunopharmaPatents, Royalties, Other Intellectual Property: I am an inventor on numerous patents related to chimeric antigen receptor therapeutics and received royalties from NIH for the CD22-CAR patent licensed to Juno therapeuticsTravel, Accommodations, Expenses: NeoImmuneTech, Roche, NektarOther Relationship: Lyell Immunopharma Michael D. JainConsulting or Advisory Role: Kite/Gilead, Novartis, Bristol Myers Squibb, TakedaTravel, Accommodations, Expenses: Kite/Gilead Saurabh DahiyaConsulting or Advisory Role: Kite/Gilead, Atara Biotherapeutics Frederick L. LockeConsulting or Advisory Role: Novartis, Celgene, GammaDelta Therapeutics, Calibr, WUGEN Inc, Alimera Sciences, Cellular Biomedicine Group, Gerson Lehrman Group, EcoR1 Capital, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, CowenResearch Funding: Kite, a Gilead company, Alimera Sciences, NovartisPatents, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2, CAR T Cells with Enhanced Metabolic Fitness. Serial Number: 62/939727, Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892292, Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy. Serial Number: 62/879534Travel, Accommodations, Expenses: Kite, a Gilead company David B. MiklosConsulting or Advisory Role: Kite, a Gilead company, Adaptive Biotechnologies, Novartis, Juno/Celgene, Pharmacyclics, Janssen, Precision Biosciences, Alimera Sciences, Miltenyi BiotecResearch Funding: Pharmacyclics, Novartis, Roche/Genentech, Kite, a Gilead company, Adaptive Biotechnologies, Alimera Sciences, Precision BiosciencesPatents, Royalties, Other Intellectual Property: Patent held with Pharmacyclics supporting Ibrutinib for cGVHD (no royalty claim).Travel, Accommodations, Expenses: Kite, a Gilead company, Pharmacyclics/Janssen, Adaptive Biotechnologies, Juno Therapeutics, Miltenyi Biotec, NovartisNo other potential conflicts of interest were reported.

Objective: Limited research of how to best taper opioids brings about an ethical and clinical dilemma. Experiments using overt and concealed administration of opioids have demonstrated the benefits of a concealed reduction to eliminate negative expectations and prolong analgesic benefits. This may allow for opioid tapering without significant increases in pain. Based on this, we investigated patient and provider acceptance of a concealed opioid reduction for chronic pain., Methods: We conducted a cross-sectional survey via REDcap with 74 patients, who are currently taking or have taken high dose opioids, and 49 providers using a validated questionnaire based on two hypothetical clinical trials comparing a patient preauthorized concealed opioid reduction vs standard tapering., Results: We found that patients and providers have positive attitudes toward a concealed reduction of opioid dosages. More than 60% of providers and patients surveyed viewed the hypothetical clinical trial as helpful to reduce pain, side effects, and withdrawal symptoms. Sixty-one percent of patients and 77.6% of providers recognized that there would be differences in pain relief depending upon which group the hypothetical participants would be enrolled in., Conclusions: Patients and providers appear to understand the benefits of a concealed opioid reduction. Our findings support future randomized controlled trials that compare concealed and overt opioid tapering in patients with chronic pain. More research is needed to understand the difference in attitudes between research and clinical practice and to test the acceptability of a concealed reduction following a participation in an active clinical trial., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This article aims to determine receptivity for advancing the Learning Healthcare System (LHS) model to a novel evidence-based health care delivery framework-Learning Health Care Community (LHCC)-in Baltimore, as a model for a national initiative. Using community-based participatory, qualitative approach, we conducted 16 in-depth interviews and 15 focus groups with 94 participants. Two independent coders thematically analyzed the transcripts. Participants included community members (38%), health care professionals (29%), patients (26%), and other stakeholders (7%). The majority considered LHCC to be a viable model for improving the health care experience, outlining certain parameters for success such as the inclusion of home visits, presentation of research evidence, and incorporation of social determinants and patients' input. Lessons learned and challenges discussed by participants can help health systems and communities explore the LHCC aspiration to align health care delivery with an engaged, empowered, and informed community.

Competing Interests: This work was funded by the Agency for Healthcare Research and Quality (R24HS022135, C.D.M./L.C.), MPowering the State: Strategic Partnership Grant (L.C.), and University of Maryland Center for Addiction Research, Education, and Service (CARES, L.C.). Dr. Colloca reports grants from Alcohol Abuse and Alcoholism (R13-AA028424), grants from National Institute of Dental Craniofacial Research (R01 DE025946), grants from National Center for Complementary and Integrative Health (R01AT01033), personal fees from Chiesi, personal fees from Averitas, and personal fees from USATXW, during the conduct of the study. C.D. Mullins reports personal fees from AstraZeneca, Bayer Pharmaceuticals, Merck, Pfizer, Sanofi, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Purpose: The Expanded Prostate Cancer Index Composite (EPIC) is the most commonly used patient reported outcome (PRO) tool in prostate cancer (PC) clinical trials, but health utilities associated with the different health states assessed with this tool are unknown, limiting our ability to perform cost-utility analyses. This study aimed to map EPIC tool to EuroQoL-5D-3L (EQ5D) to generate EQ5D health utilities., Methods and Materials: This is a secondary analysis of a prospective, randomized non-inferiority clinical trial, conducted between 04/2006 and 12/2009 at cancer centers across the United States, Canada, and Switzerland. Eligible patients included men >18 years with a known diagnosis of low-risk PC. Patient HRQoL data were collected using EPIC and health utilities were obtained using EQ5D. Data were divided into an estimation sample (n = 765, 70%) and a validation sample (n = 327, 30%). The mapping algorithms that capture the relationship between the instruments were estimated using ordinary least squares (OLS), Tobit, and two-part models. Five-fold cross-validation (in-sample) was used to compare the predictive performance of the estimated models. Final models were selected based on root mean square error (RMSE)., Results: A total of 565 patients in the estimation sample had complete information on both EPIC and EQ5D questionnaires at baseline. Mean observed EQ5D utility was 0.90±0.13 (range: 0.28-1) with 55% of patients in full health. OLS models outperformed their counterpart Tobit and two-part models for all pre-determined model specifications. The best model fit was: "EQ5D utility = 0.248541 + 0.000748*(Urinary Function) + 0.001134*(Urinary Bother) + 0.000968*(Hormonal Function) + 0.004404*(Hormonal Bother)- 0.376487*(Zubrod) + 0.003562*(Urinary Function*Zubrod)"; RMSE was 0.10462., Conclusions: This is the first study to identify a comprehensive set of mapping algorithms to generate EQ5D utilities from EPIC domain/ sub-domain scores. The study results will help estimate quality-adjusted life-years in PC economic evaluations., Competing Interests: Drs. Khairnar, Albert, Bentzen, Bruner, Chen, Currey, Dayes, DeNittis, Horwitz, Lee, Michalski, Mullins, Palumbo, Pisansky, Seaward, Shah, Shaya, and Villalonga have nothing to disclose. Dr. Feng reports personal fees from Janssen Oncology, Sanofi, Bayer, Celgene, and Blue Earth Diagnostics, grants from Zenith Epigenetics, and other from PFS Genomics, outside the submitted work; Dr. Malone reports personal fees from Sanofi, and honoraria from Amgen, Abbvie, Astellas, Janssen, Tersara, Astra Zeneca, Knight Therapeutics, and Bayer, outside the submitted work; Dr. Mishra reports grants from American Society of Radiation Oncology (ASTRO), during the conduct of the study and other from Varian Medical Systems, outside the submitted work; Dr. Sandler reports grants from ACR/NRG Oncology, during the conduct of the study; personal fees from Janssen, other from Radiogel, outside the submitted work; Dr. Pugh reports other from Millennium, other from Pfizer, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Importance: Postoperative infections after a fracture exert tremendous costs on the health care system. However, the patient economic burden associated with a postoperative infection is unclear., Objective: To evaluate the association between a postoperative infection and long-term income among patients with surgically treated fractures., Design, Setting, and Participants: A retrospective cohort study linked academic trauma center data with Maryland tax records using inverse probability of treatment weighting to estimate between-group differences among 11 673 adults who underwent surgery to treat fractures of the extremities or pelvis between January 1, 2003, and December 31, 2016. Statistical analysis was performed from November 5, 2019, to August 30, 2020., Exposure: A postoperative infection within 1 year of injury., Main Outcomes and Measures: The primary outcome was the annual household income up to 6 years after injury. Household income incorporates multiple types of income, including wage earnings, taxable Social Security benefits, workers' compensation, and disability benefits. Secondary outcomes included individual earnings, Social Security benefits, unemployment benefits, and catastrophic income loss., Results: The study included 11 673 patients (7756 male patients [66.4%]; mean [SD] age, 45.2 [19.2] years) with a mean (SD) preinjury household income of $30 505 ($89 030). A total of 403 patients (3.5%) had a postoperative infection. Postoperative infections were associated with a $6080 annual decrease (95% CI, -$12 114 to -$47; P = .048) in household income in the 6 years after injury. Postoperative infections were associated with a 6.6% increase (95% CI, 4.9%-8.3%; P < .001) in the risk of catastrophic wage loss within 2 years of the fracture and were associated with a 45% increase in the odds of receiving Social Security benefits (odds ratio, 1.45; 95% CI, 1.25-1.68; P < .001). However, incurring a postoperative infection was not associated with an increase in the value of the Social Security benefits received., Conclusions and Relevance: This study suggests that postoperative infections have significant and sustained income-associated implications for patients who experience a fracture. Current Social Security mechanisms may not offset the decreased income.

Introduction: Patients who sustain orthopaedic trauma are at an increased risk of venous thromboembolism (VTE), including fatal pulmonary embolism (PE). Current guidelines recommend low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopaedic trauma patients. However, emerging literature in total joint arthroplasty patients suggests the potential clinical benefits of VTE prophylaxis with aspirin. The primary aim of this trial is to compare aspirin with LMWH as a thromboprophylaxis in fracture patients., Methods and Analysis: PREVENT CLOT is a multicentre, randomised, pragmatic trial that aims to enrol 12 200 adult patients admitted to 1 of 21 participating centres with an operative extremity fracture, or any pelvis or acetabular fracture. The primary outcome is all-cause mortality. We will evaluate non-inferiority by testing whether the intention-to-treat difference in the probability of dying within 90 days of randomisation between aspirin and LMWH is less than our non-inferiority margin of 0.75%. Secondary efficacy outcomes include cause-specific mortality, non-fatal PE and deep vein thrombosis. Safety outcomes include bleeding complications, wound complications and deep surgical site infections., Ethics and Dissemination: The PREVENT CLOT trial has been approved by the ethics board at the coordinating centre (Johns Hopkins Bloomberg School of Public Health) and all participating sites. Recruitment began in April 2017 and will continue through 2021. As both study medications are currently in clinical use for VTE prophylaxis for orthopaedic trauma patients, the findings of this trial can be easily adopted into clinical practice. The results of this large, patient-centred pragmatic trial will help guide treatment choices to prevent VTE in fracture patients., Trial Registration Number: NCT02984384., Competing Interests: Competing interests: CDM has received grant funding as PI from Merck and receives consulting income from AstraZeneca, Bayer Pharmaceuticals, Janssen/J&J, Merck and Pfizer. ERH is/was the primary investigator of contracts from The Patient-Centred Outcomes Research Institute (PCORI) entitled 'Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient-Centred Care via Health Information Technology' (CE-12-11-4489) and 'Preventing Venous Thromboembolism (VTE): Engaging Patients to Reduce Preventable Harm from Missed/Refused Doses of VTE Prophylaxis' (DI-1603-34596); is the primary investigator of a grant from the Agency for Healthcare Research and Quality (AHRQ) (1R01HS024547) entitled 'Individualised Performance Feedback on Venous Thromboembolism Prevention Practice,' and is a co-investigator on a grant from the NIH/NHLBI (R21HL129028) entitled 'Analysis of the Impact of Missed Doses of Venous Thromboembolism Prophylaxis'; receives research grant support from the DOD/Army Medical Research Acquisition Activity and has received grant support from the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF); receives book royalties from Lippincott, Williams, Wilkins; and is a paid consultant to Vizient for their HIIN Venous Thromboembolism (VTE) Prevention Action Network., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: There are challenges in conducting a budget impact analysis (BIA) for rare disorders. Through this case study, we present some challenges and limitations of a BIA of managing patients affected with alpha-1 antitrypsin deficiency (AATD). We explored a conceptual basis and barriers for health services researchers interested in quantifying budget impacts of rare disease management program (DMP)., Methods: We developed a static budget impact cost calculator model in Microsoft Excel, obtaining the clinical impact of a DMP from the literature and translating it into costs using OLDW. Cost inputs and resource use was obtained from 2010 to 2015 claims data using the OLDW. Insurers' payments were calculated and categorized into the following cost buckets: physician visits, emergency room visits, inpatients stays, augmentation therapy, other prescription drugs costs, and other costs., Results: Data were based on 6832 patients with alpha-1 antitrypsin deficiency identified among over 21 million OLDW enrollees observed between January 1, 2010, and December 31, 2015. The introduction of a DMP was estimated to decrease costs of the management of patients with alpha-1 antitrypsin deficiency by $13.5 million over 5 years. The savings attributed to the program over the 5-year time horizon are due to 2555 exacerbations, 5180 emergency room visits, 9342 specialist visits, and 105 358 general practitioner visits avoided., Conclusions: A comprehensive DMP for a rare condition might provide cost savings to a health plan. BIAs for rare disease may be more informative if they focus on DMPs rather than on individual drugs., (Copyright © 2020 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2., (© 2020 ISPOR-The Professional Society for Health Economics and Outcomes Research and John Wiley & Sons Limited. [Published by Elsevier Inc on behalf of ISPOR-The Professional Society for Health Economics and Outcomes Research and by John Wiley & Sons Limited (“Wiley”)]. All rights reserved.)

Background: There are limited data on economic aspects of the genetic variant of chronic obstructive pulmonary disease (COPD) in the context of the more prevalent form of COPD. The objective of this study was to isolate the healthcare resource utilization and economic burden attributable to the presence of a genetic factor among COPD patients with and without Alpha-1 Antitrypsin Deficiency (AATD), twelve months before and after their initial COPD diagnosis., Methods: Retrospective analysis of OptumLabs® Data Warehouse claims (OLDW; 2000-2017). The OLDW is a comprehensive, longitudinal real-world data asset with de-identified lives across claims and clinical information. AATD-associated COPD cases were matched with up to 10 unique non-AATD-associated COPD controls. Healthcare resource use and costs were assigned into the following categories: office (OV), outpatient (OP), and emergency room visits (ER), inpatients stays (IP), prescription drugs (RX), and other services (OTH). A generalized linear model was used to estimate total pre- and post-index (initial COPD diagnosis) costs from a third-party payer's perspective (2018 USD) controlling for confounders. Healthcare resource utilization was estimated using a negative binomial regression., Results: The study population consisted of 8881 patients (953 cases matched with 7928 controls). The AATD-associated COPD cohort had higher expenditures and use of office visits (OV) and other (OTH) services, as well as OV, outpatient (OP), emergency room (ER), and prescription drugs (RX) before and after the index date, respectively. Adjusted total all-healthcare cost ratios for AATD-associated COPD patients as compared to controls were 2.04 [95% CI: 1.60-2.59] and 1.98 [95% CI: 1.55-2.52] while the incremental cost difference totaled $6861 [95% CI: $3025 - $10,698] and $5772 [95% CI: $1940 - $9604] per patient before and after the index date, respectively., Conclusions: Twelve months before and after their initial COPD diagnosis, patients with AATD incur higher healthcare utilization costs that are double the cost of similar COPD patients without AATD. This study also suggests that increased costs of AATD-associated COPD are not solely attributable to augmentation therapy use. Future studies should further explore the relationship between augmentation therapy, healthcare resource use, and other AATD-associated COPD expenditures.

Objective: Lack of evidence for efficacy and safety of treatment and limited clinical guidance have increased potential for undertreatment of depression following traumatic brain injury (TBI)., Methods: We conducted a retrospective cohort study among individuals newly diagnosed with depression from 2008 to 2014 to assess the impact of TBI on receipt of treatment for incident depression using administrative claims data. We created inverse probability of treatment-weighted populations to evaluate the impact of TBI on time to receipt of antidepressants or psychotherapy following new depression diagnosis during 24 months post-TBI or matched index date (non-TBI cohort)., Results: Of 10 428 individuals with incident depression in the TBI cohort, 44.7% received 1 or more antidepressants and 20.0% received 1 or more psychotherapy visits. Of 10 463 in the non-TBI cohort, 41.2% received 1 or more antidepressants and 17.6% received 1 or more psychotherapy visits. TBI was associated with longer time to receipt of antidepressants compared with the non-TBI cohort (average 39.6 days longer than the average 126.2 days in the non-TBI cohort; 95% confidence interval [CI], 24.6-54.7). Longer time to psychotherapy was also observed among individuals with TBI at 6 months post-TBI (average 17.1 days longer than the average 47.9 days in the non-TBI cohort; 95% CI, 4.2-30.0), although this association was not significant at 12 and 24 months post-TBI., Conclusions: This study raises concerns about the management of depression following TBI.

Background: Lack of adherence with prescribed medications among the asthma populations exacerbates health outcomes and increases social and economic costs., Objectives: The proposed study aims to model patient-centric structural determinants of adherence rates among asthma patients and explore the potential of mobile health apps such as the TRUSTR platform to improve adherence using its power of monetary and non-monetary chatbotting and non-non-monetary nudges. Following specific hypotheses are tested: (1) Patient attributes, such as their age and monetary medical condition, have significant effect on their adherence with the prescribed treatment plans. (2) Behavioral nudging with rewards and engagement via mobile health apps will increase adherence rates., Methods: The patient population (N = 37 359) consists of commercially insured patients with asthma who have been identified from administrative claims in the HealthCore Integrated Research Database (HIRD) between April 1, 2018 and March 31, 2019. Two Structural Equation Models (SEMs) are estimated to quantify direct, indirect, and total effect sizes of age and medical condition on proportion of days covered (PDC) and medical possession ratio (MPR), mediated by patient medical and pharmacy visits. Fourteen additional SEMs were estimated to lateralize TRUSTR findings and conduct sensitivity analysis., Results: HIRD data reveal mean adherence rate of 59% (standard deviation (SD) 29%) for PDC and 58% for MPR (SD 36%). Key structural findings from SEMs derived from the HIRD dataset indicate that each additional year in the age of the patient has a positive total effect on the adherence rate. Patients with poor medical condition are likely to have lower adherence rate, but this direct effect is countered by mediating variables. Further, each additional reward and higher engagement with a mobile app is likely to have a positive total effect on increasing the adherence rate., Conclusions: HIRD data reveal mean adherence rate of 59% (SD 29%), providing the evidence for the opportunity to increase adherence rate by around 40%. Statistical modeling results reveal structural determinants, such as the opportunity to nudge, are higher among younger patients, as they have higher probability of being non-adherent. Methodologically, lateralization approach demonstrates the potential to capture real-world evidence beyond clinical data and merge it with clinical data.

Multi-site clinical trials are essential within medical practice to help drive reliable and generalizable knowledge on advancing medical treatments. Although the success of multi-site trials is significantly dependent on local clinician and site research teams, best practices for engagement of site teams, or "site engagement," has not been extensively discussed. Site engagement centers on including sites in the planning and implementation of clinical trials to promote trial enrollment, compliance, and applicability to local contexts. Using a case example from the RadComp Trial, a longitudinal, multi-site clinical trial, novel site engagement practices are provided across three major research phases. In the Planning Phase, site engagement builds partnerships and commitment by active elicitation of information on site specific processes and feedback on trial design. In the Conducting Phase, sustained engagement encourages bi-directional communication and facilitates learning networks for enhanced site performance. In the Dissemination Phase, site and community partnerships are leveraged to create locally designed dissemination plans for broader scientific reach and impact. Site engagement practices discussed in this paper can be replicated or molded for application in other multi-site clinical trials., Competing Interests: Authors have no conflicts of interest to disclose., (© 2020 The Authors. Published by Elsevier Inc.)

The relationship between psychotropic medication use and traumatic brain injury (TBI) is not well understood. The objective of this study was to describe patterns of psychotropic medication use during the months before and after TBI and compare with a non-TBI cohort. We conducted a retrospective cohort study using administrative claims data for a commercially insured population from 2008 to 2014, and assessed monthly prevalence of psychotropic medication use by class before and after TBI (or matched index in the non-TBI controls). We tested time trends and quantified rates of increase using autoregressive models, and determined whether TBI impacted psychotropic medication use using difference-in-difference models. Compared with those without TBI ( n  = 414,708), individuals with TBI ( n  = 207,354) were more likely to receive any psychotropic medication both before (36.9% vs. 19.5%, p  < 0.001) and after TBI (48.2% vs. 25.7%, p  < 0.001). Prior to TBI, the rate of monthly increase in use of psychotropic medications in the TBI cohort was three to four times the rate observed in the non-TBI cohort, and was highest for antidepressants in both cohorts. After accounting for between-group and time trends, TBI was associated with increased use of several psychotropic medications including antipsychotics (rate ratio [RR] 1.08; 95% confidence interval [CI] 1.07, 1.09) and anxiolytics (RR 1.05; 95% CI 1.04, 1.06). Patterns of psychotropic medication use differed significantly between individuals with and without TBI. These results suggest that a better understanding of events leading up to and following TBI is needed to elucidate the role psychotropic medications play in the natural history of TBI.

Background: Patient and public involvement (PPI) is recommended when developing high-quality clinical practice guidelines, but the effects of different PPI strategies are largely unstudied., Objective: To assess the impact of participation and consultation strategies on guideline question development., Design: Instrumental case study design., Setting and Participants: This study used a clinical practice guideline in development by the American Academy of Neurology. A patient, two caregivers and a dementia advocate participated in the guideline development group alongside clinicians. The guideline protocol was posted for public consultation for 30 days., Interventions Studied: Participation (patient representatives on the guideline development group) and consultation (public comment, survey) PPI strategies., Main Outcome Measures: Public comment responses and guideline development group meeting transcripts were analysed descriptively. Transcript quotes were compared to the conceptual model of PPI in guideline development. The effects of participation and consultation strategies within the guideline case were compared., Results: Participation strategies shaped discussions, set a patient-centred scope, highlighted personal aspects of disease, affected how professionals viewed PPI, identified issues overlooked by medical professionals, and contributed to selecting patient-relevant guideline populations and outcomes. Professionals responded to public comment more than patient representatives. Patient survey participants confirmed the priorities voiced by patient representatives on the guideline development group. Final guideline questions included populations and outcomes promoted by patient representatives despite negative feedback from professional public commenters., Discussion and Conclusions: Participation and consultation PPI strategies have different advantages. Congruence between strategies increases the strength of the patient voice. Guideline developers should prioritize using both strategies for successful PPI., (© 2019 The Authors Health Expectations published by John Wiley & Sons Ltd.)

The International Society for Pharmacoeconomics and Outcomes Research (ISPOR)'s "Good Practices Task Force" reports are highly cited, multistakeholder perspective expert guidance reports that reflect international standards for health economics and outcomes research (HEOR) and their use in healthcare decision making. In this report, we discuss the criteria, development, and evaluation/consensus review and approval process for initiating a task force. The rationale for a task force must include a justification, including why this good practice guidance is important and its potential impact on the scientific community. The criteria include: (1) necessity (why is this task force required?); (2) a methodology-oriented focus (focus on research methods, approaches, analysis, interpretation, and dissemination); (3) relevance (to ISPOR's mission and its members); (4) durability over time; (5) broad applicability; and 6) an evidence-based approach. In addition, the proposal must be a priority specifically for ISPOR. These reports are valuable to researchers, academics, students, health technology assessors, medical technology developers and service providers, those working in other commercial entities, regulators, and payers. These stakeholder perspectives are represented in task force membership to ensure the report's overall usefulness and relevance to the global ISPOR membership. We hope that this discussion will bring transparency to the process of initiating, approving, and producing these task force reports and encourage participation from a diverse range of experts within and outside ISPOR., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

There has been increasing attention in implementation science to optimizing the fit of evidence-based interventions to the organizational settings where they are delivered. However, less is known about how to maximize intervention-context fit, particularly in community-based settings. We describe a new strategy to customize evidence-based health promotion interventions to community sites. Specifically, leaders in African American churches completed a memorandum of understanding where they were asked to identify two or more health promotion implementation strategies from a menu of 20 and select a planned implementation time frame for each. In a pilot phase with three churches, the menu-based strategy and protocols were successfully implemented and finalized in preparation for a subsequent randomized trial. The three pilot churches identified between two and nine strategies (e.g., form a health ministry, allocate space or budget for health activities, include health in church communications/sermons). The selected strategies varied widely, reinforcing the need for interventions that can be customized to fit the organizational context. Despite the challenges of integrating health promotion activities into non-health focused organizations, this approach has promise for fostering sustainable health activities in community settings.

Background: Innovations in hepatitis C virus (HCV) therapy included in traditional comparative evaluations focus on sustained virologic response (SVR) without addressing challenges patients report beyond virologic cure. This study aims to evaluate the cost-effectiveness of HCV drug therapy with a patient-centered approach., Methods: An individual-based Markov model was constructed using guidance from a stakeholder advisory board (SAB), a patient Delphi panel, and published literature to evaluate direct-acting antivirals (DAAs) compared to no treatment. The United States (US) health sector and societal perspectives were considered for 10- and 20-year time horizons. Inputs for treatment costs and effectiveness reflect a generic regimen. Indirect costs used for the societal model included estimates from self-reported productivity in a matched-control sample. Beyond the traditional quality-adjusted life-year (QALY) health outcome, this study included two novel measures developed from the Delphi panel and SAB: infected life-years and workdays missed. All costs were measured in 2018 US dollars., Results: Health sector costs and QALYs were higher in the treatment group in both 10- and 20-year models. Total infected life-years and workdays missed were reduced in the treatment group for both models. When costs of absenteeism, presenteeism, and patient/caregiver time were included, the DAA intervention was cost-saving at both 10 and 20 years. Health sector results were sensitive to drug costs and utility estimates for post-SVR health states. Societal results were sensitive to presenteeism estimates and drug costs., Conclusion: Treatment was cost-effective from a health sector perspective and cost-saving when including non-health costs such as patient/caregiver time and productivity.

Objective. To determine the role of entrepreneurism within the broader missions of schools of pharmacy and develop an educational framework to produce pharmacist entrepreneurs. Methods. Following a systematic review and six semi-structured interviews, a three-round Delphi process was conducted with an expert panel comprised of successful entrepreneurs, pharmacy faculty members and administrators, students, and community members. Participants were asked about the role of entrepreneurship in a pharmacy school's mission, how they would define a pharmacist entrepreneur, and to identify the knowledge, skills, and attitudes (KSAs) expected to be successful as a pharmacist entrepreneur. A model for entrepreneur education was also developed in accordance with Bloom's taxonomy. Participant agreement and rankings were reported. Results. Based on the semi-structured interviews and the results from the Delphi process, the following framework for a pharmacist entrepreneur was proposed along with a list of KSAs: identifies, creates, and pursues new opportunities; successfully implements new ideas into practice; is willing to take risks; fills unmet needs; creates new value through innovation; is responsive to change; makes sacrifices; includes social and intrapreneurship; leverages existing knowledge, skills, and resources; goes beyond traditional roles for pharmacists; and improves patient care. Recommendations for entrepreneurship instruction, guided by Bloom's taxonomy of cognitive processes, were created. Conclusion. According to our expert panel, a pharmacist entrepreneur combines several characteristics identified with a more traditional entrepreneur construct with the characteristics of an individual devoted to achieving outcomes beyond one's personal gain. Additional research to inform implementation and assessment of entrepreneurship within pharmacy curricula would provide more specific guidance for instructional design and accreditation evaluations., (© 2019 American Association of Colleges of Pharmacy.)

Objective: Comparative evaluations of innovations in hepatitis C virus (HCV) drug therapy typically focus on sustained virologic response (SVR) without addressing psychological and socioeconomic challenges that extend beyond virologic cure. This study aims to identify and prioritize variables important to patients when making the decision to start HCV treatment., Methods: A three-round Delphi process was conducted with the first round derived from a systematic literature review and advisory board input, including patients who have been affected by HCV, physicians, pharmacists, and a patient group representative. Delphi panelists were HCV patients who had received treatment or were considering treatment. Panelists were asked about factors influencing their HCV treatment decisions. Thematic analysis of open-ended responses based on grounded theory was used. Agreement with each category and rankings based on order of importance from the patient perspective was reported., Results: Treatment effectiveness (100% agreement), longer life (88%), fear of complications (84%), financial issues (80%), quality of life (100%), and impact on society (80%) were considered important factors to patients in decisions to seek treatment. A fear of harming others (87%) was considered more important than physical symptoms (83%) in terms of patient-reported problems caused by HCV. Medication costs (91%) were identified as the most important costs of having HCV, followed by doctor costs (77%)., Conclusions: In addition to treatment effectiveness, patient experiences with financial problems, quality of life, and altruistic desires impact HCV patients' decisions. The risk of infecting others may motivate patients to seek treatment as much as personally experienced physical symptoms.

Introduction: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer., Methods: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events., Ethics and Dissemination: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets., Trial Registration Number: NCT02603341., Competing Interests: Competing interests: JEB, SE, CDM and BK report grants from PCORI, during the conduct of the study. SNP, WB, L-MF, BGH, CK, MVM, RWM, FWP, SMM and OC report grants from University of Pennsylvania subcontracts as study investigator, during the conduct of the study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The study aimed to assess systematic differences in the characteristics of patients that consented for the trial compared with the broader pool of eligible patients in a large, pragmatic orthopaedic trauma trial., Design: A retrospective observational study performed from April 2017 to March 2018., Setting: Academic trauma centre in Baltimore, USA., Participants: There were 642 eligible adult trial participants with an operative fracture to the appendicular skeleton and were indicated for blood clot prophylaxis. The median age of the sample was 50 years (IQR: 31-63), and 60% were male., Primary Outcome Measure: The primary outcome was the refusal to enrol in the trial. Demographic and injury covariates were included in iterations of latent class models. The final model was selected based on a minimum Bayesian information criterion., Results: The final model identified three clusters with five covariates predictive of cluster membership (age, neighbourhood-based socioeconomic status, alcohol use, multiple fractures, multiple surgeries). The three clusters were associated with 22% (Cluster 1), 38% (Cluster 2) and 62% (Cluster 3) refusal rates, respectively. Members of Cluster 3 (n=84) were most commonly between 66 and 80 years of age (49% vs 6% (Cluster 1) and 21% (Cluster 2)), of high neighbourhood-based socioeconomic status (85% vs 63% (Cluster 1) and 8% (Cluster 2)), with isolated fractures (100% vs 80% (Cluster 1) and 92% (Cluster 2)), and were less likely to have multiple surgeries compared with the other clusters (28% vs 47% (Cluster 1) and 35% (Cluster 2))., Conclusion: In this study, the likelihood of refusing to participate in the trial ranged from 22% to 62% in the three identified clusters. Elderly age, high socioeconomic status, and less severe injuries defined the cluster that was most likely to refuse trial participation., Trial Registration Number: NCT02984384., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Historically, budget impact models have been used to demonstrate how a new drug or technology entering the market could influence payer budgets, with the hope of influencing coverage of the drug or technology. This article proposes the adaptation of a budget impact model framework to answer the payer question "What is the budget impact of our approaches to managing the utilization of drugs and technologies?" Throughout this article, we also describe lessons learned while collaborating with a U.S. payer to evaluate the budgetary impact of specific antidiabetic drug utilization management approaches. DISCLOSURES: The study discussed in this commentary was supported by grant number F32HS024857 from the Agency for Healthcare Research and Quality (AHRQ). The content is solely the responsibility of the authors and does not necessarily represent the official views of AHRQ, which 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; or design to submit the manuscript for publication. The findings discussed in this manuscript represent the views of the authors and do not necessarily reflect the views of the Department of Defense, the Defense Health Agency, nor the Departments of the Army, Navy, and Air Force. Hung reports personal fees from CVS Health and BlueCross BlueShield Association, outside the submitted work. Lugo has nothing to disclose. Mullins reports grants and other fees from AHRQ, during the conduct of the study; grants and personal fees from Bayer and Pfizer; and personal fees from Boehringer-Ingelheim, Janssen/J&J, Regeneron, and Sanofi, outside the submitted work. Parts of the study were presented as a poster presentation at the 2017 AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 27-30, 2017; Denver, CO, and as poster and oral presentations at the 2017 AMCP Nexus Meeting; October 16-19, 2017; Dallas, TX. The study was also published as Hung's PhD dissertation.

Background: There is a paucity of studies validating budget impact models. The lack of such studies may contribute to the underuse of budget impact models by payers in formulary decision making., Objective: To assess the face validity, internal verification, and predictive validity of a previously published model that assessed the budgetary impact of antidiabetic formulary changes., Methods: 4 experts with diverse backgrounds were selected and asked questions regarding the face validity of the structure/conceptual model, input data, and results from the budget impact model. To assess internal verification, structured "walk-throughs," unit tests, extreme condition tests, traces, replication tests, and double programming techniques were used. The predictive validity of the model was evaluated by comparing the predicted and realized budget using mean absolute scaled error. "Realized" budgetary impact of the formulary changes was calculated by taking the difference between realized budget in the year after the formulary changes and the budget had there been no formulary changes (i.e., the counterfactual). The counterfactual budget was modeled using the best fit autoregressive integrated moving average model., Results: When assessing the face validity of the model, the 4 experts brought up issues such as how to incorporate other health insurance, recent policy changes, cost inflation, and potential impacts on insulin use. The 6 internal verification techniques caught mistakes in equations, missing data, and misclassified data. The realized budget was found to be lower than the predicted budget, with 13% error and an absolute scaled error of 2.60. After removing the model assumption that past utilization trends would continue, the model's predictive accuracy improved (the absolute scaled error dropped below 1 to 0.48). The "realized" budgetary impact was found to be greater than the predicted budgetary impact, largely because of lower-than-expected utilization., Conclusions: The budget impact model overpredicted utilization in the year after the formulary changes. Discoveries through the validation process improved the accuracy and transparency of the model., Disclosures: This project was supported by grant number F32HS024857 from the Agency for Healthcare Research and Quality (AHRQ). The content is solely the responsibility of the authors and does not necessarily represent the official views of AHRQ. AHRQ 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; or design to submit the manuscript for publication. The findings discussed in this manuscript represent the views of the authors and do not necessarily reflect the views of the Department of Defense, the Defense Health Agency, nor the Departments of the Army, Navy, and Air Force. Hung reports a grant from the AHRQ, during the conduct of the study, and personal fees from CVS Health and BlueCross BlueShield Association, outside the submitted work. Mullins reports grants and personal fees from Bayer and Pfizer and personal fees from Boehringer Ingelheim, Janssen/J&J, Regeneron, and Sanofi-Aventis, outside the submitted work. Mullins, Slejko, and Shaya are employed by the University of Maryland School of Pharmacy. Haines and Lugo have nothing to disclose. Part of this content was previously presented as a poster at the 2017 AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 27-30, 2017; Denver, CO, and as poster and oral presentations at the 2017 AMCP Nexus Meeting; October 16-19, 2017; Dallas, TX. Part of this content was published as Hung's PhD dissertation.

Background: Patient and caregiver perspectives on amyloid positron emission tomography (PET) use are largely unexplored, particularly as compared with clinician views., Methods: We surveyed clinicians, patients, caregivers, and dementia advocates on topics relating to an evidence-based guideline on amyloid PET use. Topic importance was rated on a 9-point scale. Patient stakeholder and clinician views were compared using the Mann-Whitney U test., Results: Patient representatives (n=107) rated all survey topics as equal to or more important than clinicians (n=114) except 1 item discussing potential harms of false-positive diagnoses. Differences between patient representative and clinician populations were greatest when comparing the competing values of false-positive and false-negative diagnoses and the value of testing asymptomatic individuals., Conclusions: Patients and caregivers emphasized the importance of having a dementia diagnosis and placed more value on testing and outcomes for asymptomatic populations than clinicians. This underscores the importance of research investigating the effect of amyloid PET results on asymptomatic individuals and the need for amyloid PET ordering and disclosure standards.

The "Reference Case" was developed to facilitate comparability among published cost-effectiveness analyses intended to contribute to decisions about the broad allocation of healthcare resources. Although the societal perspective is recommended for Reference Case analyses, empirical estimations rarely adequately represent the patient perspective, and more often, healthcare system or payer perspectives are used. In this commentary, we discuss the evolution of the Reference Case over the past 20 years and how it now needs to further evolve. This should begin with a patient-informed societal perspective. A realignment of the societal perspective to better include patient perspectives in CEA creates a conduit for patient inclusion. Engaging patients to both derive patient-informed value elements and prioritize value elements using stated preference methods will lead to patient inclusion in the societal perspective and a patient-informed Reference Case analysis., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Patient engagement often starts after research funding is secured with little or no involvement of patients in the proposal development phase. This paper compares three levels of patient engagement and describes patients' early engagement in research proposal development process and its contemporary relevance to clinical and translational research. Authentic patient engagement is illustrated using an example of an ongoing pragmatic clinical trial. The paper also addresses key patient considerations and questions that have an impact on the proposal development. The final section presents strategies to overcome challenges to the patients' early engagement in research proposal development approach from the perspectives of both patients and researchers. Although the examples are from comparative effectiveness research, strategies discussed can be applied to all clinical and translational research.

Objective. To review literature pertaining to entrepreneurship in pharmacy practice, education, and the knowledge, skills, and attitudes (KSAs) identified for pharmacist entrepreneurs. Findings. In terms of pharmacy practice, entrepreneurship was most frequently identified with innovation and creativity to develop new opportunities for pharmacists. The most frequent role for entrepreneurship in pharmacy education was related to schools putting a greater emphasis on innovation, creativity, or divergent thinking. Risk-taking and creativity/innovation were the most frequently identified KSAs, with 17 (63.0%) manuscripts mentioning these as important for a pharmacist entrepreneur. Other KSAs pertaining to pharmacy entrepreneurship that were mentioned in the articles included self-starter, management, proactivity, communication, strategic planning, positivity, decision-making, teamwork, versatility, marketing, critical thinking, competitiveness, proposal development, numeracy, technology, self-reflection, persistence, social responsibility, and cultural competence. Summary. No consensus for entrepreneurship in pharmacy practice or education currently exists. In order to improve instructional design and assessment for pharmacy entrepreneurship education, a core set of KSAs for a pharmacist entrepreneur construct must be identified. The most commonly cited KSAs in related literature that are not already part of the Accreditation Council for Pharmacy Education standards include risk-taking, strategic planning, marketing, competitiveness, and social responsibility. These may serve as a starting point for enhancing pharmacy curricula to embrace pharmacist entrepreneurship.

Purpose: A hydrogel rectal spacer (HRS) is a medical device that is approved by the U.S. Food and Drug Administration to increase the separation between the prostate and rectum. We conducted a cost-effectiveness analysis of HRS use for reduction in radiation therapy (RT) toxicities in patients with prostate cancer (PC) undergoing external beam RT (EBRT)., Methods and Materials: A multistate Markov model was constructed from the U.S. payer perspective to examine the cost-effectiveness of HRS in men with localized PC receiving EBRT (EBRT alone vs EBRT + HRS). The subgroups analyzed included site of HRS placement (hospital outpatient, physician office, ambulatory surgery center) and proportion of patients with good baseline erectile function (EF). Data on EF, gastrointestinal and genitourinary toxicities incidence, and potential risks associated with HRS implantation were obtained from a recently published randomized clinical trial. Health utilities and costs were derived from the literature and the 2018 Physician Fee Schedule and were discounted 3% annually. Quality-adjusted life years (QALYs) and costs were modeled for a 5-year period from receipt of RT. Probabilistic sensitivity analysis and value-based threshold analyses were conducted., Results: The per-patient 5-year incremental cost for spacers administered in a hospital outpatient setting was $3578, and the incremental effectiveness was 0.0371 QALYs. The incremental cost-effectiveness ratio was $96,440/QALY for patients with PC undergoing HRS insertion in a hospital and $39,286/QALY for patients undergoing HRS insertion in an ambulatory facility. For men with good baseline EF, the incremental cost-effectiveness ratio was $35,548/QALY and $9627/QALY in hospital outpatient and ambulatory facility settings, respectively., Conclusions: Based on the current Medicare Physician Fee Schedule, HRS is cost-effective at a willingness to pay threshold of $100,000. These results contain substantial uncertainty, suggesting more evidence is needed to refine future decision-making., (Copyright © 2018. Published by Elsevier Inc.)

Background: Traditional budget impact models predict the financial consequences of a new drug entering the market. This study provides an example of applying the budget impact framework to a new research question of interest to managed care organizations-what is the budget impact of our formulary and utilization management (UM) policy changes?, Objective: To predict the 3-year annual budgetary impact of TRICARE's antidiabetic formulary and UM policy changes using TRICARE claims data., Methods: A budget impact model was built in Microsoft Excel using health plan claims data for a 3-year time horizon. Model outcomes included spending on antidiabetic medications and medications used for side effect treatment. In sensitivity analyses, medical costs from inpatient, outpatient, and emergency room visits were also estimated. Model inputs included health plan antidiabetic medication utilization, as well as publicly available drug cost, rebate, dispensing fee, and patient cost-sharing estimates. Type of enrollee and pharmacy were also incorporated into the model. Sensitivity analyses varied estimates for utilization switch rates between preferred and nonpreferred agents, drug costs, rebates, and dispensing fees, as well as predicted impact from implementation delays., Results: For the 623,827 affected by the formulary and UM policy changes, the model predicted annual savings that increased from $24 million in the first year to $43 million in the third year after the changes. The majority of savings came from drug acquisition costs, as opposed to rebates, copays, and dispensing fees. Sensitivity analyses found savings across all varied parameters and scenarios except an unlikely scenario when 0% of utilization switched from nonpreferred to preferred agents. The model also predicted that the formulary and UM policy changes would lead to $529,439 in savings from medical visit costs in Year 3., Conclusions: This budget impact model predicted cost savings from the payer's formulary and UM policy changes., Disclosures: This project was supported by grant number F32HS024857 from the Agency for Healthcare Research and Quality (AHRQ), which contracted with the University of Maryland School of Pharmacy to conduct this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, which 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; or design to submit the manuscript for publication. The findings discussed in this manuscript represent the views of the authors and do not necessarily reflect the views of the Department of Defense, the Defense Health Agency, nor the Departments of the Army, Navy, and Air Force. Hung reports a grant from the AHRQ, during the conduct of the study, and personal fees from CVS Health and BlueCross BlueShield Association, outside the submitted work. Mullins reports grants and personal fees from Bayer and Pfizer and personal fees from Boehringer-Ingelheim, Janssen/J&J, Regeneron, and Sanofi, outside the submitted work. Mullins, Slejko, and Shaya are employed by the University of Maryland School of Pharmacy. Haines and Lugo have nothing to disclose. Part of this content was previously presented as a poster at the 2017 AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 27-30, 2017; Denver, CO, and as poster and oral presentations at the 2017 AMCP Nexus Meeting; October 16-19, 2017; Dallas, TX. Part of this content was published as Hung's PhD dissertation.

Aims: This study sought to explore the decision to participate in genomics research for African American individuals. Our overall goal was to explore (1) the attributes that significantly contribute to willingness to participate in genomics research; (2) how these attributes are interpreted (what is their meaning?); (3) how trustworthiness is estimated in the decision to participate in research (i.e., what are the symbolic representations or heuristics of trustworthiness in decision-making?); and (4) how participants see factors to counterweigh each other., Methods: We sought a methodology that would afford exploration of the compensatory nature of decision-making where some choice attributes may be weighed differently than others as well as the use of heuristics (shortcuts to estimate key concepts in the mentally taxing task of decision-making) for concepts such as trustworthiness. We used a qualitative story deck to create hypothetical research scenarios with variable attributes (i.e., researcher race/ethnicity; institutional affiliation; research goal; and biospecimen requested) to determine how individuals find and interpret information to make decisions about research participation. These semi-structured interviews (n = 82) were conducted in African American barbershops in Baltimore City and Prince George's County, Maryland., Results: Quantitative and qualitative analysis was completed. Findings include that, even in the absence of interpersonal connection, trustworthiness can be communicated through multiple factors, such as (1) shared values with researchers and (2) familiarity. Conversely, (1) ambiguity, especially regarding the use of biospecimens, (2) negative reputations, and (3) perceptions of "hidden agendas" were associated with a lower willingness to participate. However, the alignment of participant and research goals was weighed more heavily in decisions than other factors., Conclusion: This study finds that negatively assessed characteristics in research design do not result in automatic rejections of participation. Negative assessments can be mitigated by emphasizing the multiple factors that communicate trustworthiness in the consent process, which may improve rates of research participation., (© 2020 S. Karger AG, Basel.)

Background: Alarming rates of unhealthy alcohol, non-prescription drug, and tobacco use highlight the preventable health risks of substance abuse and the urgent need to activate clinicians to recognize and treat risky use. Screening, brief intervention, and referral to treatment (SBIRT) is an efficacious and effective processes to identify, reduce and prevent risky use of substances. This paper describes a study protocol testing implementation of a toolkit to enhance use of SBIRT in acute care settings to recognize and address patient risky alcohol, drug, and tobacco use., Methods: This study uses a phased cluster randomized mixed method design to test nurse-led implementation of an SBIRT toolkit on one medical-surgical unit at 14 acute care hospitals (critical access, community and academic health centers). Medical surgical units will be randomly assigned to implement the SBIRT toolkit (engagement and communication, assessment, planning, training, and evaluation tools) or a wait-list usual care control group that begins implementation 6 months later. Primary endpoints are documentation of SBIRT delivery in randomly selected electronic medical records at baseline, 6 months and 12 months after group 1 implementation (61 records per unit per time period, N = 2562). Two surveys will be administered to unit nurses: smoking cessation activities will be assessed at baseline and SBIRT use will be assessed on randomly-selected days after implementation. In addition, site coordinators will complete a baseline capacity assessment, an implementation fidelity survey post-implementation, and a structured interview at the end of the study. Multilevel mixed-effects effects logistic and linear models will be used to analyze use of SBIRT and cost outcomes., Discussion: This study will guide subsequent SBIRT implementation, dissemination, and spread across rural, community and urban healthcare systems throughout the state and beyond. The long-term objective is to activate clinicians to recognize, intervene and refer people with risky substance use to improve health and decrease substance use disorders. Trial registration ClinicalTrials.gov NCT03560076.