Dawn Craig

Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis

OBJECTIVES To evaluate the effectiveness and cost-effectiveness of interventions that promote or inhibit breastfeeding or feeding with breastmilk for infants admitted to neonatal units, and to identify an agenda for future research. DATA SOURCES Electronic databases were searched (including MEDLINE and MEDLINE In-Process Citations, EMBASE, CINAHL, Maternity and Infant Care, PsycINFO, British Nursing Index and Archive, Health Management Information Consortium, Cochrane Central Register of Controlled Trials, Science Citation Index, Pascal, Latin American and Caribbean Health Sciences, MetaRegister of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessment Database, National Research Register) from inception to February 2008. Advisors identified further published or unpublished material. REVIEW METHODS All papers fulfilled eligibility criteria covering participants, interventions, study design and outcomes. Results from primary studies were assessed and summarised in a qualitative synthesis for each type of intervention and across types of intervention. To estimate long-term cost utility, a decision tree was developed to synthesise data on enhanced staff contact, breastmilk effectiveness, incidence of necrotising enterocolitis (NEC) and sepsis, resource use, survival and utilities. RESULTS Forty-eight studies met the selection criteria for the effectiveness review, of which 65% (31/48) were RCTs, and 17% (8/48) were conducted in the UK. Seven were rated as good quality and 28 as moderate quality. No studies met the selection criteria for the health economics review. There is strong evidence that short periods of kangaroo skin-to-skin contact increased the duration of any breastfeeding for 1 month after discharge [risk ratio (RR) 4.76, 95% confidence interval (CI) 1.19 to 19.10] and for more than 6 weeks (RR 1.95, 95% CI 1.03 to 3.70) among clinically stable infants in industrialised settings. There is strong evidence for the effectiveness of peer support at home (in Manila) for mothers of term, low birthweight infants on any breastfeeding up to 24 weeks (RR 2.18, 95% CI 1.45 to 3.29) and exclusive breastfeeding from birth to 6 months (RR 65.94, 95% CI 4.12 to 1055.70), and for the effectiveness of peer support in hospital and at home for mothers of infants in Special Care Baby Units on providing any breastmilk at 12 weeks [odds ratio (OR) 2.81, 95% CI 1.11 to 7.14; p = 0.01]. There is more limited evidence for the effectiveness of skilled professional support in a US Neonatal Intensive Care Unit on infants receiving any breastmilk at discharge (OR 2.0, 95% CI 1.2 to 3.2, p = 0.004). Multidisciplinary staff training may increase knowledge and can increase initiation rates and duration of breastfeeding, although evidence is limited. Lack of staff training is an important barrier to implementation of effective interventions. Baby Friendly accreditation of the associated maternity hospital results in improvements in several breastfeeding-related outcomes for infants in neonatal units. Limited evidence suggests that cup feeding (versus bottle feeding) may increase breastfeeding at discharge and reduce the frequency of oxygen desaturation. Breastmilk expression using simultaneous pumping with an electric pump has advantages in the first 2 weeks. Pharmaceutical galactagogues have little benefit among mothers who have recently given birth. Our economic analysis found that additional skilled professional support in hospital was more effective and less costly (due to reduced neonatal illness) than normal staff contact. Additional support ranged from 0.009 quality-adjusted life-years (QALYs) to 0.251 QALYs more beneficial per infant and ranged from 66 pounds to 586 pounds cheaper per infant across the birthweight subpopulations. Donor milk would become cost-effective given improved mechanisms for its provision. CONCLUSIONS Despite the limitations of the evidence base, kangaroo skin-to-skin contact, peer support, simultaneous breastmilk pumping, multidisciplinary staff training and the Baby Friendly accreditation of the associated maternity hospital have been shown to be effective, and skilled support from trained staff in hospital has been shown to be potentially cost-effective. All these point to future research priorities. Many of these interventions inter-relate: it is unlikely that specific clinical interventions will be effective if used alone. There is a need for national surveillance of feeding, health and cost outcomes for infants and mothers in neonatal units; to assist this goal, we propose consensus definitions of the initiation and duration of breastfeeding/breastmilk feeding with specific reference to infants admitted to neonatal units and their mothers.

Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups

BACKGROUND There is currently no standard practice for the monitoring of patients receiving treatment for osteoporosis. Repeated dual-energy X-ray absorptiometry (DXA) is commonly used for monitoring treatment response, but it has its limitations. Bone turnover markers have advantages over DXA as they are non-invasive, relatively cheap and can detect changes in bone turnover rates earlier. However, they do have disadvantages, particularly high within- and between-patient variability. The ability of bone turnover markers to identify treatment non-responders and predict future fracture risk has yet to be established. OBJECTIVES We aimed to determine the clinical effectiveness, test accuracy, reliability, reproducibility and cost-effectiveness of bone turnover markers for monitoring the response to osteoporosis treatment. DATA SOURCES We searched 12 electronic databases (including MEDLINE, EMBASE, The Cochrane Library and trials registries) without language restrictions from inception to March 2012. We hand-searched three relevant journals for the 12 months prior to May 2012, and websites of five test manufacturers and the US Food and Drug Administration (FDA). Reference lists of included studies and relevant reviews were also searched. REVIEW METHODS A systematic review of test accuracy, clinical utility, reliability and reproducibility, and cost-effectiveness of two formation and two resorption bone turnover markers, in patients being treated for osteoporosis with any of bisphosphonate [alendronate (Fosamax, MSD), risedronate (Actonel, Warner Chilcott Company), zolendronate (Zometa, Novartis)], raloxifene (Evista, Eli Lilly and Company Ltd), strontium ranelate (Protelos, Servier Laboratories Ltd), denosumab (Prolia, Amgen Ltd) or teriparatide (Forsteo, Eli Lilly and Company Ltd), was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Given the breadth of the review question, a range of study designs and outcome measures were eligible. The development of a decision model was planned to determine the cost-effectiveness of bone turnover markers for informing changes in patient management if clinical effectiveness could be established. RESULTS Forty-two studies (70 publications) met the inclusion criteria; none evaluated cost-effectiveness. Only five were randomised controlled trials (RCTs); these assessed only the impact of bone marker monitoring on aspects of adherence. No RCTs evaluated the effectiveness of bone turnover marker monitoring on treatment management. One trial suggested that feedback of a good response decreased non-persistence [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53 to 0.95], and feedback of a poor response increased non-persistence (HR 2.22, 95% CI 1.27 to 3.89); it is not clear whether or not the trial recruited a population representative of that seen in clinical practice. Thirty-three studies reported results of some assessment of test accuracy, mostly correlations between changes in bone turnover and bone mineral density. Only four studies reported on intra- or interpatient reliability and reproducibility in treated patients. Overall, the results were inconsistent and inconclusive, owing to considerable clinical heterogeneity across the studies and the generally small sample sizes. As clinical effectiveness of bone turnover monitoring could not be established, a decision-analytic model was not developed. CONCLUSIONS There was insufficient evidence to inform the choice of which bone turnover marker to use in routine clinical practice to monitor osteoporosis treatment response. The research priority is to identify the most promising treatment-test combinations for evaluation in subsequent, methodologically sound, RCTs. In order to determine whether or not bone turnover marker monitoring improves treatment management decisions, and ultimately impacts on patient outcomes in terms of reduced incidence of fracture, RCTs are required. Given the large number of potential patient population-treatment-test combinations, the most promising combinations would initially need to be identified in order to ensure that any RCTs focus on evaluating those strategies. As a result, the research priority is to identify these promising combinations, by either conducting small variability studies or initiating a patient registry to collect standardised data. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Effectiveness and implementation of enhanced recovery after surgery programmes: a rapid evidence synthesis

Objectives To assess the evidence on the impact of enhanced recovery programmes for patients undergoing elective surgery in acute hospital settings in the UK. Design Rapid evidence synthesis. Eight databases were searched from 1990 to March 2013 without language restrictions. Relevant reports and guidelines, websites and reference lists of retrieved articles were scanned to identify additional studies. Systematic reviews, RCTs not included in the systematic reviews, economic evaluations and UK NHS cost analysis, implementation case studies and surveys of patient experience in a UK setting were eligible for inclusion. Primary and secondary outcome measures We assessed the impact of enhanced recovery programmes on health or cost-related outcomes, and assessed implementation case studies and patient experience in UK settings. Studies were quality assessed where appropriate using the Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects critical appraisal process. Results 17 systematic reviews and 12 additional RCTs were included. Ten relevant economic evaluations were included. No cost analysis studies were identified. Most of the evidence focused on colorectal surgery. 14 innovation case studies and 15 implementation case studies undertaken in National Health Service settings described factors critical to the success of an enhanced recovery programme. Evidence for colorectal surgery suggests that enhanced recovery programmes may reduce hospital stays by 0.5–3.5 days compared with conventional care. There were no significant differences in reported readmission rates. Other surgical specialties showed greater variation in reductions in length of stay reflecting the limited evidence identified. Findings relating to other outcomes were hampered by a lack of robust evidence and poor reporting. Conclusions There is consistent, albeit limited, evidence that enhanced recovery programmes can reduce length of patient hospital stay without increasing readmission rates. The extent to which managers and clinicians considering implementing enhanced recovery programmes in UK settings can realise savings will depend on length of stay achieved under their existing care pathway.

Golimumab for the Treatment of Psoriatic Arthritis: A NICE Single Technology Appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer’s submission and identified areas requiring clarification, for which the manufacturer provided additional evidence.The main clinical effectiveness data were derived from a single phase III randomized controlled trial (GO-REVEAL) that compared golimumab with placebo for the treatment of active and progressive patients who were symptomatic despite the use of previous DMARDs or NSAIDs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 (relative risk [RR] 5.73, 95%CI 3.24, 10.56) and Psoriatic Arthritis Response Criteria (PsARC) [RR 3.45, 95% CI 2.49, 4.87], and significantly improved skin disease response as measured by Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62, 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients’ functional status as measured by Health Assessment Questionnaire change from baseline at 24 weeks (−0.33; p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. The ERG identified several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice.No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics.The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer’s claim that golimumab was a cost-effective treatment option, the manufacturer’s own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion.However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally effective, then etanercept, adalimumab and golimumab had almost equal costs and equal QALYs, and all had an ICER of about £15 000 per QALY versus palliative care, whilst infliximab, with a higher acquisition cost, was dominated by the other biologics.The Appraisal Committee altered its position between the Appraisal Consultation Document and the Final Appraisal Determination. It ultimately recommended that golimumab be provided as an option for the treatment of active and progressive PsA in adults only if (i) it is used as described for other tumour necrosis factor inhibitor treatments in ‘Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis’ (NICE clinical guideline 199); and (ii) the manufacturer provides the 100mg dose of golimumab at the same cost as the 50mg dose.

An overview and methodological assessment of systematic reviews and meta-analyses of enhanced recovery programmes in colorectal surgery

Objectives To identify and critically assess the extent to which systematic reviews of enhanced recovery programmes for patients undergoing colorectal surgery differ in their methodology and reported estimates of effect. Design Review of published systematic reviews. We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) Database from 1990 to March 2013. Systematic reviews of enhanced recovery programmes for patients undergoing colorectal surgery were eligible for inclusion. Primary and secondary outcome measures The primary outcome was length of hospital stay. We assessed changes in pooled estimates of treatment effect over time and how these might have been influenced by decisions taken by researchers as well as by the availability of new trials. The quality of systematic reviews was assessed using the Centre for Reviews and Dissemination (CRD) DARE critical appraisal process. Results 10 systematic reviews were included. Systematic reviews of randomised controlled trials have consistently shown a reduction in length of hospital stay with enhanced recovery compared with traditional care. The estimated effect tended to increase from 2006 to 2010 as more trials were published but has not altered significantly in the most recent review, despite the inclusion of several unique trials. The best estimate appears to be an average reduction of around 2.5 days in primary postoperative length of stay. Differences between reviews reflected differences in interpretation of inclusion criteria, searching and analytical methods or software. Conclusions Systematic reviews of enhanced recovery programmes show a high level of research waste, with multiple reviews covering identical or very similar groups of trials. Where multiple reviews exist on a topic, interpretation may require careful attention to apparently minor differences between reviews. Researchers can help readers by acknowledging existing reviews and through clear reporting of key decisions, especially on inclusion/exclusion and on statistical pooling.

Economic evaluation of enhanced staff contact for the promotion of breastfeeding for low birth weight infants.

OBJECTIVES There is evidence that breastmilk feeding reduces mortality and short and long-term morbidity among infants born too soon or too small. The aim of this study was to evaluate the cost-effectiveness of enhanced staff contact for mothers with infants in a neonatal unit with a birth weight of 500-2,500 g from the perspective of the UK National Health Service. METHODS A decision-tree model linked clinical outcomes with long-term health outcomes. The study population was divided into three weight bands: 500-999 g, 1000-1,749 g, and 1,750-2,500 g. Clinical and resource use data were obtained from literature reviews. The measure of benefit was quality-adjusted life-years. Uncertainty was evaluated using cost-effectiveness acceptability curves and sensitivity analyses. RESULTS The intervention was less costly and more effective than the comparator in the base-case analysis for each birth weight group. The results were quite robust to the sensitivity analyses performed. CONCLUSIONS This is the first economic evaluation in this complex field and offers a model to be developed in future research. The results provide preliminary indications that enhanced staff contact may be cost-effective. However, the limited evidence available, and the limited UK data in particular, suggest that further research is required to provide results with confidence.

Modelling the cost-effectiveness of biologic treatments for psoriatic arthritis

OBJECTIVES A probabilistic model was developed to determine the cost-effectiveness of three biologics, etanercept, infliximab and adalimumab, compared with palliative care for the treatment of active and progressive PsA in patients who have an inadequate response to standard treatment (including DMARDs). METHODS A previous model was revised to evaluate the impact of biologics on both skin and joint disease and to include new evidence from the clinical review and evidence synthesis. Initial response to biologics was determined using the PsA response criteria. The impact of biologics on the arthritis component of the disease is then modelled via a change in the HAQ and the impact of the psoriasis component measured using the Psoriasis Area and Severity Index. RESULTS For PsA patients with mild to moderate skin disease, the incremental cost-effectiveness ratio (ICER) for etanercept vs palliative care is around £18 000, and the ICER for infliximab vs etanercept is around £44 000 per quality-adjusted life year (QALY). Adalimumab is extendedly dominated. The probability that etanercept is cost effective is 0.436 at a threshold of £20 000 per QALY. Etanercept is also likely to be cost effective for patients with moderate to severe psoriasis or negligible skin involvement. CONCLUSIONS Further investigation is required to reduce uncertainties around a number of model parameters, in particular the length of time over which biologics are assumed to be effective and the progression of HAQ on and off treatment.

Growth monitoring for short stature: update of a systematic review and economic model.

OBJECTIVES The aim of the project was to compare different screening rules and/or referral cut-offs for the identification of children with disorders of short stature. We undertook an update of a previous systematic review and economic model that addressed the same question. DATA SOURCES Sources searched included MEDLINE, EMBASE, Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index - Science/Social Science & Humanities, Cochrane Library 2009 Issue 4, Office of Health Economics Health Economic Evaluations Database, and the NHS Economic Evaluation Database. REVIEW METHODS The review was conducted as an update to our previous assessment in 2007. Searching covered January 2005 to November 2009 with no language or publication restrictions. Two reviewers examined full papers for relevance. Data extraction was conducted by one reviewer and independently checked by a second. In addition, searches were conducted to identify quality of life or utility papers to inform the economic evaluation. We developed a probabilistic decision analytic model to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and personal social services. The model was a cohort model, assuming a homogeneous population of 5-year-olds at baseline. RESULTS One study was included in the systematic review. The study was not UK based, but had been identified in the brief as relevant to the UK setting. The studys authors examined the performance of a number of rules to determine sensitivity and specificity of referral for short stature in four patient groups and three reference groups in the Netherlands. They derived an algorithm for referral based on the optimal rules. No new studies were located that provided appropriate quality of life or utilities data for the economic model. The model was based on the previous assessment which was updated to better reflect current UK clinical practice. We compared two alternative monitoring strategies, one of which was based on the study identified in our systematic review (Grote strategy); the other was based on UK consensus (UK strategy). We identified that the UK strategy was the least effective and least costly, with a mean gain of 0.001 QALYs at a mean cost of £21. The Grote strategy was both more expensive and more effective, with a mean cost of £68 and a mean QALY gain of 0.042. The incremental cost-effectiveness ratio was £1144 per QALY gained. CONCLUSIONS This assessment contributes further knowledge, but does not provide definitive answers on how to deliver growth monitoring. In particular, we were unable to ascertain current practice in the UK for growth screening. Further, we were unable to evaluate through the use of identified studies and modelling an optimal referral cut-off and age at which to screen. We identified a number of research questions that would further inform referral strategies, which in summary would involve further primary and secondary data collection. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Are the best available clinical effectiveness data used in economic evaluations of drug therapies

Objectives: Use of evidence on clinical effectiveness that is of poor quality or is biased in favour of the therapy under study is a concern in economic evaluations and may contribute to a mistrust of pharmacoeconomic studies. This study aimed to determine whether the authors of economic evaluations use the best available evidence for clinical effectiveness. Methods: One hundred economic evaluations of drug therapies (published in 2001–2003) were sampled randomly from the National Health Service Economic Evaluation Database, and the source of clinical evidence was identified. For each therapy, alternative, high quality sources of clinical effectiveness data were sought by searching the Database of Abstracts of Reviews of Effects and Health Technology Assessment databases. The magnitude and direction of the effect size in the different sources of evidence were compared. Results: Relevant systematic reviews were found for only 32 of the 100 economic evaluations in the sample. In three cases these reviews had been identified by the authors of the economic evaluations and two of these cases were used in the evaluation. Comparisons were possible in 21 cases. The clinical effects reported in all 21 comparisons were similar in direction but differed in magnitude. Compared to the systematic reviews, the authors of economic evaluations used evidence that was more favourable in five cases, less favourable in four cases, and similar in 12 cases. Six of the economic evaluations and corresponding systematic reviews did not present measures of effectiveness in a manner that allowed comparison. Conclusions: Authors of economic evaluations have not made sufficient use of the evidence available from systematic reviews of clinical effectiveness. The central role of economic evaluations in health policy makes it essential that improvements in economic methods are accompanied by a structured search for the highest quality information on clinical effectiveness.

Economic evaluation databases as an aid to healthcare decision makers and researchers.

Economic evaluation databases have been developed to assist in setting priorities and facilitating research within the healthcare sector. This paper presents an overview of the major databases of economic evaluations currently available (HEED, NHS EED, the CEA Registry, CODECS, PEDE, EURONHEED and JEED). It describes the key features of each database and the main user groups. It also presents evidence of the value of access to economic evaluation databases, particularly for the researchers and decision makers who form their main target audience. The research available shows that both decision makers and researchers find economic evaluation databases helpful as a source of information. However, database producers may also need to better understand the requirements of their users and consider adaptations to their products.