Using Expert Elicitation to Adjust Published Intervention Effects to Reflect the Local Context.

Background. Local health services make limited use of economic evaluation to inform decisions to fund new health service interventions. One barrier is the relevance of published intervention effects to the local setting, given these effects can strongly reflect the original evaluation context. Expert elicitation methods provide a structured approach to explicitly and transparently adjust published effect estimates, which can then be used in local-level economic evaluations to increase their local relevance. Expert elicitation was used to adjust published effect estimates for 2 interventions targeting the prevention of inpatient hypoglycemia. Methods. Elicitation was undertaken with 6 clinical experts. They were systematically presented with information regarding potential differences in patient characteristics and quality of care between the published study and local contexts, and regarding the design and application of the published study. The experts then assessed the intervention effects and provided estimates of the most realistic, most pessimistic, and most optimistic intervention effect sizes in the local context. Results. The experts estimated both interventions would be less effective in the local setting compared with the published effect estimates. For one intervention, the experts expected the lower complexity of admitted patients in the local setting would reduce the intervention's effectiveness. For the other intervention, the reduced effect was largely driven by differences in the scope of implementation (hospital-wide in the local setting compared with targeted implementation in the evaluation). Conclusions. The pragmatic elicitation methods reported in this article provide a feasible and acceptable approach to assess and adjust published intervention effects to better reflect expected effects in the local context. Further development and application of these methods is proposed to facilitate the use of local-level economic evaluation. Highlights: Local health services make limited use of economic evaluation to inform their decisions on the funding of new health service interventions. One barrier to use is the relevance of published intervention evaluations to the local setting.Expert elicitation methods provide a structured way to consider differences between the evaluation and local settings and to explicitly and transparently adjust published effect estimates for use in local economic evaluations.The pragmatic elicitation methods reported in this article offer a feasible and acceptable approach to adjusting published intervention effects to better reflect the effects expected in the local context. This increases the relevance of economic evaluations for local decision makers.

A framework for local-level economic evaluation to inform implementation decisions: health service interventions to prevent hospital-acquired hypoglycemia.

OBJECTIVES: Published evidence on health service interventions should inform decision-making in local health services, but primary effectiveness studies and cost-effectiveness analyses are unlikely to reflect contexts other than those in which the evaluations were undertaken. A ten-step framework was developed and applied to use published evidence as the basis for local-level economic evaluations that estimate the expected costs and effects of new service intervention options in specific local contexts. METHODS: Working with a multidisciplinary group of local clinicians, the framework was applied to evaluate intervention options for preventing hospital-acquired hypoglycemia. The framework included: clinical audit and analyses of local health systems data to understand the local context and estimate baseline event rates; pragmatic literature review to identify evidence on relevant intervention options; expert elicitation to adjust published intervention effect estimates to reflect the local context; and modeling to synthesize and calibrate data derived from the disparate data sources. RESULTS: From forty-seven studies identified in the literature review, the working group selected three interventions for evaluation. The local-level economic evaluation generated estimates of intervention costs and a range of cost, capacity and patient outcome-related consequences, which informed working group recommendations to implement two of the interventions. CONCLUSIONS: The applied framework for modeled local-level economic evaluation was valued by local stakeholders, in particular the structured, formal approach to identifying and interpreting published evidence alongside local data. Key methodological issues included the handling of alternative reported outcomes and the elicitation of the expected intervention effects in the local context.

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension-connective tissue disease subtype: A systematic review and meta-analysis.

INTRODUCTION: There is limited information regarding the effectiveness of endothelin receptor antagonists (ERA) in patients with connective tissue disease-pulmonary arterial hypertension (CTD-PAH), a condition that is characterized by poorer clinical outcomes compared to other PAH subtypes. OBJECTIVE: To conduct a systematic review and meta-analysis of the effectiveness and safety of ERA in CTD-PAH. METHODS: A literature search, using MEDLINE, COCHRANE, CINAHL and EMBASE databases was conducted, from inception to May 2019 to identify randomized control studies of ERA, as monotherapy or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in CTD-PAH. A protocol was registered in PROSPERO (CRD42019136956). Efficacy outcomes, including the 6-minute walk distance (6MWD) and composite clinical failure endpoints (CFE), and safety outcomes were evaluated. RESULTS: A total of 13 studies, including 784 CTD-PAH participants, were identified. ERA, as monotherapy, did not reduce the risk of CFE compared to placebo (odds ratio [OR] 0.77, 95% CI 0.50-1.19, P = .25). By contrast, combination therapy (ERA + PDE5i) significantly reduced the risk of developing CFE vs monotherapy (OR 0.54, 95% CI 0.32-0.90, P = .02). 6MWD did not improve when comparing monotherapy vs placebo (+17.41 m; 95% CI -19.83-54.66) P = .36) or combination therapy vs monotherapy (+13.17 m; 95% CI -16.44-42.78, P = .38). ERA-related adverse events rates in CTD-PAH and general PAH cohorts were comparable. CONCLUSIONS: ERA, when used in combination with PDE5is, are associated with reduced risk of CFE, but no significant changes in 6MWD, in CTD-PAH. This warrants further studies investigating early combination therapy as a standard of care in this group.

The pharmacokinetics of metformin in patients receiving intermittent haemodialysis.

The aims of this study were to characterise the population pharmacokinetics of metformin in patients receiving haemodialysis, and to determine the doses that will maintain median metformin plasma concentrations below 5 mg L-1 for a typical individual. Metformin plasma concentrations from 5 patients receiving thrice weekly intermittent haemodialysis followed by metformin 500 mg postdialysis were fitted to a published pharmacokinetic model. Additional models to describe the dialytic pharmacokinetics of metformin were explored. Doses of 250 and 500 postdialysis were simulated from the model for a typical haemodialysis patient. The published 2-compartment pharmacokinetic model with an additional parameter to describe haemodialysis clearance provided a reasonable fit to the data. Deterministic simulations from the model for a typical individual suggest that metformin doses of 250-500 mg postdialysis and 250 mg given once daily should maintain median metformin plasma concentrations below 5 mg L-1 .

Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy.

With the increasing prevalence of type 2 diabetes mellitus (T2DM) in women of childbearing age, prescribing antidiabetic medications in first-trimester pregnancy is becoming more common. Metformin treatment during this time is usually avoided in countries with well-resourced healthcare. This is based on historical concerns about safety to the foetus and the widespread availability of insulin. However, there is now increasing interest in the potential benefits of metformin in pregnant women with T2DM. In this commentary, the main evidence supporting metformin safety in pregnancy is summarized, with an emphasis on the first trimester. Based on a structured literature search, the recent randomized controlled trials comparing metformin and insulin are reviewed. We then show that prescribing advice for metformin in pregnancy is inconsistent and product information/package inserts (PI) are universally out of date. This causes confusion and pushes some women and their clinicians to change from metformin to insulin. The potential advantages of metformin in pregnant women with T2DM are then discussed, including oral dosing and improved acceptability, lower resource utilization and cost, decreased insulin requirements, less maternal weight gain and less risk of maternal and neonatal hypoglycaemia. The conclusion is that metformin is a cheap and efficacious antidiabetic medication for many pregnant women with T2DM, with reasonable evidence for safety. Drug information resources should be updated so that metformin can be considered more broadly in women with T2DM who present for antenatal care.

Effectiveness of Interventions to Deprescribe Inappropriate Proton Pump Inhibitors in Older Adults.

BACKGROUND: The use of proton pump inhibitors (PPIs) in older adults is high, often inappropriate, and may cause harm. Deprescribing is defined as the reduction, withdrawal, or discontinuation of inappropriate medication. OBJECTIVE: We conducted a systematic review to determine the effectiveness of interventions to deprescribe inappropriate PPIs in older adults. METHODS: We searched MEDLINE, PubMed, Embase, the Cochrane Library, ProQuest Dissertations and Theses Global, and Google from inception to January 2017 for randomized and non-randomized studies describing the outcomes of interventions to deprescribe inappropriate PPIs in older adults (mean or median age of ≥65 years). Where available, clinically relevant outcomes were also assessed. RESULTS: We included 21 articles in our review. Six studies demonstrated effective interventions, 11 were inconclusive, and four were ineffective. Effective interventions included a population-wide education and promotion strategy, academic detailing for general practitioners, and inpatient geriatrician-led deprescribing. Methodological issues limited the interpretation of several studies. Standardization in outcome reporting was lacking, and clinical outcome data were absent. A comparison of intervention effectiveness was not possible because of their heterogeneity, which precluded a meta-analysis. CONCLUSION: The limited available evidence suggests that some strategies are more successful than others in effectively deprescribing inappropriate PPIs in older adults. However, whether PPI deprescribing translates into better clinical outcomes remains unclear.

Continuous subcutaneous hydrocortisone infusion therapy in Addison's disease: a randomized, placebo-controlled clinical trial.

CONTEXT: Patients with Addison's disease (AD) report impaired subjective health status (SHS). Since cortisol exhibits a robust circadian cycle that entrains other biological clocks, impaired SHS may be due to the noncircadian cortisol profile achieved with conventional glucocorticoid replacement. Continuous subcutaneous hydrocortisone infusion (CSHI) reproduces a circadian cortisol profile, but its effects on SHS have not been objectively evaluated. OBJECTIVE: The aim of this study was to determine the effect of CSHI on SHS in AD. SETTING AND DESIGN: This was a multicentre, double-blind, placebo-controlled trial of CSHI vs oral glucocorticoid therapy. Participants received in random order 4 weeks of: CSHI and oral placebo, and subcutaneous placebo and oral hydrocortisone, separated by a 2-week washout period. SHS was assessed using the Short-Form 36 (SF-36), General Health Questionnaire (GHQ-28), Fatigue Scale (FS), Gastrointestinal Symptom Rating Scale (GSRS); and Addison's Quality of Life Questionnaire (AddiQoL). Participants were asked their (blinded) treatment preference. Twenty-four hour urine free cortisol (UFC) and diurnal salivary cortisol collections compared cortisol exposure during each treatment. RESULTS: Ten participants completed the study. Baseline SHS scores (mean ± SE) were consistent with mild impairment: SF-36 physical component summary 48.4 (± 2.4), mental component summary 53.3 (± 3.0); GHQ-28 18.1 (± 3.3); GSRS 3.7 (± 1.6), and AddiQoL 94.7 (± 3.7). FS was similar to other AD cohorts 13.5 (± 1.0) (P = 0.82). UFC between treatments was not different (P = 0.87). The salivary cortisol at 0800 h was higher during CSHI (P = 0.03), but not at any other time points measured. There was no difference between the treatments in the SHS assessments. Five participants preferred CSHI, four oral hydrocortisone, and one was uncertain. CONCLUSIONS: Biochemical measurements indicate similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD.