Thirimon Moe-Byrne

A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation

BackgroundThe grading of recommendation, assessment, development and evaluation (GRADE) approach is widely implemented in health technology assessment and guideline development organisations throughout the world. GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention, but is complex and therefore challenging to apply in a consistent manner.MethodsWe developed a checklist to guide the researcher to extract the data required to make a GRADE assessment. We applied the checklist to 29 meta-analyses of randomised controlled trials on the effectiveness of health care interventions. Two reviewers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome.ResultsFor most (70%) checklist items, there was good agreement between reviewers. The main problems were for items relating to indirectness where considerable judgement is required.ConclusionsThere was consistent agreement between reviewers on most items in the checklist. The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessments, particularly for inexperienced users or in rapid reviews without the resources to conduct assessments by two researchers independently.

Screening for poststroke major depression: a meta-analysis of diagnostic validity studies

Background Major depression is common in stroke patients and associated with increased rates of disability and mortality. Identifying depression may improve mental and physical health. The aim of this review was to determine the most accurate tool for detecting poststroke depression. Methods Seven databases were searched up to November 2012. Two authors selected studies using International Classification of Disease or Diagnostic and Statistical Manual diagnosis of depression as the reference standard. Two authors extracted data and assessed methodological quality. Included studies were synthesised using meta-analyses. Results A total of 24 included studies provided data on 2907 participants. The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures. However, the clinical utility of all tools was modest for case-finding. Interpretation There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding. Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options. Although it should be noted such scales should not be used in isolation but followed up with a more detailed clinical assessment. While there is promising data for the PHQ-2 in other populations, it performed less well than other measures.

A systematic review on the clustering and co-occurrence of multiple risk behaviours.

BackgroundRisk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK.MethodsKey databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses.ResultsThirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse.The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications).ConclusionsAmong general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours.This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status.

Lower versus higher oxygen concentration for delivery room stabilisation of preterm neonates: systematic review

Background Emerging evidence suggests that initiating delivery room respiratory support or resuscitation for term infants using lower rather than higher concentrations of oxygen reduces mortality and the risk of serious morbidity. Uncertainty exists with regard to applicability of this strategy for preterm infants who have different underlying reasons for respiratory distress and risks for harm at birth than term infants. Methods We performed a systematic review and meta-analysis of randomised controlled trials to determine the effect on mortality and morbidity of using lower (21– 50%) versus higher (>50%) oxygen concentrations for delivery room transition support of preterm infants. Results We identified six randomised controlled trials in which a total of 484 infants participated. Most participants were preterm infants born before 32 weeks’ gestation. One trial was quasi-randomised and in one trial allocation concealment was not described. Clinicians and investigators were aware of the interventions in all but one trial. Meta-analyses found a statistically significant reduction in the risk of death pooled risk ratio 0.65 (95% confidence interval 0.43, 0.98), but this effect disappeared when only the four trials with adequate allocation concealment were included [pooled risk ratio 1.0 (95% confidence interval 0.45, 2.24)]. None of the trials has evaluated any neuro-developmental outcomes. Conclusions The available trial data do not provide strong evidence that using lower versus higher oxygen concentrations for delivery room transition support for preterm infants confers important benefits or harms. Lack of allocation concealment and blinding of clinicians and assessors are the major sources of bias in the existing trials. Further, large, good-quality trials are needed to resolve on-going uncertainties and inform clinical practice.

Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation

BACKGROUND Tumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE. OBJECTIVE To determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation). DESIGN Systematic review and economic model. DATA SOURCES Fifteen databases were searched for relevant studies in July 2014. REVIEW METHODS Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturers submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The model has a lifetime horizon (60 years) and considers costs from the perspective of the NHS and personal social services. Health effects were expressed in terms of quality-adjusted life-years. RESULTS In total, 28 eligible RCTs were identified and 26 were placebo controlled (mostly up to 12 weeks); 17 extended into open-label active treatment-only phases. Most RCTs were judged to have a low risk of bias overall. In both AS and nr-AxSpA populations, anti-TNFs produced clinically important benefits to patients in terms of improving function and reducing disease activity; for AS, the relative risks for ASAS 40 ranged from 2.53 to 3.42. The efficacy estimates were consistently slightly smaller for nr-AxSpA than for AS. Statistical (and clinical) heterogeneity was more apparent in the nr-AxSpA analyses than in the AS analyses; both the reliability of the nr-AxSpA meta-analysis results and their true relevance to patients seen in clinical practice are questionable. In AS, anti-TNFs are approximately equally effective. Effectiveness appears to be maintained over time, with around 50% of patients still responding at 2 years. Evidence for an effect of anti-TNFs delaying disease progression was limited; results from ongoing long-term studies should help to clarify this issue. Sequential treatment with anti-TNFs can be worthwhile but the drug survival response rates and benefits are reduced with second and third anti-TNFs. The de novo model, which addressed many of the issues of earlier evaluations, generated incremental cost-effectiveness ratios ranging from £19,240 to £66,529 depending on anti-TNF and modelling assumptions. CONCLUSIONS In both AS and nr-AxSpA populations anti-TNFs are clinically effective, although more so in AS than in nr-AxSpA. Anti-TNFs may be an effective use of NHS resources depending on which assumptions are considered appropriate. FUTURE WORK RECOMMENDATIONS Randomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs. STUDY REGISTRATION This study is registered as PROSPERO CRD42014010182. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Behaviour change interventions to promote prescribing of generic drugs: a rapid evidence synthesis and systematic review

Objective To summarise evidence on the effectiveness of behaviour change interventions to encourage prescribing of generic forms of prescription drugs where clinically appropriate in the UK National Health Service (NHS) and similar settings. Design Systematic review. Search strategy We conducted a rapid evidence synthesis in two stages: First, we searched databases, such as the Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE), for systematic reviews of interventions that reported outcomes related to utilisation of generic drugs. In the second stage, we searched several databases including MEDLINE and EMBASE to identify primary studies of any interventions not covered by systematic reviews. Data extraction and quality assessment Data were extracted into a standardised data extraction form. Standardised quality assessment tools were used to assess study quality. Two reviewers were involved in data extraction and quality assessment. Results 10 reviews were included for the initial evidence synthesis, but most were of limited usefulness to our focused review question. One review evaluated the effect of prescribing policies using financial incentives and showed an increase in generic prescribing. Thirteen primary studies of other interventions were included for the rapid review. Two studies showed an increase in percentage of overall generic prescribing with an educational intervention; two studies showed an improvement in generic prescribing rates when physicians collaborated with pharmacists, though in one study this was not statistically significant; two US studies showed improvements in generic prescribing with electronic prescribing. Five out of seven studies showed positive results with multifaceted interventions. Conclusions The existing evidence remains insufficient to determine which behaviour change intervention or combination of interventions is most effective due to methodological weaknesses and conflicting results. Based on the evidence, financial incentives with educational intervention and audit/feedback look promising but decision-makers should take into account the practicality and costs of the interventions before implementation.

Certolizumab pegol and secukinumab for treating active psoriatic arthritis following inadequate response to disease-modifying antirheumatic drugs: a systematic review and economic evaluation.

BACKGROUND Several biologic therapies are approved by the National Institute for Health and Care Excellence (NICE) for psoriatic arthritis (PsA) patients who have had an inadequate response to two or more synthetic disease-modifying antirheumatic drugs (DMARDs). NICE does not specifically recommend switching from one biologic to another, and only ustekinumab (UST; STELARA®, Janssen Pharmaceuticals, Inc., Horsham, PA, USA) is recommended after anti-tumour necrosis factor failure. Secukinumab (SEC; COSENTYX®, Novartis International AG, Basel, Switzerland) and certolizumab pegol (CZP; CIMZIA®, UCB Pharma, Brussels, Belgium) have not previously been appraised by NICE. OBJECTIVE To determine the clinical effectiveness and cost-effectiveness of CZP and SEC for treating active PsA in adults in whom DMARDs have been inadequately effective. DESIGN Systematic review and economic model. DATA SOURCES Fourteen databases (including MEDLINE and EMBASE) were searched for relevant studies from inception to April 2016 for CZP and SEC studies; update searches were run to identify new comparator studies. REVIEW METHODS Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis (NMA) methods to investigate the relative efficacy of SEC and CZP compared with comparator therapies. A de novo model was developed to assess the cost-effectiveness of SEC and CZP compared with the other relevant comparators. The model was specified for three subpopulations, in accordance with the NICE scope (patients who have taken one prior DMARD, patients who have taken two or more prior DMARDs and biologic-experienced patients). The models were further classified according to the level of concomitant psoriasis. RESULTS Nineteen eligible RCTs were included in the systematic review of short-term efficacy. Most studies were well conducted and were rated as being at low risk of bias. Trials of SEC and CZP demonstrated clinically important efficacy in all key clinical outcomes. At 3 months, patients taking 150 mg of SEC [relative risk (RR) 6.27, 95% confidence interval (CI) 2.55 to 15.43] or CZP (RR 3.29, 95% CI 1.94 to 5.56) were more likely to be responders than patients taking placebo. The NMA results for the biologic-naive subpopulations indicated that the effectiveness of SEC and CZP relative to other biologics and each other was uncertain. Limited data were available for the biologic-experienced subpopulation. Longer-term evidence suggested that these newer biologics reduced disease progression, with the benefits being similar to those seen for older biologics. The de novo model generated incremental cost-effectiveness ratios (ICERs) for three subpopulations and three psoriasis subgroups. In subpopulation 1 (biologic-naive patients who had taken one prior DMARD), CZP was the optimal treatment in the moderate-severe psoriasis subgroup and 150 mg of SEC was optimal in the subgroups of patients with mild-moderate psoriasis or no concomitant psoriasis. In subpopulation 2 (biologic-naive patients who had taken two or more prior DMARDs), etanercept (ETN; ENBREL®, Pfizer Inc., New York City, NY, USA) is likely to be the optimal treatment in all subgroups. The ICERs for SEC and CZP versus best supportive care are in the region of £20,000-30,000 per quality-adjusted life-year (QALY). In subpopulation 3 (biologic-experienced patients or patients in whom biologics are contraindicated), UST is likely to be the optimal treatment (ICERs are in the region of £21,000-27,000 per QALY). The optimal treatment in subpopulation 2 was sensitive to the choice of evidence synthesis model. In subpopulations 2 and 3, results were sensitive to the algorithm for Health Assessment Questionnaire-Disability Index costs. The optimal treatment is not sensitive to the use of biosimilar prices for ETN and infliximab (REMICADE®, Merck Sharp & Dohme, Kenilworth, NJ, USA). CONCLUSIONS SEC and CZP may be an effective use of NHS resources, depending on the subpopulation and subgroup of psoriasis severity. There are a number of limitations to this assessment, driven mainly by data availability. FUTURE WORK Trials are needed to inform effectiveness of biologics in biologic-experienced populations. STUDY REGISTRATION This study is registered as PROSPERO CRD42016033357. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Randomization Methods in Emergency Setting Trials: A Descriptive Review.

Background Quasi‐randomization might expedite recruitment into trials in emergency care settings but may also introduce selection bias. Methods We searched the Cochrane Library and other databases for systematic reviews of interventions in emergency medicine or urgent care settings. We assessed selection bias (baseline imbalances) in prognostic indicators between treatment groups in trials using true randomization versus trials using quasi‐randomization. Results Seven reviews contained 16 trials that used true randomization and 11 that used quasi‐randomization. Baseline group imbalance was identified in four trials using true randomization (25%) and in two quasi‐randomized trials (18%). Of the four truly randomized trials with imbalance, three concealed treatment allocation adequately. Clinical heterogeneity and poor reporting limited the assessment of trial recruitment outcomes. Conclusions We did not find strong or consistent evidence that quasi‐randomization is associated with selection bias more often than true randomization. High risk of bias judgements for quasi‐randomized emergency studies should therefore not be assumed in systematic reviews. Clinical heterogeneity across trials within reviews, coupled with limited availability of relevant trial accrual data, meant it was not possible to adequately explore the possibility that true randomization might result in slower trial recruitment rates, or the recruitment of less representative populations.