Felix A. Achana

Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis

Aims/hypothesisSedentary (sitting) behaviours are ubiquitous in modern society. We conducted a systematic review and meta-analysis to examine the association of sedentary time with diabetes, cardiovascular disease and cardiovascular and all-cause mortality.MethodsMedline, Embase and the Cochrane Library databases were searched for terms related to sedentary time and health outcomes. Cross-sectional and prospective studies were included. RR/HR and 95% CIs were extracted by two independent reviewers. Data were adjusted for baseline event rate and pooled using a random-effects model. Bayesian predictive effects and intervals were calculated to indicate the variance in outcomes that would be expected if new studies were conducted in the future.ResultsEighteen studies (16 prospective, two cross-sectional) were included, with 794,577 participants. Fifteen of these studies were moderate to high quality. The greatest sedentary time compared with the lowest was associated with a 112% increase in the RR of diabetes (RR 2.12; 95% credible interval [CrI] 1.61, 2.78), a 147% increase in the RR of cardiovascular events (RR 2.47; 95% CI 1.44, 4.24), a 90% increase in the risk of cardiovascular mortality (HR 1.90; 95% CrI 1.36, 2.66) and a 49% increase in the risk of all-cause mortality (HR 1.49; 95% CrI 1.14, 2.03). The predictive effects and intervals were only significant for diabetes.Conclusions/interpretationSedentary time is associated with an increased risk of diabetes, cardiovascular disease and cardiovascular and all-cause mortality; the strength of the association is most consistent for diabetes.

Estimating the budget impact of orphan drugs in Sweden and France 2013-2020

BackgroundThe growth in expenditure on orphan medicinal products (OMP) across Europe has been identified as a concern. Estimates of future expenditure in Europe have suggested that OMPs could account for a significant proportion of total pharmaceutical expenditure in some countries, but few of these forecasts have been well validated. This analysis aims to establish a robust forecast of the future budget impact of OMPs on the healthcare systems in Sweden and France.MethodsA dynamic forecasting model was created to estimate the budget impact of OMPs in Sweden and France between 2013 and 2020. The model used historical data on OMP designation and approval rates to predict the number of new OMPs coming to the market. Average OMP sales were estimated for each year post-launch by regression analysis of historical sales data. Total forecast sales were compared with expected sales of all pharmaceuticals in each country to quantify the relative budget impact.ResultsThe model predicts that by 2020, 152 OMPs will have marketing authorization in Europe. The base case OMP budget impacts are forecast to grow from 2.7% in Sweden and 3.2% in France of total drug expenditure in 2013 to 4.1% in Sweden and 4.9% in France by 2020. The principal driver of expenditure growth is the number of new OMPs obtaining OMP designation. This is tempered by the slowing success rate for new approvals and the loss of intellectual property protection on existing orphan medicines. Given the forward-looking nature of the analysis, uncertainty exists around model parameters and sensitivity analysis found peak year budget impact varying between 2% and 11%.ConclusionThe budget impact of OMPs in Sweden and France is likely to remain sustainable over time and a relatively small proportion of total pharmaceutical expenditure. This forecast could be affected by changes in the success rate for OMP approvals, average cost of OMPs, and the type of companies developing OMPs.

A Mediterranean diet improves HbA1c but not fasting blood glucose compared to alternative dietary strategies: a network meta‐analysis

BACKGROUND Overweight or obese individuals with type 2 diabetes are encouraged to lose weight for optimal glucose management, yet many find this difficult. Determining whether alterations in dietary patterns irrespective of weight loss can aid glucose control has not been fully investigated. METHODS We conducted a systematic review and meta-analysis aiming to determine the effects of a Mediterranean diet compared to other dietary interventions on glycaemic control irrespective of weight loss. Electronic databases were searched for controlled trials that included a Mediterranean diet intervention. The interventions included all major components of the Mediterranean diet and were carried out in free-living individuals at high risk or diagnosed with type 2 diabetes. Network meta-analysis compared all interventions with one another at the same time as maintaining randomisation. Analyses were conducted within a Bayesian framework. RESULTS Eight studies met the inclusion criteria, seven examined fasting blood glucose (n = 972), six examined fasting insulin (n = 1330) and three examined HbA1c (n = 487). None of the interventions were significantly better than the others in lowering glucose parameters. The Mediterranean diet reduced HbA1c significantly compared to usual care but not compared to the Palaeolithic diet. CONCLUSIONS The effect of alterations in dietary practice irrespective of weight loss on glycaemic control cannot be concluded from the present review. The need for further research in this area is apparent because no firm conclusions about relative effectiveness of interventions could be drawn as a result of the paucity of the evidence.

Network meta-analysis of multiple outcome measures accounting for borrowing of information across outcomes

BackgroundNetwork meta-analysis (NMA) enables simultaneous comparison of multiple treatments while preserving randomisation. When summarising evidence to inform an economic evaluation, it is important that the analysis accurately reflects the dependency structure within the data, as correlations between outcomes may have implication for estimating the net benefit associated with treatment. A multivariate NMA offers a framework for evaluating multiple treatments across multiple outcome measures while accounting for the correlation structure between outcomes.MethodsThe standard NMA model is extended to multiple outcome settings in two stages. In the first stage, information is borrowed across outcomes as well across studies through modelling the within-study and between-study correlation structure. In the second stage, we make use of the additional assumption that intervention effects are exchangeable between outcomes to predict effect estimates for all outcomes, including effect estimates on outcomes where evidence is either sparse or the treatment had not been considered by any one of the studies included in the analysis. We apply the methods to binary outcome data from a systematic review evaluating the effectiveness of nine home safety interventions on uptake of three poisoning prevention practices (safe storage of medicines, safe storage of other household products, and possession of poison centre control telephone number) in households with children. Analyses are conducted in WinBUGS using Markov Chain Monte Carlo (MCMC) simulations.ResultsUnivariate and the first stage multivariate models produced broadly similar point estimates of intervention effects but the uncertainty around the multivariate estimates varied depending on the prior distribution specified for the between-study covariance structure. The second stage multivariate analyses produced more precise effect estimates while enabling intervention effects to be predicted for all outcomes, including intervention effects on outcomes not directly considered by the studies included in the analysis.ConclusionsAccounting for the dependency between outcomes in a multivariate meta-analysis may or may not improve the precision of effect estimates from a network meta-analysis compared to analysing each outcome separately.

Pre-hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest (PARAMEDIC-2): Trial protocol

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest. This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant. 8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes). Trial registration (ISRCTN73485024).

The Effectiveness of Different Interventions to Promote Poison Prevention Behaviours in Households with Children: A Network Meta-Analysis

Background There is evidence from 2 previous meta-analyses that interventions to promote poison prevention behaviours are effective in increasing a range of poison prevention practices in households with children. The published meta-analyses compared any intervention against a “usual care or no intervention” which potentially limits the usefulness of the analysis to decision makers. We aim to use network meta-analysis to simultaneously evaluate the effectiveness of different interventions to increase prevalence of safe storage of i) Medicines only, ii) Other household products only, iii) Poisons (both medicines and non-medicines), iv) Poisonous plants; and v) Possession of poison control centre (PCC) telephone number in households with children. Methods Data on the effectiveness of poison prevention interventions was extracted from primary studies identified in 2 newly-undertaken systematic reviews. Effect estimates were pooled across studies using a random effects network meta-analysis model. Results 28 of the 47 primary studies identified were included in the analysis. Compared to usual care intervention, the intervention with education and low cost/free equipment elements was most effective in promoting safe storage of medicines (odds ratio 2.51, 95% credible interval 1.01 to 6.00) while interventions with education, low cost/free equipment, home safety inspection and fitting components were most effective in promoting safe storage of other household products (2.52, 1.12 to 7.13), safe storage of poisons (11.10, 1.60 to 141.50) and possession of PCC number (38.82, 2.19 to 687.10). No one intervention package was more effective than the others in promoting safe storage of poisonous plants. Conclusion The most effective interventions varied by poison prevention practice, but education alone was not the most effective intervention for any poison prevention practice. Commissioners and providers of poison prevention interventions should tailor the interventions they commission or provide to the poison prevention practices they wish to promote. Highlights Network meta-analysis is useful for comparing multiple injury-prevention interventions. More intensive poison prevention interventions were more effective than education alone. Education and low cost/free equipment was most effective in promoting safe storage of medicines. Education, low cost/free equipment, home safety inspection and fitting was most effective in promoting safe storage of household products and poisons. Education, low cost/free equipment and home inspection were most effective in promoting possession of a poison control centre number. None of the intervention packages was more effective than the others in promoting safe storage of poisonous plants.

Systematic Review and Meta-Analysis of Response Rates and Diagnostic Yield of Screening for Type 2 Diabetes and Those at High Risk of Diabetes.

Background Screening for type 2 diabetes (T2DM) and individuals at risk of diabetes has been advocated, yet information on the response rate and diagnostic yield of different screening strategies are lacking. Methods Studies (from 1998 to March/2015) were identified through Medline, Embase and the Cochrane library and included if they used oral glucose tolerance test (OGTT) and WHO-1998 diagnostic criteria for screening in a community setting. Studies were one-step strategy if participants were invited directly for OGTT and two, three/four step if participants were screened at one or more levels prior to invitation to OGTT. The response rate and diagnostic yield were pooled using Bayesian random-effect meta-analyses. Findings 47 studies (422754 participants); 29 one-step, 11 two-step and seven three/four-step were identified. Pooled response rate (95% Credible Interval) for invitation to OGTT was 65.5% (53.7, 75.6), 63.1% (44.0, 76.8), and 85.4% (76.4, 93.3) in one, two and three/four-step studies respectively. T2DM yield was 6.6% (5.3, 7.8), 13.1% (4.3, 30.9) and 27.9% (8.6, 66.3) for one, two and three/four-step strategies respectively. The number needed to invite to the OGTT to detect one case of T2DM was 15, 7.6 and 3.6 in one, two, and three/four-step strategies. In two step strategies, there was no difference between the response or yield rates whether the first step was blood test or risk-score. There was evidence of substantial heterogeneity in rates across study populations but this was not explained by the method of invitation, study location (rural versus urban) and developmental index of the country in which the study was performed. Conclusions Irrespective of the invitation method, developmental status of the countries and or rural/urban location, using a multi-step strategy increases the initial response rate to the invitation to screening for diabetes and reduces the number needed to have the final diagnostic test (OGTT in this study) for a definite diagnosis.

An exploration of synthesis methods in public health evaluations of interventions concludes that the use of modern statistical methods would be beneficial

OBJECTIVES To review the methods currently used to synthesize evidence in public health evaluations and demonstrate the availability of more sophisticated approaches. STUDY DESIGN AND SETTING A systematic review of National Institute for Health and Care Excellence (NICE) public health appraisals published between 2006 and 2012 was performed to assess the methods used for the synthesis of effectiveness evidence. The ability of new developments in evidence synthesis methodology to address the challenges and opportunities present in a public health context is demonstrated. RESULTS Nine (23%) of the 39 NICE appraisals included in the review performed pairwise meta-analyses as part of the effectiveness review with one of these also including a network meta-analysis. Of the remainder, 29 (74.4%) presented narrative summaries of the evidence only, and 1 (2.6%) appraisal did not present any review of effectiveness and/or cost-effectiveness evidence. Heterogeneity of outcomes, methods, and interventions were the main reasons given for not pooling the data. Exploration of quantitative synthesis methods shows that pairwise meta-analyses can be extended to incorporate individual participant data (when it is available), extend the number of interventions being compared using a network meta-analysis, and adjust for both subject- and summary-level covariates. All these can contribute to ensuring the analysis answers directly the policy-relevant questions. CONCLUSION More sophisticated methods in evidence synthesis should be considered to make evaluations in public health more useful for decision makers.

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.

Network meta-analysis to evaluate the effectiveness of interventions to prevent falls in children under age 5 years

Background This study aimed to simultaneously evaluate the effectiveness of a range of interventions to increase the possession of safety equipment or behaviours to prevent falls in children under 5 years of age in the home. Methods A recently published systematic review identified studies to be included in a network meta-analysis; an extension of pairwise meta-analysis that enables comparison of all evaluated interventions simultaneously, including comparisons not directly compared in individual studies. Results 29 primary studies were identified, of which 16 were included in at least 1 of 4 network meta-analyses. For increasing possession of a fitted stair gate, the most intensive intervention (including education, low cost/free home safety equipment, home safety inspection and fitting) was the most likely to be the most effective, with an OR versus usual care of 7.80 (95% CrI 3.08 to 21.3). For reducing possession or use of a baby walker: education only was most likely to be most effective, with an OR versus usual care of 0.48 (95% CrI 0.31 to 0.84). Little difference was found between interventions for possession of window locks (most intensive intervention versus usual care OR=1.56 (95% CrI 0.02 to 89.8)) and for not leaving a child alone on a high surface (education vs usual care OR=0.89 (95% CrI 0.10 to 9.67)). There was insufficient evidence for network meta-analysis for possession and use of bath mats. Conclusions These results will inform healthcare providers of the most effective components of interventions and can be used in cost-effectiveness analyses.