Economic Evaluations of CAR-T Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aims to systematically review evidence on the cost-effectiveness of chimeric antigen receptor (CAR)-T therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments and economic evaluations that compared costs and effects of CAR-T therapy in cancer patients were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US Dollars RESULTS: Our search yielded 1,809 records, 47 of which were included. The majority of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared to various standard-of-care chemotherapies. The incremental cost-effective ratio (ICER) for CAR-T therapies ranged from $9,424 to $4,124,105 per QALY in adults and from $20,784 to $243,177 per QALY in pediatric patients. ICERs were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness were uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Interventions on gender equity in the workplace: a scoping review.

BACKGROUND: Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity). METHODS: Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework. RESULTS: We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes. CONCLUSIONS: There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex. TRIAL REGISTRATION: Open Science Framework https://osf.io/x8yae .

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Relationship Between Gestational Weight Gain and Health Service Utilization in Early Childhood: A Retrospective Cohort Study.

OBJECTIVE: Gestational weight gain (GWG) outside recommended ranges can negatively impact both the woman and child. The long-term effects of below-recommended or above-recommended GWG on the child are unclear. METHODS: This retrospective cohort study used a population-based birth registry of 258,005 live births to evaluate the relationship between maternal GWG and paediatric health service use. RESULTS: The results suggest below recommended GWG in underweight women in particular is associated with an increased rate of hospitalizations and specialist visits for the child in the first 24 months. CONCLUSION: Findings indicate that GWG may impact paediatric outcomes in ways that depend on pre-pregnancy body mass index, as derived from maternal height and weight measures.

Pharmacologic Procedural Distress Management During Laceration Repair in Children: A Systematic Review.

OBJECTIVES: To systematically appraise the literature on the relative effectiveness of pharmacologic procedural distress management agents for children undergoing laceration repair. METHODS: Six databases were searched in August 2021, and the search was updated in January 2023. We included completed randomized or quasi-randomized trials involving ( a ) children younger than 15 years undergoing laceration repair in the emergency department; ( b ) randomization to at least one anxiolytic, sedative, and/or analgesic agent versus any comparator agent or placebo; ( c ) efficacy of procedural distress management measured on any scale. Secondary outcomes were pain during the procedure, administration acceptance, sedation duration, additional sedation, length of stay, and stakeholder satisfaction. Cochrane Collaboration's risk-of-bias tool assessed individual studies. Ranges and proportions summarized results where applicable. RESULTS: Among 21 trials (n = 1621 participants), the most commonly studied anxiolytic agents were midazolam, ketamine, and N 2 O. Oral midazolam, oral ketamine, and N 2 O were found to reduce procedural distress more effectively than their comparators in 4, 3, and 2 studies, respectively. Eight studies comparing routes, doses, or volumes of administration of the same agent led to indeterminate results. Meta-analysis was not performed because of heterogeneity in comparators, routes, and outcome measures across studies. CONCLUSIONS: Based on procedural distress reduction, this study favors oral midazolam and oral ketamine. However, this finding should be interpreted with caution because of heterogeneous comparators across studies and minor conflicting results. An optimal agent for procedural distress management cannot be recommended based on the limited evidence. Future research should seek to identify the minimal, essential measures of patient distress during pharmacologic anxiolysis and/or sedation in laceration repair to guide future trials and reviews.

The success of publicly funded rotavirus vaccine programs for preventing community- and hospital-acquired rotavirus infections in Canadian pediatric hospitals: an observational study.

BACKGROUND: Canadian immunization programs for rotavirus started in 2011. We sought to determine their effect on the burden of community-acquired admissions and hospital-acquired rotavirus at pediatric hospitals. METHODS: The Canadian Immunization Monitoring Program Active (IMPACT) network conducted active surveillance for rotavirus-positive hospital admissions between 2005 and 2020 at 12 pediatric hospitals. We used yearly rates of community-acquired rotavirus per 10 000 admissions and hospital-acquired rotavirus infections per 1000 patient-days to determine changes in the pre- and post-vaccine program periods. RESULTS: During the 15-year study period, 5691 rotavirus hospital admissions and hospital-acquired infections were detected, including 4323 (76%) community-acquired infections and 1368 (24%) hospital-acquired infections. The average community-acquired rate in the pre-vaccine period was 60.3 (95% confidence interval [CI] 53.7-68.3) per 10 000 admissions, with a decline to 11.0 (95% CI 7.5-15.1) per 10 000 admissions in the post-vaccine period, resulting in an average reduction of 81.7% (95% CI 74.4%-87.8%). The rate of hospital-acquired rotavirus declined from 0.35 (95% CI 0.29-0.41) per 1000 patient-days in the pre-vaccine period to 0.05 (95% CI 0.03-0.07) per 1000 patient-days in the post-vaccine period, resulting in an 85.3% (95% CI 77.7%-91.9%) average decline. Herd protection was present among children aged 2-16 years. INTERPRETATION: Although start dates of rotavirus vaccine programs across provinces varied, there was around an 80% average decrease in both community-acquired and hospital-acquired rotavirus infections at pediatric hospitals in Canada in the 1- to 9-year interval after implementation of rotavirus vaccine programs. Herd protection is an important aspect of rotavirus vaccines for other children who are not vaccine eligible, and rotavirus vaccines continue to provide important benefits both for children and health care systems.

The role of quantitative bias analysis for nonrandomized comparisons in health technology assessment: recommendations from an expert workshop.

The use of treatment effects derived from nonrandomized studies (NRS) in health technology assessment (HTA) is growing. NRS carry an inherently greater risk of bias than randomized controlled trials (RCTs). Although bias can be mitigated to some extent through appropriate approaches to study design and analysis, concerns around data availability and quality and the absence of randomization mean residual biases typically render the interpretation of NRS challenging. Quantitative bias analysis (QBA) methods are a range of methods that use additional, typically external, data to understand the potential impact that unmeasured confounding and other biases including selection bias and time biases can have on the results (i.e., treatment effects) from an NRS. QBA has the potential to support HTA bodies in using NRS to support decision-making by quantifying the magnitude, direction, and uncertainty of biases. However, there are a number of key aspects of the use of QBA in HTA which have received limited discussion. This paper presents recommendations for the use of QBA in HTA developed using a multi-stakeholder workshop of experts in HTA with a focus on QBA for unmeasured confounding.

Protocol for a living evidence synthesis on variants of concern and COVID-19 vaccine effectiveness.

BACKGROUND: It is evident that COVID-19 will remain a public health concern in the coming years, largely driven by variants of concern (VOC). It is critical to continuously monitor vaccine effectiveness as new variants emerge and new vaccines and/or boosters are developed. Systematic surveillance of the scientific evidence base is necessary to inform public health action and identify key uncertainties. Evidence syntheses may also be used to populate models to fill in research gaps and help to prepare for future public health crises. This protocol outlines the rationale and methods for a living evidence synthesis of the effectiveness of COVID-19 vaccines in reducing the morbidity and mortality associated with, and transmission of, VOC of SARS-CoV-2. METHODS: Living evidence syntheses of vaccine effectiveness will be carried out over one year for (1) a range of potential outcomes in the index individual associated with VOC (pathogenesis); and (2) transmission of VOC. The literature search will be conducted up to May 2023. Observational and database-linkage primary studies will be included, as well as RCTs. Information sources include electronic databases (MEDLINE; Embase; Cochrane, L*OVE; the CNKI and Wangfang platforms), pre-print servers (medRxiv, BiorXiv), and online repositories of grey literature. Title and abstract and full-text screening will be performed by two reviewers using a liberal accelerated method. Data extraction and risk of bias assessment will be completed by one reviewer with verification of the assessment by a second reviewer. Results from included studies will be pooled via random effects meta-analysis when appropriate, or otherwise summarized narratively. DISCUSSION: Evidence generated from our living evidence synthesis will be used to inform policy making, modelling, and prioritization of future research on the effectiveness of COVID-19 vaccines against VOC.

Maternal weight and paediatric health use: mediating role of adverse birth outcomes: a retrospective cohort study.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) above or below recommendations have been associated with increased paediatric health service utilization as well as increased risk of adverse birth outcomes, including small for gestational age (SGA) and preterm birth (PTB). SGA and PTB are associated with numerous adverse health outcomes in the child, including delayed growth, motor and cognitive impairment. Previous research has identified birth weight and gestational age on the causal pathway in the association between maternal pre-pregnancy BMI and child hospital admissions, there are no studies to date to quantify this relationship across other areas of health service utilization, nor the impact of gestational weight gain. This study aimed to assess if SGA or PTB partially explain the association between maternal weight and paediatric health service utilization. METHODS: The study population consisted of all women who delivered a singleton, live infant in Ontario between 2012 and 2014, and was assembled from data contained in the provincial birth registry. Health service utilization over the first 24 months following birth was examined by linking data from the registry with other provincial health administrative databases housed at ICES. The mediating roles of PTB and SGA were assessed using the Baron-Kenny method and causal mediation analysis. RESULTS: A total of 204,162 infants were included in the analysis of maternal pre-pregnancy BMI and 171,127 infants were included in the GWG analysis. The small magnitude of association between maternal BMI and paediatric health service utilization impacted our ability to estimate the indirect effect of maternal BMI through adverse birth outcomes (adjusted indirect effect = 0.00). 56.7% of the association between below recommended GWG and increased hospitalizations was attributed to PTB, while 6.8% of the association was attributed to SGA. CONCLUSION: Paediatric hospitalizations may be partially attributable to PTB and SGA in children born to mothers with below-recommended GWG. However, maternal weight also appears to be related to increased paediatric health service utilization independent of PTB and SGA.

Cost-Effectiveness of Colchicine for Recurrent Cardiovascular Events.

Background: Colchicine is an anti-inflammatory therapy with a low associated cost that has been shown in 2 large studies to reduce cardiovascular (CV) events, but its use is associated with side effects. The main objective for this analysis is to determine whether colchicine therapy is cost-effective for the prevention of recurrent CV events in patients who have suffered a myocardial infarction (MI). Methods: A decision model was developed to estimate the healthcare costs in Canadian dollars and the clinical outcomes among patients who have suffered an MI and are treated with colchicine. Probabilistic Markov modelling was used in combination with Monte Carlo simulation to derive expected lifetime costs and quality-adjusted life-years, which permitted the calculation of incremental cost-effectiveness ratios. Models were derived for both short-term (20 months) and long-term (lifelong) colchicine use in this population. Results: Long-term colchicine use was dominant over standard of care, with lower average lifetime costs per patient (CAD$91,552.80 vs $97,085.84) and a higher average number of quality-adjusted life-years per patient (19.92 vs 19.80). Short-term colchicine use also dominated over standard of care. Results were consistent over a range of scenario analyses. Conclusions: Based on 2 large randomized controlled trials, treatment of patients post-MI with colchicine appears cost-effective, compared to the standard of care at the current price. Based on these studies and currently accepted willingness-to-pay thresholds in Canada, healthcare payers could consider funding long-term colchicine therapy for CV secondary prevention while we await results from ongoing trials.

Contexte: La colchicine est un traitement anti-inflammatoire peu coûteux qui, selon deux grandes études, réduit le taux d'événements cardiovasculaires (CV), mais son utilisation est également associée à des effets secondaires. L'objectif principal de cette analyse était de déterminer si le traitement par la colchicine présente un rapport coût-efficacité intéressant en prévention des événements CV récurrents chez les patients ayant subi un infarctus du myocarde (IM). Méthodologie: Un modèle décisionnel a été mis au point pour estimer les coûts des soins de santé en dollars canadiens et les issues cli-niques chez les patients qui ont subi un IM et qui sont traités par la colchicine. Un modèle probabiliste de Markov a été utilisé en association avec une simulation de Monte-Carlo pour obtenir le coût attendu pendant la vie et le nombre d'années de vie ajustées en fonction de la qualité, données qui ont permis de calculer les rapports coût-efficacité différentiels. Les modèles ont été adaptés pour l'utilisation de la colchicine à court terme (20 mois) et à long terme (à vie) dans la même population. Résultats: L'utilisation de colchicine à long terme donnait de meilleurs résultats que le traitement de référence, avec un coût moyen à vie par patient plus faible (91 552,80 $ CA c. 97 085,84 $ CA) et un plus grand nombre moyen d'années de vie ajustées selon la qualité (19,92 c. 19,80). L'utilisation à court terme de la colchicine donnait aussi de meilleurs résultats que le traitement de référence. Ces résultats ont été observés pour un éventail de scénarios analysés. Conclusions: Selon deux grands essais randomisés contrôlés, le traitement par la colchicine des patients ayant subi un IM semble avoir un meilleur rapport coût-efficacité que le traitement de référence en fonction des coûts actuels. Selon ces études et les seuils de propension à payer actuellement acceptés au Canada, les payeurs pourraient envisager de financer le traitement à long terme par la colchicine en prévention d'événements CV secondaires, jusqu'à l'obtention des résultats des essais en cours.

Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Cost-Effectiveness Study.

BACKGROUND: Clinical practice guidelines recommend indefinite anticoagulation for a first unprovoked venous thromboembolism (VTE). OBJECTIVE: To estimate the benefit-harm tradeoffs of indefinite anticoagulation in patients with a first unprovoked VTE. DESIGN: Markov modeling study. DATA SOURCES: Systematic reviews and meta-analyses for the long-term risks and case-fatality rates of recurrent VTE and major bleeding. Published literature for costs, quality of life, and other clinical events. TARGET POPULATION: Patients with a first unprovoked VTE who have completed 3 to 6 months of initial anticoagulant treatment. TIME HORIZON: Lifetime. PERSPECTIVE: Canadian health care public payer. INTERVENTION: Indefinite anticoagulation with direct oral anticoagulants. OUTCOME MEASURES: Recurrent VTE events, major bleeding events, costs in 2022 Canadian dollars (CAD), and quality-adjusted life-years (QALYs). RESULTS OF BASE-CASE ANALYSIS: When compared with discontinuing anticoagulation after initial treatment in a hypothetical cohort of 1000 patients aged 55 years, indefinite anticoagulation prevented 368 recurrent VTE events, which included 14 fatal pulmonary emboli, but induced an additional 114 major bleeding events, which included 30 intracranial hemorrhages and 11 deaths from bleeding. Indefinite anticoagulation cost CAD $16 014 more per person and did not increase QALYs (-0.075 per person). RESULTS OF SENSITIVITY ANALYSIS: Model results were most sensitive to the case-fatality rate of major bleeding and the annual risk for major bleeding during extended anticoagulation. LIMITATION: The model assumed that risks for recurrent VTE and major bleeding measured in clinical trials at 1 year remained constant during extended anticoagulation. CONCLUSION: Clinicians should use shared decision making to incorporate individual patient preferences and values when considering treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Rationale and Design of the Rivaroxaban Post-Transradial Access for the Prevention of Radial Artery Occlusion Trial (CAPITAL-RAPTOR).

INTRODUCTION: Transradial access (TRA) has rapidly emerged as the preferred vascular access site for coronary angiography and percutaneous coronary intervention. Radial artery occlusion (RAO) remains as an important complication of TRA as it precludes future ipsilateral transradial procedures. While intraprocedural anticoagulation has been studied extensively, the definitive role of postprocedural anticoagulation has not yet been established. METHODS AND ANALYSIS: The Rivaroxaban Post-Transradial Access for the Prevention of Radial Artery Occlusion trial is a multicentre, prospective, randomised, open-label, blinded-endpoint design study investigating the efficacy and safety of rivaroxaban to reduce the incidence of RAO. Eligible patients will undergo randomisation to receive either rivaroxaban 15 mg once daily for 7 days or to no additional postprocedural anticoagulation. Doppler ultrasound to assess radial artery patency will be performed at 30 days. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ottawa Health Science Network Research Ethics Board (approval number 20180319-01H). The study results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03630055.

Trajectory of hearing loss in children with unilateral hearing loss.

Introduction: The aim of this study was to quantify the amount of deterioration in hearing and to document the trajectory of hearing loss in early identified children with unilateral hearing loss (UHL). We also examined whether clinical characteristics were associated with the likelihood of having progressive hearing loss. Methods: As part of the Mild and Unilateral Hearing Loss Study, we followed a population-based cohort of 177 children diagnosed with UHL from 2003 to 2018. We applied linear mixed models to examine hearing trends over time including the average amount of change in hearing. Logistic regression models were used to examine the relationship between age and severity at diagnosis, etiology, and the likelihood of progressive loss and amount of deterioration in hearing. Results: The median age of the children at diagnosis was 4.1 months (IQR 2.1, 53.9) and follow-up time was 58.9 months (35.6, 92.0). Average hearing loss in the impaired ear was 58.8 dB HL (SD 28.5). Over the 16-year period, 47.5% (84/177) of children showed deterioration in hearing in one or both ears from their initial diagnostic assessment to most recent assessment including 21 (11.9%) who developed bilateral hearing loss. Average deterioration in the impaired ear ranged from 27 to 31 dB with little variation across frequencies. Deterioration resulted in a change in category of severity for 67.5% (52/77) of the children. Analysis for children who were followed for at least 8 years showed that most lost a significant amount of hearing rapidly in the first 4 years, with the decrease stabilizing and showing a plateau in the last 4 years. Age and severity at diagnosis were not significantly associated with progressive/stable loss after adjusting for time since diagnosis. Etiologic factors (ENT external/middle ear anomalies, inner ear anomalies, syndromic hearing loss, hereditary/genetic) were found to be positively associated with stable hearing loss. Conclusion: Almost half of children with UHL are at risk for deterioration in hearing in one or both ears. Most deterioration occurs within the first 4 years following diagnosis. Most children did not experience sudden "large" drops in hearing but more gradual decrease over time. These results suggest that careful monitoring of UHL especially in the early years is important to ensure optimal benefit from early hearing loss detection.

Protocol for a modelling study to assess the clinical and cost-effectiveness of indefinite anticoagulant therapy for first unprovoked venous thromboembolism.

INTRODUCTION: Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE. METHODS AND ANALYSIS: We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal.

Universal ophthalmia neonatorum prophylaxis in Ontario: a cost-effectiveness analysis.

BACKGROUND: Although prophylaxis for ophthalmia neonatorum at birth is required by law in Ontario, declining prevalence of disease and efficacy of prophylaxis have called this practice into question. The objective of this modelling study was to assess the cost-effectiveness of universal prophylaxis for ophthalmia neonatorum to inform decision-makers on the potential impact of a change in this policy. METHODS: We compared the cost-effectiveness of prophylaxis for ophthalmia neonatorum with no prophylaxis through cost-utility analysis with a lifetime time horizon, considering a provincial government payer, for a hypothetical population of newborns in Ontario. We assessed both the mean incremental costs of prophylaxis and its mean incremental effectiveness using a hybrid (part decision tree, part Markov) model. We used a scenario analysis to evaluate alternative time horizons and discount rates. We conducted a threshold analysis to evaluate the impact of variations in the cost of prophylaxis and in the prevalence of sexually transmitted infections (gonorrhea and chlamydia). RESULTS: In our model, prophylaxis for ophthalmia neonatorum did not meet a willingness-to-pay threshold of Can$50 000 per quality-adjusted life-year (QALY). Although prophylaxis was effective in reducing morbidity associated with ophthalmia neonatorum, the number needed to treat to prevent 1 case of ophthalmia neonatorum blindness was 500 000, with an associated cost of more than Can$4 000 000. When compared with no prophylaxis, prophylaxis had an incremental cost of Can$355 798 per long-term QALY gained (incremental cost-effectiveness ratio). INTERPRETATION: We found that prophylaxis for ophthalmia neonatorum, although individually inexpensive, leads to very high costs on a population level. These findings contribute to the discussion on mandatory prophylaxis currently underway in several jurisdictions.

The Resistance Exercise in Already Active Diabetic Individuals (READI) Randomized Clinical Trial.

CONTEXT: Resistance exercise training (strength training) and aerobic exercise training are both recommended for people with type 1 diabetes, but it is unknown whether adding resistance exercise provides incremental benefits in people with this condition who already perform aerobic exercise regularly. OBJECTIVE: This work aimed to evaluate the incremental effect of resistance training on glycated hemoglobin A1c (HbA1c), fitness, body composition, and cardiometabolic risk factors in aerobically active people with type 1 diabetes. METHODS: The Resistance Exercise in Already-active Diabetic Individuals (READI) trial (NCT00410436) was a 4-center, randomized, parallel-group trial. After a 5-week run-in period with diabetes management optimization, 131 aerobically active individuals with type 1 diabetes were randomly assigned to resistance exercise (n = 71, intervention-INT) or control (n = 60, CON) for 22 additional weeks. Both groups maintained their aerobic activities and were provided dietary counseling throughout. Exercise training was 3 times per week at community-based facilities. The primary outcome was HbA1c, and secondary outcomes included fitness (peak oxygen consumption, muscle strength), body composition (anthropometrics, dual-energy x-ray absorptiometry, computed tomography), and cardiometabolic risk markers (lipids, apolipoproteins). Assessors were blinded to group allocation. RESULTS: There were no significant differences in HbA1c change between INT and CON. Declines in HbA1c (INT: 7.75 ± 0.10% [61.2 ± 1.1 mmol/mol] to 7.55 ± 0.10% [59 ± 1.1 mmol/mol]; CON: 7.70 ± 0.11% [60.7 ± 1.2 mmol/mol] to 7.57 ± 0.11% [59.6 ± 1.3 mmol/mol]; intergroup difference in change -0.07 [95% CI, -0.31 to 0.18]). Waist circumference decreased more in INT than CON after 6 months (P = .02). Muscular strength increased more in INT than in CON (P < .001). There were no intergroup differences in hypoglycemia or any other variables. CONCLUSION: Adding resistance training did not affect glycemia, but it increased strength and reduced waist circumference, in aerobically active individuals with type 1 diabetes.

Engaging Patients and Caregivers in an Early Health Economic Evaluation: Discerning Treatment Value Based on Lived Experience.

BACKGROUND: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment. OBJECTIVE: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. METHODS: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data. RESULTS: Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration. CONCLUSIONS: Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models.

Principles of risk decision-making.

Risk management decisions in public health require consideration of a number of complex, often conflicting factors. The aim of this review was to propose a set of 10 fundamental principles to guide risk decision-making. Although each of these principles is sound in its own right, the guidance provided by different principles might lead the decision-maker in different directions. For example, where the precautionary principle advocates for preemptive risk management action under situations of scientific uncertainty and potentially catastrophic consequences, the principle of risk-based decision-making encourages decision-makers to focus on established and modifiable risks, where a return on the investment in risk management is all but guaranteed in the near term. To evaluate the applicability of the 10 principles in practice, one needs to consider 10 diverse risk issues of broad concern and explore which of these principles are most appropriate in different contexts. The 10 principles presented here afford substantive insight into the process of risk management decision-making, although decision-makers will ultimately need to exercise judgment in reaching appropriate risk decisions, accounting for all of the scientific and extra-scientific factors relevant to the risk decision at hand.

Cost-effectiveness of integrated disease management for high risk, exacerbation prone, patients with chronic obstructive pulmonary disease in a primary care setting.

BACKGROUND: We evaluate the cost-effectiveness of the 'Best Care' integrated disease management (IDM) program for high risk, exacerbation prone, patients with chronic obstructive pulmonary disease (COPD) compared to usual care (UC) within a primary care setting from the perspective of a publicly funded health system (i.e., Ontario, Canada). METHODS: We conducted a model-based, cost-utility analysis using a Markov model with expected values of costs and outcomes derived from a Monte-Carlo Simulation with 5000 replications. The target population included patients started in GOLD II with a starting age of 68 years in the trial-based analysis. Key input parameters were based on a randomized control trial of 143 patients (i.e., UC (n = 73) versus IDM program (n = 70)). Results were shown as incremental cost per quality-adjusted life year (QALY) gained. RESULTS: The IDM program for high risk, exacerbation prone, patients is dominant in comparison with the UC group. After one year, the IDM program demonstrated cost savings and improved QALYs (i.e., UC was dominated by IDM) with a positive net-benefit of $5360 (95% CI: ($5175, $5546) based on a willingness to pay of $50,000 (CAN) per QALY. CONCLUSIONS: This study demonstrates that the IDM intervention for patients with COPD in a primary care setting is cost-effective in comparison to the standard of care. By demonstrating the cost-effectiveness of IDM, we confirm that investment in the delivery of evidence based best practices in primary care delivers better patient outcomes at a lower cost than UC.

Cost-Effectiveness of Canakinumab From a Canadian Perspective for Recurrent Cardiovascular Events.

Background: Cardiovascular (CV) disease is a condition with high levels of morbidity and mortality. Canakinumab is a novel monoclonal antibody therapy that has been shown to reduce CV events but is associated with side effects and high cost. The main objective for this analysis is to determine whether canakinumab use is cost-effective for the prevention of recurrent CV events. Methods: A decision model was developed to estimate the direct costs and outcomes among patients who have suffered a myocardial infarction and are treated with canakinumab. A lifetime study horizon was used to analyze the base-case costs and utilities from the perspective of the Canadian publicly funded healthcare system. Markov modeling was used in combination with Monte Carlo simulation to derive expected values for costs and quality-adjusted life years (QALYs), permitting the calculation of incremental cost-effectiveness ratios. Results: Canakinumab was associated with higher average lifetime costs per patient ($457,982 vs $82,565) and higher average QALYs per patient (14.90 vs 14.20), compared with standard of care. Thus, the incremental cost per QALY gained for canakinumab treatment vs standard-of-care therapy was $535,365. The probability that canakinumab treatment is cost-effective was 0%. Results were consistent over a range of scenario analyses. Conclusions: Treatment of patients post-myocardial infarction with canakinumab is not cost-effective, compared with standard-of-care therapy at the current price. Based on currently accepted willingness-to-pay thresholds in Canada, a reduction in price of 91% is required to yield a cost per patient that would be considered appropriate.

Introduction: La maladie cardiovasculaire (CV) est une affection à forts taux de morbidité et de mortalité. Le canakinumab est un nouveau traitement par anticorps monoclonaux qui s'est avéré diminuer les événements CV, mais qui est associé à des effets secondaires et des coûts élevés. Le principal objectif de la présente analyse est de déterminer si l'utilisation du canakinumab est rentable dans la prévention des événements CV récidivants. Méthodes: Nous avons élaboré un modèle de prise de décision pour estimer les coûts directs et les résultats chez les patients qui ont souffert d'un infarctus du myocarde et qui sont traités par canakinumab. Nous avons utilisé un horizon d'étude sur la vie entière pour l'analyse coût-utilité de référence selon la perspective du système de soins de santé du Canada financé par l'État. La modélisation de Markov qui a été utilisée en combinaison avec la simulation Monte Carlo pour obtenir les valeurs attendues des coûts et des années de vie ajustées en fonction de la qualité (AVAQ) a permis le calcul des ratios coûts-efficacité différentiels. Résultats: Le canakinumab a été associé à des coûts moyens sur la vie entière plus élevés par patient (457 982 $ vs 82 565 $) et une AVAQ moyenne plus élevée par patient (14,90 vs 14,20) que le traitement selon la norme de soins. Par conséquent, le coût différentiel par AVAQ obtenu avec le traitement par canakinumab vs le traitement selon la norme de soins était de 535 365 $. La probabilité que le traitement par canakinumab soit rentable était de 0 %. Les résultats étaient cohérents dans un éventail d'analyses de scénarios. Conclusions: Le traitement des patients après un infarctus du myocarde par canakinumab n'est pas rentable comparativement au traitement selon la norme de soins au prix actuel. Selon les seuils de propension à payer actuellement acceptés au Canada, une réduction du prix de 91 % est requise pour obtenir un coût par patient qui serait considéré comme approprié.