Joanne Lord

GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence

OBJECTIVES In this article, we describe how to include considerations about resource utilization when making recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. STUDY DESIGN AND SETTINGS We focus on challenges with rating the confidence in effect estimates (quality of evidence) and incorporating resource use into evidence profiles and Summary of Findings (SoF) tables. RESULTS GRADE recommends that important differences in resource use between alternative management strategies should be included along with other important outcomes in the evidence profile and SoF table. Key steps in considering resources in making recommendations with GRADE are the identification of items of resource use that may differ between alternative management strategies and that are potentially important to decision makers, finding evidence for the differences in resource use, making judgments regarding confidence in effect estimates using the same criteria used for health outcomes, and valuing the resource use in terms of costs for the specific setting for which recommendations are being made. CONCLUSIONS With our framework, decision makers will have access to concise summaries of recommendations, including ratings of the quality of economic evidence, and better understand the implications for clinical decision making.

Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis

Objectives To investigate the cost effectiveness of cyclo-oxygenase-2 (COX 2) selective inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs), and the addition of proton pump inhibitors to these treatments, for people with osteoarthritis. Design An economic evaluation using a Markov model and data from a systematic review was conducted. Estimates of cardiovascular and gastrointestinal adverse events were based on data from three large randomised controlled trials, and observational data were used for sensitivity analyses. Efficacy benefits from treatment were estimated from a meta-analysis of trials reporting total Western Ontario and McMaster Universities (WOMAC) osteoarthritis index score. Other model inputs were obtained from the relevant literature. The model was run for a hypothetical population of people with osteoarthritis. Subgroup analyses were conducted for people at high risk of gastrointestinal or cardiovascular adverse events. Comparators Licensed COX 2 selective inhibitors (celecoxib and etoricoxib) and traditional NSAIDs (diclofenac, ibuprofen, and naproxen) for which suitable data were available were compared. Paracetamol was also included, as was the possibility of adding a proton pump inhibitor (omeprazole) to each treatment. Main outcome measures The main outcome measure was cost effectiveness, which was based on quality adjusted life years gained. Quality adjusted life year scores were calculated from pooled estimates of efficacy and major adverse events (that is, dyspepsia; symptomatic ulcer; complicated gastrointestinal perforation, ulcer, or bleed; myocardial infarction; stroke; and heart failure). Results Addition of a proton pump inhibitor to both COX 2 selective inhibitors and traditional NSAIDs was highly cost effective for all patient groups considered (incremental cost effectiveness ratio less than £1000 (€1175,

Cost-effectiveness of digital photographic screening for retinopathy of prematurity in the United Kingdom

1650)). This finding was robust across a wide range of effectiveness estimates if the cheapest proton pump inhibitor was used. In our base case analysis, adding a proton pump inhibitor to a COX 2 selective inhibitor (used at the lowest licensed dose) was a cost effective option, even for patients at low risk of gastrointestinal adverse events (incremental cost effectiveness ratio approximately £10 000). Uncertainties around relative adverse event rates meant relative cost effectiveness for individual COX 2 selective inhibitors and traditional NSAIDs was difficult to determine. Conclusions Prescribing a proton pump inhibitor for people with osteoarthritis who are taking a traditional NSAID or COX 2 selective inhibitor is cost effective. The cost effectiveness analysis was sensitive to adverse event data and the specific choice of COX 2 selective inhibitor or NSAID agent should, therefore, take into account individual cardiovascular and gastrointestinal risks.

Secondary analysis of economic data: a review of cost-benefit studies of neonatal screening for phenylketonuria.

OBJECTIVES To compare the cost-effectiveness of alternative methods of screening for retinopathy of prematurity (ROP) in the United Kingdom, including the existing method of indirect ophthalmoscopy by ophthalmologists and digital photographic screening by nurses. METHODS A decision tree model was used to compare five screening modalities for the UK population of preterm babies, using a health service perspective. Data were taken from published sources, observation at a neonatal intensive care unit (NICU), and expert judgment. RESULTS We estimated that use of standard digital cameras by nurses in NICUs would cost more than current methods (pound 371 compared with pound 321 per baby screened). However, a specialist nurse visiting units with a portable camera would be cheaper (pound 172 per baby). These estimates rely on nurses capturing and interpreting the images, with suitable training and supervision. Alternatively, nurses could capture the images then transmit them to a central unit for interpretation by ophthalmologists, although we estimate that this would be rather more expensive (pound 390 and pound 201, respectively, for NICU and visiting nurses). Sensitivity analysis was used to examine the robustness of estimates. CONCLUSIONS It is likely that there is an opportunity to improve the efficiency of the ROP screening program. We estimate that screening by specialist nurses trained in image capture and interpretation using portable digital cameras is a cost-effective alternative to the current program of direct visualization by ophthalmologists. This option would require the development of a suitable portable machine. Direct comparative research is strongly needed to establish the accuracy of the various screening options.

Weekend specialist intensity and admission mortality in acute hospital trusts in England: a cross-sectional study

STUDY OBJECTIVE: To estimate the net financial benefit of neonatal screening for phenylketonuria (PKU): by a simple pooling of cost data from the literature; and by a more complex modelling approach. DESIGN: A systematic literature review was conducted to identify papers containing data on the monetary costs and benefits of neonatal screening for PKU. The methodological quality of the studies was appraised, and data were extracted on resource use and expenditure. Monetary data were converted to common currency units, and standardised to UK incidence rates. Net benefits were calculated for median, best case and worst case scenarios, and the effect of excluding poor quality studies and data was tested. The net benefit was also estimated from a model based on data from the literature and assumptions appropriate for the current UK situation. Extensive sensitivity analysis was conducted. MAIN RESULTS: The direct net benefit of screening based on the median costs and benefits from the 13 studies identified was 143,400 Pounds per case detected and treated (39,000 Pounds and 241,800 Pounds for worst case and best case scenarios respectively). The direct net benefit obtained by the modelling approach was lower at 93,400 Pounds per case detected and treated. Screening remained cost saving under sensitivity analysis, except with low residential care costs (less than 12,300 Pounds per annum), or very low incidence rates (less than 1 in 27,000). CONCLUSIONS: The economic literature on PKU screening is of variable quality. The two methods of secondary analysis lead to the same conclusion: that neonatal PKU screening is worthwhile in financial terms alone in the UK, and that it justifies the infrastructure for collecting and testing neonatal blood samples. This result cannot necessarily be extrapolated to other countries.

Exercises to improve function of the rheumatoid hand (SARAH): a randomised controlled trial.

Summary Background Increased mortality rates associated with weekend hospital admission (the so-called weekend effect) have been attributed to suboptimum staffing levels of specialist consultants. However, evidence for a causal association is elusive, and the magnitude of the weekend specialist deficit remains unquantified. This uncertainty could hamper efforts by national health systems to introduce 7 day health services. We aimed to examine preliminary associations between specialist intensity and weekend admission mortality across the English National Health Service. Methods Eligible hospital trusts were those in England receiving unselected emergency admissions. On Sunday June 15 and Wednesday June 18, 2014, we undertook a point prevalence survey of hospital specialists (consultants) to obtain data relating to the care of patients admitted as emergencies. We defined specialist intensity at each trust as the self-reported estimated number of specialist hours per ten emergency admissions between 0800 h and 2000 h on Sunday and Wednesday. With use of data for all adult emergency admissions for financial year 2013–14, we compared weekend to weekday admission risk of mortality with the Sunday to Wednesday specialist intensity ratio within each trust. We stratified trusts by size quintile. Findings 127 of 141 eligible acute hospital trusts agreed to participate; 115 (91%) trusts contributed data to the point prevalence survey. Of 34 350 clinicians surveyed, 15 537 (45%) responded. Substantially fewer specialists were present providing care to emergency admissions on Sunday (1667 [11%]) than on Wednesday (6105 [42%]). Specialists present on Sunday spent 40% more time caring for emergency patients than did those present on Wednesday (mean 5·74 h [SD 3·39] vs 3·97 h [3·31]); however, the median specialist intensity on Sunday was only 48% (IQR 40–58) of that on Wednesday. The Sunday to Wednesday intensity ratio was less than 0·7 in 104 (90%) of the contributing trusts. Mortality risk among patients admitted at weekends was higher than among those admitted on weekdays (adjusted odds ratio 1·10, 95% CI 1·08–1·11; p<0·0001). There was no significant association between Sunday to Wednesday specialist intensity ratios and weekend to weekday mortality ratios (r −0·042; p=0·654). Interpretation This cross-sectional analysis did not detect a correlation between weekend staffing of hospital specialists and mortality risk for emergency admissions. Further investigation is needed to evaluate whole-system secular change during the implementation of 7 day services. Policy makers should exercise caution before attributing the weekend effect mainly to differences in specialist staffing. Funding National Institute for Health Research Health Services and Delivery Research Programme.

Evaluating healthcare policies: the case of clinical audit

BACKGROUND Disease-modifying biological agents and other drug regimens have substantially improved control of disease activity and joint damage in people with rheumatoid arthritis of the hand. However, commensurate changes in function and quality of life are not always noted. Tailored hand exercises might provide additional improvements, but evidence is lacking. We estimated the effectiveness and cost-effectiveness of tailored hand exercises in addition to usual care during 12 months. METHODS In this pragmatic, multicentre, parallel-group trial, at 17 National Health Service sites across the UK we randomly assigned 490 adults with rheumatoid arthritis who had pain and dysfunction of the hands and had been on a stable drug regimen for at least 3 months, to either usual care or usual care plus a tailored strengthening and stretching hand exercise programme. Participants were randomly assigned with stratification by centre. Allocation was computer generated and unmasked to participants and therapists delivering treatment after randomisation. Outcome assessors and all investigators were masked to allocation. Physiotherapists or occupational therapists gave the treatments. The primary outcome was the Michigan Hand Outcomes Questionnaire overall hand function score at 12 months. The analysis was by intention to treat. We calculated cost per quality-adjusted life-year. This trial is registered as ISRCTN 89936343. FINDINGS Between Oct 5, 2009, and May 10, 2011, we screened 1606 people, of whom 490 were randomly assigned to usual care (n=244) or tailored exercises (n=246). 438 of 490 participants (89%) provided 12 month follow-up data. Improvements in overall hand function were 3·6 points (95% CI 1·5-5·7) in the usual care group and 7·9 points (6·0-9·9) in the exercise group (mean difference between groups 4·3, 95% CI 1·5-7·1; p=0·0028). Pain, drug regimens, and health-care resource use were stable for 12 months, with no difference between the groups. No serious adverse events associated with the treatment were recorded. The cost of tailored hand exercise was £156 per person; cost per quality-adjusted life-year was £9549 with the EQ-5D (£17,941 with imputation for missing data). INTERPRETATION We have shown that a tailored hand exercise programme is a worthwhile, low-cost intervention to provide as an adjunct to various drug regimens. Maximisation of the benefits of biological and DMARD regimens in terms of function, disability, and health-related quality of life should be an important treatment aim. FUNDING UK National Institute of Health Research Health Technology Assessment Programme (NIHR HTA), project number 07/32/05.

The EQ-5D-5L health status questionnaire in COPD: validity, responsiveness and minimum important difference

Clinicians are under increasing pressure to show that their services are effective and efficient. Some have recently suggested that policymakers should be subject to the same discipline.1 Before the introduction of radical changes in the NHS in 1991 the governments decision not to pilot the proposals or evaluate them was widely criticised. One component of the reforms was a national programme to promote clinical audit by doctors, later extended to nurses and therapy professionals. This was generally welcomed, though dissenting voices questioned the underlying political motivations2 and pointed to a lack of evidence on the value of clinical audit.3 4 5 Since then there have been repeated calls for the evaluation of audit,6 and the public accounts committee has expressed concern at the failure to assess the overall cost effectiveness of the programme.7 In fact, the NHS Executive has commissioned several evaluations of audit,8 9 as well as monitoring progress through local and regional annual reports. However, it has not been possible to use scientifically rigorous methods to quantify the overall costs or benefits of national or local programmes of audit.10 This paper describes the various approaches that have been tried (see box) and outlines the merits and disadvantages of each approach. ### Box 1: Methods used to evaluate clinical audit and examples Experimental studies of specific audit projects Before-after studies of specific audit projects Quantitative observational studies of audit programmes Qualitative studies of audit programmes …

Strengthening and stretching for rheumatoid arthritis of the hand (SARAH). A randomised controlled trial and economic evaluation

Background The EQ-5D, a generic health status questionnaire that is widely used in health economic evaluation, was recently expanded to the EQ-5D-5L to address criticisms of unresponsiveness and ceiling effect. Aims To describe the validity, responsiveness and minimum important difference of the EQ-5D-5L in COPD. Methods Study 1: The validity of the EQ-5D-5L utility index and visual analogue scale (EQ-VAS) was compared with four established disease-specific health status questionnaires and other measures of disease severity in 616 stable outpatients with COPD. Study 2: The EQ-5D-5L utility index and EQ-VAS were measured in 324 patients with COPD before and after 8 weeks of pulmonary rehabilitation. Distribution and anchor-based approaches were used to estimate the minimum important difference. Results There were moderate-to-strong correlations between utility index and EQ-VAS with disease-specific questionnaires (Pearsons r=0.47–0.72). A ceiling effect was seen in 7% and 2.6% of utility index and EQ-VAS. Utility index decreased (worsening health status) with indices of worsening disease severity. With rehabilitation, mean (95% CI) changes in utility index and EQ-VAS were 0.065 (0.047 to 0.083) and 8.6 (6.5 to 10.7), respectively, with standardised response means of 0.39 and 0.44. The mean (range) anchor estimates of the minimum important difference for utility index and EQ-VAS were 0.051 (0.037 to 0.063) and 6.9 (6.5 to 8.0), respectively. Conclusions The EQ-5D-5L is a valid and responsive measure of health status in COPD and may provide useful additional cost-effectiveness data in clinical trials.

Is brief advice in primary care a cost-effective way to promote physical activity?

BACKGROUND The effectiveness of exercise for improving hand and wrist function in people with rheumatoid arthritis (RA) is uncertain. OBJECTIVES The study aims were (1) to estimate the clinical effectiveness and cost-effectiveness of adding an optimised exercise programme for hands and upper limbs to standard care for patients with RA; and (2) to qualitatively describe the experience of participants in the trial with a particular emphasis on acceptability of the intervention, exercise behaviours and reasons for adherence/non-adherence. DESIGN A pragmatic, multicentred, individually randomised controlled trial with an embedded qualitative study. Outcome assessors were blind to group assignment and independent of treatment delivery. SETTING Seventeen NHS trusts in England comprising 21 rheumatology and therapy departments. PARTICIPANTS Adults with RA who had pain and dysfunction of the hands and/or wrists and had been on stable medication for at least 3 months. Patients were excluded if they were under 18 years old, had undergone upper limb surgery/fracture in the last 6 months, were on a waiting list for upper limb surgery or were pregnant. INTERVENTIONS Usual care or usual care plus an individualised exercise programme. Usual care consisted of joint protection education, general exercise advice and functional splinting if required. The exercise programme consisted of six sessions of strengthening and stretching exercises with a hand therapist, daily home exercises and strategies to maximise adherence. MAIN OUTCOME MEASURES The primary outcome was the Michigan Hand Outcome Questionnaire (MHQ) overall hand function subscale score at 12 months. Secondary outcome measures included the full MHQ, pain, health-related quality of life (Short Form questionnaire-12 items), impairment (grip strength, dexterity and range of motion) and self-efficacy. European Quality of Life-5 Dimensions, medication and health-care use were collected for the health economics evaluation. Follow-up was at 4 and 12 months post randomisation. Analysis was performed on an intention-to-treat basis. RESULTS We randomised 490 patients (244 to usual care, 246 to exercise programme). Compliance with the treatments was very good (93% of usual care participants and 75% of exercise programme participants completed treatment). Outcomes were obtained for 89% of participants at 12 months (222 for usual care, 216 for exercise programme). There was a statistically significant difference in favour of the exercise programme for the primary outcome at 4 and 12 months [mean difference 4.6 points, 95% confidence interval (CI) 2.2 to 7.0 points; and mean difference 4.4 points, 95% CI 1.6 to 7.1 points, respectively]. There were no significant differences in pain scores or adverse events. The estimated difference in mean quality-adjusted life-years (QALYs) accrued over 12 months was 0.01 greater (95% CI -0.03 to 0.05) in the exercise programme group. Imputed analysis produced incremental cost-effectiveness ratio estimates of £17,941 (0.59 probability of cost-effectiveness at willingness-to-pay threshold of £30,000 per QALY). The qualitative study found the exercise programme to be acceptable and highlighted the importance of the therapist in enabling patients to establish a routine and incorporate the exercises into their lives. CONCLUSIONS The results of the Strengthening And stretching for Rheumatoid Arthritis of the Hand trial suggest that the addition of an exercise programme for RA hands/wrists to usual care is clinically effective and cost-effective when compared with usual care alone. No adverse effects were associated with the exercise programme. The economic analysis suggests that the intervention is likely to be cost-effective. STUDY REGISTRATION Current Controlled Trials ISRCTN 89936343.