Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy.

BACKGROUND: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. OBJECTIVES: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. METHODS: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. RESULTS: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: -6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. CONCLUSIONS: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786).

Combining Aortic Size With Arterial Hemodynamics Enhances Assessment of Future Thoracic Aortic Aneurysm Expansion.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a deadly disease whose current method for risk stratification (aneurysm size) is imperfect. We sought to evaluate whether combining aortic size with hemodynamic measures that reflect the aorta's function was superior to aortic size alone in the assessment of TAA expansion. METHODS: One hundred thirty-seven nonoperated participants with TAA were followed prospectively. Aortic stiffness and pulsatile hemodynamics were noninvasively assessed at baseline with a combination of arterial tonometry with echocardiography using validated methodology. Aneurysm growth was calculated from standard imaging modalities. Multivariable linear regression models adjusted for potential confounders evaluated the association of aneurysm size and arterial hemodynamics, alone and in combination, with TAA growth. RESULTS: Sixty-nine percent of participants were male. Mean ± SD age, baseline aneurysm size, follow-up, and aneurysm expansion were, respectively, 62.2 ± 11.4 years, 45.9 ± 4.0 mm, 4.5 ± 1.9 years, and 0.41 ± 0.46 mm/year. In the linear regression models, the standardised ß (ß∗) for the association of aneurysm size with aneurysm expansion was 0.178 (P = 0.044). This was improved by combining aortic size with most measures of aortic function, with ß∗ ranging from 0.192 (for aneurysm size combined with central diastolic blood pressure) to 0.484 (for aneurysm size combined with carotid-femoral pulse-wave velocity) (P ≤ 0.05 for each). CONCLUSIONS: Combining aneurysm size with measures of arterial function improves assessment of aneurysm growth over TAA size alone, which is the standard for clinical decisions in TAA. Thus, combining aneurysm size with measures of aortic function provides a clinical advantage in the assessment of TAA disease activity.

Assessment of the quality and content of clinical practice guidelines (CPGs) for vitamin D and for immigrants using the AGREE-II instrument: a protocol for systematic review.

INTRODUCTION: Worldwide, more immigrants experience vitamin D (vitD) deficiency than non-immigrants, which is attributed to ethnic variations, place or region of birth, skin pigmentation, clothing style, and resettlement-related changes in diet, physical activity, and sun exposure. Current recommendations in clinical practice guidelines (CPGs) concerning vitD are inadequate to address vitD deficiency among immigrants. CPGs may also lack guidance for physicians on vitD supplementation for immigrants. Moreover, there are concerns about the overall quality of these CPGs. OBJECTIVES: This systematic review will collate and critically appraise CPGs relevant to immigrants' health and vitD. Moreover, we will evaluate whether the CPGs of vitD including recommendations for immigrants and clarify whether the CPGs of immigrants include recommendations on vitD. METHODS: A systematic search of Ovid MEDLINE® ALL, EMBASE, and Turning Research Into Practice (TRIP) electronic databases, guideline repositories, and gray literature will be conducted to identify relevant CPGs. Two reviewers will independently evaluate the methodological quality of the retrieved guidelines using the Appraisal of Guidelines, Research, and Evaluation-II (AGREE-II) instrument. CPGs scoring ≥60% in at least four domains, including "rigor of development," will be considered high quality. CONCLUSION: Evaluating the quality and content of relevant CPGs may support researchers in developing national and global guidelines for immigrants. Furthermore, it may support vitD testing, nutritional counseling, and supplementation for vulnerable immigrant sub-populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021240562.

How effects on health equity are assessed in systematic reviews of interventions.

BACKGROUND: Enhancing health equity is endorsed in the Sustainable Development Goals. The failure of systematic reviews to consider potential differences in effects across equity factors is cited by decision-makers as a limitation to their ability to inform policy and program decisions.  OBJECTIVES: To explore what methods systematic reviewers use to consider health equity in systematic reviews of effectiveness. SEARCH METHODS: We searched the following databases up to 26 February 2021: MEDLINE, PsycINFO, the Cochrane Methodology Register, CINAHL, Education Resources Information Center, Education Abstracts, Criminal Justice Abstracts, Hein Index to Foreign Legal Periodicals, PAIS International, Social Services Abstracts, Sociological Abstracts, Digital Dissertations and the Health Technology Assessment Database. We searched SCOPUS to identify articles that cited any of the included studies on 10 June 10 2021. We contacted authors and searched the reference lists of included studies to identify additional potentially relevant studies. SELECTION CRITERIA: We included empirical studies of cohorts of systematic reviews that assessed methods for measuring effects on health inequalities. We define health inequalities as unfair and avoidable differences across socially stratifying factors that limit opportunities for health. We operationalised this by assessing studies which evaluated differences in health across any component of the PROGRESS-Plus acronym, which stands for Place of residence, Race/ethnicity/culture/language, Occupation, Gender or sex, Religion, Education, Socioeconomic status, Social capital. "Plus" stands for other factors associated with discrimination, exclusion, marginalisation or vulnerability such as personal characteristics (e.g. age, disability), relationships that limit opportunities for health (e.g. children in a household with parents who smoke) or environmental situations which provide limited control of opportunities for health (e.g. school food environment). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a pre-tested form. Risk of bias was appraised for included studies according to the potential for bias in selection and detection of systematic reviews.  MAIN RESULTS: In total, 48,814 studies were identified and the titles and abstracts were screened in duplicate. In this updated review, we identified an additional 124 methodological studies published in the 10 years since the first version of this review, which included 34 studies. Thus, 158 methodological studies met our criteria for inclusion. The methods used by these studies focused on evidence relevant to populations experiencing health inequity (108 out of 158 studies), assess subgroup analysis across PROGRESS-Plus (26 out of 158 studies), assess analysis of a gradient in effect across PROGRESS-Plus (2 out of 158 studies) or use a combination of subgroup analysis and focused approaches (20 out of 158 studies). The most common PROGRESS-Plus factors assessed were age (43 studies), socioeconomic status in 35 studies, low- and middle-income countries in 24 studies, gender or sex in 22 studies, race or ethnicity in 17 studies, and four studies assessed multiple factors across which health inequity may exist. Only 16 studies provided a definition of health inequity. Five methodological approaches to consider health equity in systematic reviews of effectiveness were identified: 1) descriptive assessment of reporting and analysis in systematic reviews (140 of 158 studies used a type of descriptive method); 2) descriptive assessment of reporting and analysis in original trials (50 studies); 3) analytic approaches which assessed differential effects across one or more PROGRESS-Plus factors (16 studies); 4) applicability assessment (25 studies) and 5) stakeholder engagement (28 studies), which is a new finding in this update and examines the appraisal of whether relevant stakeholders with lived experience of health inequity were included in the design of systematic reviews or design and delivery of interventions. Reporting for both approaches (analytic and applicability) lacked transparency and was insufficiently detailed to enable the assessment of credibility. AUTHORS' CONCLUSIONS: There is a need for improvement in conceptual clarity about the definition of health equity, describing sufficient detail about analytic approaches (including subgroup analyses) and transparent reporting of judgments required for applicability assessments in order to consider health equity in systematic reviews of effectiveness.

Sex differences after coronary artery bypass grafting with a second arterial conduit.

OBJECTIVES: Double arterial conduit use during coronary artery bypass grafting is associated with improved clinical outcomes compared with single arterial conduits in the general population. However, the sex-specific outcomes of this strategy remain unknown and are needed to inform sex-specific revascularization guidelines. METHODS: We conducted a population-based, retrospective cohort study of all Ontarians who underwent primary isolated coronary artery bypass grafting with single arterial conduits or double arterial conduits between October 2008 and September 2017. The primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiac and cerebrovascular events, defined as a composite of myocardial infarction, heart failure hospitalization, repeat revascularization, and stroke. We used inverse probability of treatment weighting to account for group imbalances. RESULTS: A total of 9135 women and 36,748 men underwent coronary artery bypass grafting. At 30 days, there was no between-group difference in mortality or major adverse cardiac and cerebrovascular events in men. However, among women, a double arterial conduit was associated with an increased rate of 30-day death (hazard ratio, 1.48; 95% confidence interval, 1.23-1.79) and major adverse cardiac and cerebrovascular events (hazard ratio, 1.32; 95% confidence interval, 1.14-1.51). The risk of medium-term mortality with double arterial conduits was less in men (hazard ratio, 0.88; 95% confidence interval, 0.84-0.92) and women (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94), as was the medium-term risk of major adverse cardiac and cerebrovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94) [men]; hazard ratio, 0.91; 95% confidence interval, 0.86-0.97) [women]). The incremental improvement in 9-year survival was 4.0% in women with a double arterial conduit and 0.9% in men. CONCLUSIONS: Double arterial conduit is associated with better medium-term survival and cardiovascular outcomes in both sexes. Double arterial conduits are associated with increased perioperative risk in women, but the medium-term benefit is greater than in men.

Remote Monitoring of Cardiovascular Implantable Electronic Devices in Canada: Survey of Patients and Device Health Care Professionals.

BACKGROUND: Remote monitoring is used to supplement in-clinic follow-up for patients with cardiac implantable electronic devices (CIEDs) every 6-12 months. There is a need to optimize remote management for CIEDs because of the consistent increases in CIED implants over the past decade. The objective of this study was to investigate real and perceived barriers to the use of remote patient management strategies in Canada and to better understand how remote models of care can be optimized. METHODS: We surveyed 512 CIED patients and practitioners in 22 device clinics in Canada. RESULTS: Device clinic surveys highlighted significant variation and inconsistency in follow-up care for in-clinic and remote visits across and within clinics. This survey showed that funding policies and management of additional workflow are barriers to optimal use and uptake. Despite this, device clinics perceive remote follow-up as a valuable resource and an efficient way to manage patient follow-up. Patients were broadly satisfied with their CIED follow-up care but identified barriers related to coordination of care, visit logistics, and information needs. Views varied as a function of clinical or sociodemographic characteristics. Most patients (n = 228; 91%) expressed a desire to receive a phone call from their device clinic after a remote transmission has been received. CONCLUSIONS: Lack of a unified, guideline-supported approach to follow-up after CIED implant, and discrepant funding policies across jurisdictions, are significant barriers to the use of remote patient management strategies in Canada. Efforts to increase or expand use of remote follow-up must recognize these barriers and the needs of specific subgroups of patients.

INTRODUCTION: La télésurveillance sert de complément à la consultation en clinique des patients porteurs d'un dispositif cardiaque électronique implantable (DCEI) tous les 6 à 12 mois. Il est nécessaire d'optimiser la prise en charge à distance des patients porteurs de DCEI en raison de la constante augmentation des implantations de DCEI au cours de la dernière décennie. L'objectif de la présente étude était d'examiner les obstacles réels et perçus à l'utilisation des stratégies de prise en charge à distance des patients du Canada et de mieux comprendre la façon d'optimiser les modèles de soins à distance. MÉTHODES: Nous avons interrogé 512 patients porteurs de DCEI et praticiens de 22 cliniques spécialisées en DCEI du Canada. RÉSULTATS: Les enquêtes des cliniques spécialisées en DCEI ont fait ressortir la variation importante et le manque d'uniformité dans les soins de suivi lors des consultations en clinique et à distance au sein de toutes les cliniques et entre elles. Cette enquête a montré que les politiques de financement et la gestion du flux de travail supplémentaire sont les obstacles qui empêchent l'utilisation optimale et l'adoption. Malgré cela, les cliniques spécialisées en DCEI perçoivent le suivi à distance comme une ressource très utile et un moyen efficace de prendre en charge le suivi du patient. Les patients étaient dans l'ensemble satisfaits de leurs soins de suivi relatifs à leur DCEI, mais relevaient des obstacles liés à la coordination des soins, à la logistique des consultations et à leurs besoins d'information. Les points de vue variaient en fonction des caractéristiques cliniques et sociodémographiques. La plupart des patients (n = 228 ; 91 %) ont fait part de leur souhait de recevoir un appel téléphonique de leur clinique spécialisée en DCEI après la réception de la transmission à distance. CONCLUSIONS: L'absence d'une approche unifiée et fondée sur les lignes directrices qui porte sur le suivi après l'implantation de DCEI, et la divergence des politiques de financement des provinces et territoires sont des obstacles importants à l'utilisation de stratégies de prise en charge à distance des patients au Canada. Les efforts visant à accroître ou à étendre l'utilisation du suivi à distance doivent tenir compte de ces obstacles et des besoins des sous-groupes particuliers de patients.

Remote-only monitoring for patients with cardiac implantable electronic devices: a before-and-after pilot study.

BACKGROUND: Outcomes for patients with cardiac implantable electronic devices are better when follow-up incorporates remote monitoring technology in addition to in-clinic visits. For patients with implantable devices, we sought to determine the feasibility, safety and associated health care utilization of remote-only follow-up, along with its effects on patients' quality of life and costs. METHODS: This multicentre before-and-after pilot study involved patients with new or existing pacemakers or implantable cardioverter defibrillators. The "before" phase of the study spanned the period October 2015 to February 2017; the "after" phase spanned the period October 2016 to February 2018. The exposure was remote-only follow-up in combination with Remote View, a service that facilitates access to device data, allowing device settings to be viewed remotely to facilitate remote programming. Outcomes at 12 months were feasibility (adherence to remote monitoring), safety (rate of adverse events) and health care utilization (remote and in-clinic appointments). We also assessed quality of life, using 3 validated scales, and costs, taking into account both health care system and patient costs. RESULTS: A total of 176 patients were enrolled. Adherence (defined as at least 1 successful remote transmission during follow-up) was 87% over a mean follow-up of 11.7 (standard deviation 2.2) months. There was a reduction in in-clinic visits at specialized sites among patients with both implantable defibrillators (26 v. 5, p < 0.001, n = 48) and pacemakers (42 v. 10, p < 0.001, n = 51). There was no significant change in visits to community sites for patients with defibrillators (13 v. 17, p = 0.3, n = 48). The composite rate of death, stroke, cardiovascular hospitalization and device-related hospitalization was 7% (n = 164). No adverse events were linked to the intervention. There was no change in quality-of-life scales between baseline and 12 months. Health care costs were reduced by 31% for patients with defibrillators and by 44% for those with pacemakers. INTERPRETATION: This pilot study showed the feasibility of remote-only follow-up, with no increase in adverse clinical outcomes and no effect on quality of life, but with reductions in costs and health care utilization. These results support progression to a larger-scale study of whether superior effectiveness and reduced cost can be achieved, with preservation of safety, through use of remote-only follow-up. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02585817.

GRADE Concept Paper 1: Validating the "F.A.C.E" instrument using stakeholder perceptions of feasibility, acceptability, cost, and equity in guideline implement.

BACKGROUND AND OBJECTIVE: To present a structured approach for assessing stakeholder perceptions and implementing the approach in guideline development. METHODS: This work was carried out by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Equity and Stakeholder Engagement Project Groups through brainstorming and iterative frameworks, stakeholder engagement, pilot testing, refinement of ideas, using input from workshops, and discussions at GRADE Working Group meetings to produce this document, which constitutes a GRADE conceptual article on implementation. RESULTS: We introduce the FACE implementation criteria, feasibility, acceptability, cost, and equity; priority; and "intent to implement" criterion. We outline the implementation importance of networks and approaches to patient and other stakeholder engagement. Implementation is often highly contextual and can benefit from stakeholder engagement and other assessments. Our FACE approach provides stakeholder questions and language to inform guideline implementation and tools. CONCLUSION: The FACE criteria propose a series of knowledge translation questions to guide the assessment of implementation for evidence-based guidelines. It is desirable for guideline developers to use a conceptual approach, such as FACE, to tailor implementation and inform end of guideline dissemination and knowledge translation activities.

Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Economic Evaluation of Cannabinoid Oil for Dravet Syndrome: A Cost-Utility Analysis.

INTRODUCTION: Cannabinoid oils are being increasingly used to treat Dravet syndrome, yet the long-term costs and outcomes of this approach are unknown. Thus, we examined the cost effectiveness of cannabinoid oil as an adjunctive treatment (added to clobazam and valproate), compared with adjunctive stiripentol or with clobazam and valproate alone, for the treatment of Dravet syndrome in children. METHODS: We performed a probabilistic cost-utility analysis from the perspective of the Canadian public health care system, comparing cannabinoid oil and stiripentol (both on a background of clobazam and valproate) with clobazam and valproate alone. Costs and quality-adjusted life-years (QALYs) were estimated using a Markov model that followed a cohort of children aged from 5 to 18 years through model states related to seizure frequency. Model inputs were obtained from the literature. The cost effectiveness of adjunctive cannabinoid oil, adjunctive stiripentol, and clobazam/valproate alone was assessed through sequential analysis. The influence of perspective and other assumptions were explored in scenario analyses. All costs are expressed in 2019 Canadian dollars, and costs and QALYs were discounted at a rate of 1.5% per year. RESULTS: The incremental cost per QALY gained with the use of adjunctive cannabinoid oil, from the health care system perspective, was $32,399 compared with clobazam and valproate. Stiripentol was dominated by cannabinoid oil, producing fewer QALYs at higher costs. At a willingness-to-pay threshold of $50,000, cannabinoid oil was the optimal treatment in 76% of replications. From a societal perspective, cannabinoid oil dominated stiripentol and clobazam/valproate. The interpretation of the results was insensitive to model and input assumptions. CONCLUSION: Compared with clobazam/valproate, adjunctive cannabinoid oil may be a cost-effective treatment for Dravet syndrome, if a decision maker is willing to pay at least $32,399 for each QALY gained. The opportunity costs of continuing to fund stiripentol, but not cannabinoid oil, should be considered.

Reporting of health equity considerations in cluster and individually randomized trials.

BACKGROUND: The randomized controlled trial (RCT) is considered the gold standard study design to inform decisions about the effectiveness of interventions. However, a common limitation is inadequate reporting of the applicability of the intervention and trial results for people who are "socially disadvantaged" and this can affect policy-makers' decisions. We previously developed a framework for identifying health-equity-relevant trials, along with a reporting guideline for transparent reporting. In this study, we provide a descriptive assessment of health-equity considerations in 200 randomly sampled equity-relevant trials. METHODS: We developed a search strategy to identify health-equity-relevant trials published between 2013 and 2015. We randomly sorted the 4316 records identified by the search and screened studies until 100 individually randomized (RCTs) and 100 cluster randomized controlled trials (CRTs) were identified. We developed and pilot-tested a data extraction form based on our initial work, to inform the development of our reporting guideline for equity-relevant randomized trials. RESULTS: In total, 39 trials (20%) were conducted in a low- and middle-income country and 157 trials (79%) in a high-income country focused on socially disadvantaged populations (78% CRTs, 79% RCTs). Seventy-four trials (37%) reported a subgroup analysis across a population characteristic associated with disadvantage (25% CRT, 49% RCTs), with 19% of included studies reporting subgroup analyses across sex, 9% across race/ethnicity/culture, and 4% across socioeconomic status. No subgroup analyses were reported for place of residence, occupation, religion, education, or social capital. One hundred and forty-one trials (71%) discussed the applicability of their results to one or more socially disadvantaged populations (68% of CRT, 73% of RCT). DISCUSSION: In this set of trials, selected for their relevance to health equity, data that were disaggregated for socially disadvantaged populations were rarely reported. We found that even when the data are available, opportunities to analyze health-equity considerations are frequently missed. The recently published equity extension of the Consolidated Reporting Standards for Randomized Trials (CONSORT-Equity) may help improve delineation of hypotheses related to socially disadvantaged populations, and transparency and completeness of reporting of health-equity considerations in RCTs. This study can serve as a baseline assessment of the reporting of equity considerations.

Study protocol: Worldwide comparison of vitamin D status of immigrants from different ethnic origins and native-born populations-a systematic review and meta-analysis.

BACKGROUND: A growing body of literature indicates that, worldwide, immigrants experience health deterioration after their arrival into their adopted country, and moreover, they have lower vitamin D compared to the native-born population. We plan to review if the levels of vitamin D are comparable between different ethnic groups in different regions of the world with those of native-born populations and to identify the possible associations between vitamin D deficiency and disease status among immigrants. METHODS/DESIGN: A systematic review and meta-analysis will be conducted following the methods of the Cochrane handbook for systematic reviews. A literature search was performed to identify studies on immigrants and vitamin D. The primary outcome is vitamin D levels, and the secondary outcome is any vitamin D deficiency-related disease. Study design and participant characteristics will be extracted, including ethnicity, country of birth and/or origin, and the host country. Descriptive and meta-analytic summaries of the outcomes will be derived. Distiller-SR and RevMan will be used respectively for data management and meta-analysis. DISCUSSION: This systematic review may partially help clarify vitamin D-related health deterioration in migrants; moreover, to develop a global guideline that specifies sub-populations, in which the evidence and vitamin D-related recommendations might differ from the overall immigrant population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018086729.

Decision Models for Assessing the Cost Effectiveness of Treatments for Pediatric Drug-Resistant Epilepsy: A Systematic Review of Economic Evaluations.

BACKGROUND: Drug-resistant epilepsy affects about one-third of children with epilepsy and is associated with high costs to the healthcare system, yet the cost effectiveness of most treatments is unclear. Use of cannabis-based products for epilepsy is increasing, and the cost effectiveness of such strategies relative to conventional pharmacologic treatments must be considered. OBJECTIVE: The objective of this systematic review was to identify economic evaluations of cannabis-based treatments for pediatric drug-resistant epilepsy. We also sought to identify and appraise decision models that have been used in economic evaluations of pharmacologic treatments (i.e., antiepileptic drugs) in this population. METHODS: Electronic searches of MEDLINE, EMBASE, and the Cochrane library, as well as a targeted grey literature search, were undertaken (11 June 2018). Model-based full economic evaluations involving cannabis-based treatments or pharmacologic treatments for drug-resistant epilepsy in children were eligible for inclusion. Two independent reviewers selected studies for inclusion, and study quality was assessed by use of the Drummond and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. Study findings, as well as model characteristics, are narratively summarized. RESULTS: Nine economic evaluations involving children with drug-resistant epilepsy were identified; however, none involved cannabis-based treatments. All studies involved pharmacologic treatments compared with other pharmacologic treatments or non-pharmacologic treatments (i.e., ketogenic diet, epilepsy surgery, vagus nerve stimulation). Few studies have assessed the cost effectiveness of pharmacologic treatments in specific drug-resistant epilepsy syndromes, including Dravet and Lennox-Gastaut syndromes. Five included studies involved use of Markov models with a similar structure (i.e., health states based on seizure frequency relative to baseline). There was a wide range of methodological quality, and few studies fully addressed context-specific issues such as weight gain and treatment switching. CONCLUSION: Whether cannabis-based treatments for pediatric drug-resistant epilepsy represent good value for money has yet to be investigated. Economic evaluations of such treatments are needed and should address issues of particular importance in pediatric epilepsy, including weight gain over time, switching or discontinuation of treatments, effectiveness of interventions and comparators, and long-term effectiveness beyond the duration of available clinical studies. PROSPERO REGISTRATION: CRD42018099591.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

BACKGROUND: Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. METHODS: We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. DISCUSSION: Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no.: CRD42018099591 .

OMERACT Filter 2.1: Elaboration of the Conceptual Framework for Outcome Measurement in Health Intervention Studies.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Filter 2.0 framework was developed in 2014 to aid core outcome set development by describing the full universe of "measurable aspects of health conditions" from which core domains can be selected. This paper provides elaborations and updated concepts (OMERACT Filter 2.1). METHODS: At OMERACT 2018, we discussed challenges in the framework application caused by unclear or ambiguous wording and terms and incompletely developed concepts. RESULTS: The updated OMERACT Filter 2.1 framework makes benefits and harms explicit, clarifies concepts, and improves naming of various terms. CONCLUSION: We expect that the Filter 2.1 framework will improve the process of core set development.

Improving Benefit-harm Assessment of Therapies from the Patient Perspective: OMERACT Premeeting Toward Consensus on Core Sets for Randomized Controlled Trials.

OBJECTIVE: Outcome Measures in Rheumatology (OMERACT) convened a premeeting in 2018 to bring together patients, regulators, researchers, clinicians, and consumers to build upon previous OMERACT drug safety work, with patients fully engaged throughout all phases. METHODS: Day 1 included a brief introduction to the history of OMERACT and methodology, and an overview of current efforts within and outside OMERACT to identify patient-reported medication safety concerns. On Day 2, two working groups presented results; after each, breakout groups were assembled to discuss findings. RESULTS: Five themes pertaining to drug safety measurement emerged. CONCLUSION: Current approaches have failed to include data from the patient's perspective. A better understanding of how individuals with rheumatic diseases view potential benefits and harms of therapies is essential.

Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis.

BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment-resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality-adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration.

Cost Effectiveness of Ventricular Tachycardia Ablation Versus Escalation of Antiarrhythmic Drug Therapy: The VANISH Trial.

OBJECTIVES: This analysis uses the data from the randomized controlled trial to assess the cost effectiveness of catheter ablation (n = 132) versus escalated antiarrhythmic therapy (n = 127). BACKGROUND: For survivors of myocardial infarction with implantable cardioverter-defibrillator shocks despite antiarrhythmic drugs, the VANISH (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) trial demonstrated improved clinical outcomes with catheter ablation compared with more aggressive antiarrhythmic pharmacotherapy. METHODS: Health care resource use and quality-of-life data were used to determine the cost effectiveness of catheter ablation. Published references were used to estimate costs (in 2015 Canadian dollars). The analysis was over 3 years, with a 5% discount rate. Adjustment was made for censoring and baseline utilities. RESULTS: Ablation resulted in greater quality-adjusted life-years (QALYs) than escalated drug therapy did (1.63 vs. 1.49; difference: 0.14; 95% confidence interval [CI]: -0.20 to 0.46) and higher cost ($65,126 vs. $60,269; difference: $4,857; 95% CI: -$19,757 to $27,106); with an incremental cost per QALY gained for ablation versus escalated drug therapy of $34,057 primarily due to the initial costs of ablation, which were partially offset by the costs of subsequent ablations and adverse outcomes in the escalated drug therapy arm. For patients with amiodarone-refractory ventricular tachycardia, ablation dominated escalated drug therapy, with greater QALYs (1.48 vs. 1.26; difference: 0.22; 95% CI: -0.19 to 0.59) and lower costs ($67,614 vs. $68,383; difference: -$769; 95% CI: -$35,330 to $27,092). For those with sotalol-refractory ventricular tachycardia, ablation resulted in similar QALYs (1.90 vs. 1.90; difference: -0.00; 95% CI: -0.59 to 0.62) and higher costs ($60,455 vs. $45,033; difference: $15,422; 95% CI: -$10,968 to $48,555). CONCLUSIONS: For the total trial population, results are suggestive that ablation is cost effective compared with escalation of drug therapy. This result was only manifest for the subgroup of patients whose qualifying arrhythmia occurred despite amiodarone.

Are iso-osmolar, as compared to low-osmolar, contrast media cost-effective in patients undergoing cardiac catheterization? An economic analysis.

PURPOSE: Contrast-induced acute kidney injury is a prominent complication following cardiac catheterization, though the risk has progressively decreased in recent times with appropriate risk stratification and use of safer contrast agents. Despite data supporting further lowering of risk with the iso-osmolar agent, iodixanol, uptake has lagged, perhaps due to increased upfront cost of this agent. We undertook an economic analysis to estimate the cost-effectiveness of a strategy utilizing iodixanol compared to using a low-osmolar contrast agent. METHODS: We created a Markov model to evaluate the two strategies, and included a differential relative risk of contrast-induced acute kidney injury, based on a systematic review of the literature. Downstream clinical events, including need for dialysis and mortality, were modeled using data from existing published literature. A third-party payer perspective was utilized for the analysis and presentation of the primary economic analysis. RESULTS: The strategy of using iodixanol dominated in both the low-risk and high-risk base case analyses. However, the difference was quite small in the low-risk scenario (lifetime cost: C$678,034 vs. C$678,059 and life expectancy: 19.80 vs. 19.72 years). The difference was more marked (life expectancy 15.65 vs. 14.15 years and cost C$680,989 vs. C$682,023) in the high-risk case analysis. This was robust across most of the variables tested in sensitivity analyses. CONCLUSION: The use of iodixanol, compared with low-osmolar contrast agents, for cardiac catheterization, results in a small benefit clinical outcomes, and in a savings in direct healthcare costs. Overall, our analysis supports the use of iodixanol for cardiac catheterization, especially in patients at high risk of acute kidney injury.