Using multicentre RCT-based individual patient level data to populate decision analytic cost-effectiveness models for location-specific decision making

Objectives: To develop methodology for the analysis of individual patient level data from multicentre/multinational randomized controlled trials with the aim of estimating location-specific parameters to populate decision models for location-specific decision making. Methods: Multilevel or hierarchical modelling is the analytical framework used to handle hierarchical cost-effectiveness data. Hierarchical modelling was developed in a Bayesian framework and Bayesian shrinkage estimation procedures were used to obtain location-specific cost-effectiveness estimates. Results: Using data from a recently conducted economic analysis of the RITA 3 trial, locationspecific cost-effectiveness measures were obtained and compared to the trial-wide results. For the analysed centres, the centre-specific cost-effectiveness planes showed higher variability in mean differential cost and mean differential QALY estimates compared to the trial wide results, with the latter having longer left tail estimate distribution. The majority of the location-specific incremental cost-effectiveness ratio results show higher cost per QALY for the intervention strategy compared to the trial wide results (approx. £41,400/QALY). With respect to centre-specific cost-effectiveness acceptability curves, the curves for the selected centres display great variability across centres in cost-effectiveness for given values of the threshold, λ. If the decision maker is willing to pay £50,000 for an additional QALY, the probability that the intervention strategy is cost-effective is, for instance, 0.34 for centre 37, compared to the 0.65 for the trial wide results. Conclusions: This thesis shows how Bayesian hierarchical modelling can be used to estimate more appropriate cluster-specific parameters for use in decision analytic models where individual patient level data from a multi-location trial are available. Bayesian hierarchical modelling estimates can be used to explore correctly the variability between centres/countries of the cost-effectiveness results allowing the correct quantification of uncertainty by adjusting the standard errors to reflect the estimates variability both within and between locations

Bayesian econometric modelling of observational data for cost-effectiveness analysis : establishing the value of Negative Pressure Wound Therapy in the healing of open surgical wounds

Background/Introduction In the absence of evidence from randomised controlled trials on the relative effectiveness of treatments, cost-effectiveness analyses increasingly use observational data instead. Treatment assignment is not, however, randomised, and naïve estimates of treatment effect may be biased. To deal with this bias, one may need to adjust for observed and unobserved confounders. In this work we aim to explore and discuss the challenges of these adjustment strategies using a case study of negative pressure wound therapy (NPWT) versus standard dressings for the treatment of open surgical wounds. Methods Time to wound healing, was estimated using Bayesian inference methods: i) OLS models, ii) OLS model adjusting for potential observed confounders and iii) two-stage instrumental variable (IV) models. A panel data regression approach was used to model health-related quality of life weights and costs. Cost-effectiveness estimates were obtained for selected models. Results The case study was a longitudinal cohort study of 393 participants followed up by on average 500 days. In all the modelling approaches we implemented, the treatment NPWT was estimated to offer less benefit at higher costs than competing interventions. Conclusions This study shows how to use observational data to assess cost-effectiveness by adjusting for both observable and unobservable confounders. Within the case study, we could not demonstrate that existing uncontrolled confounding affects the effectiveness of NPWT. There was no evidence that NPWT was effective or cost-effective compared to standard dressings for the treatment of SWHSI

Methods for network meta-analysis of continuous outcomes using individual patient data : a case study in acupuncture for chronic pain

Background: Network meta-analysis methods, which are an extension of the standard pair-wise synthesis framework, allow for the simultaneous comparison of multiple interventions and consideration of the entire body of evidence in a single statistical model. There are well-established advantages to using individual patient data to perform network meta-analysis and methods for network meta-analysis of individual patient data have already been developed for dichotomous and time-to-event data. This paper describes appropriate methods for the network meta-analysis of individual patient data on continuous outcomes. Methods: This paper introduces and describes network meta-analysis of individual patient data models for continuous outcomes using the analysis of covariance framework. Comparisons are made between this approach and change score and final score only approaches, which are frequently used and have been proposed in the methodological literature. A motivating example on the effectiveness of acupuncture for chronic pain is used to demonstrate the methods. Individual patient data on 28 randomised controlled trials were synthesised. Consistency of endpoints across the evidence base was obtained through standardisation and mapping exercises. Results: Individual patient data availability avoided the use of non-baseline-adjusted models, allowing instead for analysis of covariance models to be applied and thus improving the precision of treatment effect estimates while adjusting for baseline imbalance. Conclusions: The network meta-analysis of individual patient data using the analysis of covariance approach is advocated to be the most appropriate modelling approach for network meta-analysis of continuous outcomes, particularly in the presence of baseline imbalance. Further methods developments are required to address the challenge of analysing aggregate level data in the presence of baseline imbalance

Immediate Versus Triggered Transfusion for Children with Uncomplicated Severe Anaemia

Background: The World Health Organization recommends a haemoglobin transfusion threshold of 0.2) nor evidence of differences between groups in re-admissions (p=0.36), serious adverse events (p=0.36) nor in haemoglobin recovery at 180-days (p=0.08). Length-of-stay was mean 0.9 days longer in the triggered group. Conclusions: There was no evidence of differences in clinical outcomes over 6 months with triggered vs immediate transfusion. Triggered transfusion reduced blood-volume requirements by 60% but increased length-of-stay by 20% and required repeated haemoglobin monitoring and surveillance

Cost Effectiveness of Digital Interventions for Generalised Anxiety Disorder : A Model-Based Analysis

BACKGROUND: Digital interventions (DIs) are increasingly being used in mental health care, despite limited evidence regarding their value for money. This study aimed to evaluate the cost effectiveness of DIs for generalised anxiety disorder (GAD), in comparison with alternative care options, from the perspective of the UK health care system. METHODS: An open-source decision analytic cohort model was used to extrapolate the results of a network meta-analysis over a patient's lifetime and estimate the costs and outcomes (quality-adjusted life-years) of DIs and their comparators. The net monetary benefit (NMB) and probability of cost effectiveness was estimated for each comparator, and we conducted a Value of Information analysis to evaluate the scale and drivers of uncertainty. RESULTS: DIs were associated with lower NMB compared with medication and with group therapy, but greater NMB compared with non-therapeutic controls and with usual care. DIs that were supported by a clinician, an assistant or a lay person had higher delivery costs than purely patient-self-directed DIs, yielding a greater NMB when opportunity cost was above £3000/QALY. There was considerable uncertainty in the findings driven largely by uncertainty in the estimated treatment effects. The value of further research to establish the effectiveness of DIs for GAD was substantial, at least £12.9 billion. CONCLUSIONS: The high uncertainty about these results does not allow for recommendations based on the cost effectiveness of DIs. However, the analysis highlights areas for future research, and demonstrates that apparent cost savings associated with DIs can be offset by reduced effectiveness

Cost-effectiveness of in-house vs contracted-out vision rehabilitation services in England

Context: Vision rehabilitation (VR) services in England promote users’ health and wellbeing, and support all aspects of daily living through two dominant models: in-house and contracted-out VR services. The two models differ in terms of service delivery, but they share a common aim to enhance service users’ quality of life and reduce utilisation of social and health care services. Objective: This study investigated the cost-effectiveness of in-house vs contracted-out VR services. Methods: The analysis was performed from a social care perspective and a social and health care perspective. The analyses used data from a 6-month follow-up observational study of VR users. Regression analysis was used to estimate differential outcomes and costs, taking user and local authority characteristics into account. Findings: At a cost-effectiveness threshold of £13,000 and £30,000 per QALY, in-house VR services have a high probability (greater than 90% vs contracted-out VR services) of being cost-effective from a social care perspective. In-house VR services have a lower probability (lower than XX% vs contracted-out VR services) of being cost-effective from a social and health care perspective. Limitations: Observational studies are prone to selection bias compared to randomised controlled trials due to confounding. We employed econometric techniques that control for several user and LA characteristics to reduce potential bias. Implications: Contracted-out VR services may be better value for money compared to in-house VR services in the context of integrated social and health care due to substantial healthcare resource savings

What Are The Benefits Of Treatment Of Familial Hypercholesterolaemia? : A Cost-Effectiveness Model Based On Real-World Data Considering Cholesterol Burden

Objectives: To develop a new cost-effectiveness model, using real-world data, to predict long-term health outcomes and costs of patients with familial hypercholesterolaemia (FH), with and without treatment, and considering the increased effect of low-density lipoprotein cholesterol (LDL-C) over time on cardiovascular risk (known as cholesterol burden). Methods: We used routinely collected healthcare and mortality data from FH patients in the UK to estimate parametric survival models for cardiovascular events given age, sex, LDL-C, prior cardiovascular history, and to estimate the effect of treatment on LDL-C. We developed a new cohort Markov model over a lifetime horizon to predict health outcomes (e.g., quality-adjusted life years, QALYs) and UK National Health Service costs. Since the routine data was from treated patients, we estimated the counterfactual risk had they not been treated with and without accounting for cholesterol burden. Results: Accounting for cholesterol burden, treatment increases event-free survival by up to 30 years with greater benefits in younger patients, men, those with higher LDL-C and prior cardiovascular history. Treatment results in savings in those with LDL-C < 4.5 mmol/L and, in most patients, is cost-effective (incremental net health benefit at £15,000/QALY up to 2.4 QALYs). If cholesterol burden is not considered, the model predicts smaller benefits from treatment (e.g., 11 years event-free survival gain) and, in some patients, it is not cost-effective (e.g., patients < 18 years with LDL-C < 4 mmol/L). Conclusions: Treatment results in large health benefits and is highly cost-effective, but magnitude of benefits depends on whether cholesterol burden is considered, particularly in younger patients. Further research is warranted on effect size of cholesterol burden and how best to consider it in cost-effectiveness modelling

Transfusion Volume for Children with Severe and LifeThreatening Anaemia

Background: Severe anaemia (haemoglobin37.5C) at screening. 30mls/kg reduced mortality in the 1943(61%) children without fever (28-day HR=0.43 (0.27,0.69) p=0.001), but increased mortality in the 1253(39%) children with fever (HR=1.91 (1.04,3.49) p=0.04). There was no evidence of differences between groups in re-admissions (p=0.38), serious adverse events (p=0.58) nor in haemoglobin recovery at 180-days (p=0.10). Conclusions: Mortality could be reduced by transfusing 30mls/kg whole blood equivalent in children presenting with severe anaemia without fever

Acupuncture for chronic pain and depression in primary care : a programme of research

Abstract Background There has been an increase in the utilisation of acupuncture in recent years, yet the evidence base is insufficiently well established to be certain about its clinical effectiveness and cost-effectiveness. Addressing the questions related to the evidence base will reduce uncertainty and help policy- and decision-makers with regard to whether or not wider access is appropriate and provides value for money. Aim Our aim was to establish the most reliable evidence on the clinical effectiveness and cost-effectiveness of acupuncture for chronic pain by drawing on relevant evidence, including recent high-quality trials, and to develop fresh evidence on acupuncture for depression. To extend the evidence base we synthesised the results of published trials using robust systematic review methodology and conducted a randomised controlled trial (RCT) of acupuncture for depression. Methods and results We synthesised the evidence from high-quality trials of acupuncture for chronic pain, consisting of musculoskeletal pain related to the neck and low back, osteoarthritis of the knee, and headache and migraine, involving nearly 18,000 patients. In an individual patient data (IPD) pairwise meta-analysis, acupuncture was significantly better than both sham acupuncture (p < 0.001) and usual care (p < 0.001) for all conditions. Using network meta-analyses, we compared acupuncture with other physical therapies for osteoarthritis of the knee. In both an analysis of all available evidence and an analysis of a subset of better-quality trials, using aggregate-level data, we found acupuncture to be one of the more effective therapies. We developed new Bayesian methods for analysing multiple individual patient-level data sets to evaluate heterogeneous continuous outcomes. An accompanying cost-effectiveness analysis found transcutaneous electrical nerve stimulation (TENS) to be cost-effective for osteoarthritis at a threshold of £20,000 per quality-adjusted life-year when all trials were synthesised. When the analysis was restricted to trials of higher quality with adequate allocation concealment, acupuncture was cost-effective. In a RCT of acupuncture or counselling compared with usual care for depression, in which half the patients were also experiencing comorbid pain, we found acupuncture and counselling to be clinically effective and acupuncture to be cost-effective. For patients in whom acupuncture is inappropriate or unavailable, counselling is cost-effective. Conclusion We have provided the most robust evidence from high-quality trials on acupuncture for chronic pain. The synthesis of high-quality IPD found that acupuncture was more effective than both usual care and sham acupuncture. Acupuncture is one of the more clinically effective physical therapies for osteoarthritis and is also cost-effective if only high-quality trials are analysed. When all trials are analysed, TENS is cost-effective. Promising clinical and economic evidence on acupuncture for depression needs to be extended to other contexts and settings. For the conditions we have investigated, the drawing together of evidence on acupuncture from this programme of research has substantially reduced levels of uncertainty. We have identified directions for further research. Our research also provides a valuable basis for considering the potential role of acupuncture as a referral option in health care and enabling providers and policy-makers to make decisions based on robust sources of evidence

Patients with Surgical Wounds Healing by Secondary Intention: A Prospective, Cohort Study

Background: Surgical wounds healing by secondary intention can be difficult and costly to manage and are profoundly under researched. This prospective inception, cohort study aimed to derive a better understanding of surgical wounds healing by secondary intention and to facilitate the design of future research investigating effective treatments. Objectives: To investigate the clinical characteristics of patients with surgical wounds healing by secondary intention and the surgeries that preceded their wounds; to clearly delineate the clinical outcomes of these patients, specifically focusing on time to wound healing and its determinants; to explore the types of treatments for surgical wounds healing by secondary intention; and to assess the impact surgical wounds healing by secondary intention have on patients’ quality of life. Design: Prospective, inception cohort study. Setting: Acute and community settings in eight sites across two large centres in the United Kingdom (Hull and Leeds, UK). Methods: Patients with a surgical wounds healing by secondary intention (an open wound, < 3 weeks’ duration, resulting from surgery), were recruited and followed up for at least 12 months. Key outcome events included: time to healing; treatment type; infection; hospital re-admission and further procedures; health-related quality of life and pain. Results: In total, 393 patients were recruited. Common co-morbidities were cardiovascular disease (38%), diabetes (26%) and peripheral vascular disease (14.5%). Baseline median SWHSI area was 6 cm2 (range 0.01-1200). Abdominal (n=132), foot (n=59), leg (n=58) and peri-anal (n=34) wounds were common. The majority of wounds (236, 60.1%) were intentionally left open following surgery; the remainder were mostly dehisced wounds. Healing was observed in 320 (81.4%) wounds with a median time to healing of 86 days (95% CI: 75-130). Factors associated with delayed healing included wound infection at any point and baseline wound area above the median. Health-related quality of life scores were low at baseline but improved with time and healing. Conclusions: This is the first inception cohort study in patients with surgical wounds healing by secondary intention. Patient characteristics have been clearly defined, with prolonged healing times and adverse events being common impacting on patient’s health-related quality of life. Areas for, and factors crucial to the design of, future research have been identified. Key Words: Surgical wounds, secondary intention, inception cohort, characteristics, clinical outcomes, treatments, quality of life