Exploring the potential cost-effectiveness of a new computerised decision support tool for identifying fetal compromise during monitored term labours: an early health economic model.

BACKGROUND: Around 60% of term labours in the UK are continuously monitored using cardiotocography (CTG) to guide clinical labour management. Interpreting the CTG trace is challenging, leading to some babies suffering adverse outcomes and others unnecessary expedited deliveries. A new data driven computerised tool combining multiple clinical risk factors with CTG data (attentive CTG) was developed to help identify term babies at risk of severe compromise during labour. This paper presents an early health economic model exploring its potential cost-effectiveness. METHODS: The model compared attentive CTG and usual care with usual care alone and simulated clinical events, healthcare costs, and infant quality-adjusted life years over 18 years. It was populated using data from a cohort of term pregnancies, the literature, and administrative datasets. Attentive CTG effectiveness was projected through improved monitoring sensitivity/specificity and potential reductions in numbers of severely compromised infants. Scenario analyses explored the impact of including litigation costs. RESULTS: Nationally, attentive CTG could potentially avoid 10,000 unnecessary alerts in labour and 2400 emergency C-section deliveries through improved specificity. A reduction of 21 intrapartum stillbirths amongst severely compromised infants was also predicted with improved sensitivity. Attentive CTG could potentially lead to cost savings and health gains with a probability of being cost-effective at £25,000 per QALY ranging from 70 to 95%. Potential exists for further cost savings if litigation costs are included. CONCLUSIONS: Attentive CTG could offer a cost-effective use of healthcare resources. Prospective patient-level studies are needed to formally evaluate its effectiveness and economic impact in routine clinical practice.

Healthcare and wider societal implications of stillbirth: a population-based cost-of-illness study.

OBJECTIVE: To extend previous work and estimate health and social care costs, litigation costs, funeral-related costs, and productivity losses associated with stillbirth in the UK. DESIGN: A population-based cost-of-illness study using a synthesis of secondary data. SETTING: The National Health Service (NHS) and wider society in the UK. POPULATION: Stillbirths occurring within a 12-month period and subsequent events occurring over the following 2 years. METHODS: Costs were estimated using published data on events, resource use, and unit costs. MAIN OUTCOME MEASURES: Mean health and social care costs, litigation costs, funeral-related costs, and productivity costs for 2 years, reported for a single stillbirth and at a national level. RESULTS: Mean health and social care costs per stillbirth were £4191. Additionally, funeral-related costs were £559, and workplace absence (parents and healthcare professionals) was estimated to cost £3829 per stillbirth. For the UK, the annual health and social care costs were estimated at £13.6 million, and total productivity losses amounted to £706.1 million (98% of this cost was attributable to the loss of the life of the baby). The figures for total productivity losses were sensitive to the perspective adopted about the loss of life of the baby. CONCLUSION: This work expands the current intelligence on the costs of stillbirth beyond the health service to costs for parents and society, and yet these additional findings must still be regarded as conservative estimates of the true economic costs. TWEETABLE ABSTRACT: The costs of stillbirth are significant, affecting the health service, parents, professionals, and society. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? The personal, social, and emotional consequences of stillbirth are profound. Placing a monetary value on such consequences is emotive, yet necessary, when deciding how best to invest limited healthcare resources. We estimated the average costs associated with a single stillbirth and the costs for all stillbirths occurring in the UK over a 1-year period. What were the main findings? The average cost to the National Health Service (NHS) of care related to the stillbirth and a first subsequent pregnancy was £4191 for each stillbirth. For the UK, this cost was £13.6 million annually. Clinical negligence payments to bereaved parents were estimated at £2.5 million per year. Parents were estimated to spend £1.8 million per year on funerals. The cost of workplace absence as parents cope with the effects of grief was estimated at £2476 per stillbirth. For the UK, this cost was £8.1 million annually. The loss of a baby is also the loss of an individual with the potential to become a valued and productive member of society. The expected value of an adult's lifetime working hours was taken as an estimate of this productivity loss, and was £213,304 for each stillbirth. The annual cost for all stillbirths was £694 million. We know from parents that the birth of a subsequent child in no way replaces a stillborn baby. We found that 52% of women fall pregnant within 12 months of a stillbirth. From a purely economic perspective concerned only with the number of individuals in society, babies born during this period could potentially replace the productivity losses of the stillborn baby. Adopting this approach, which we understand is controversial and difficult for bereaved parents, the expected productivity losses would be lower, at £333 million. What are the limitations of the work? For some categories, existing data were unavailable and we used clinical opinion to estimate costs. Furthermore, we were unable to quantify some indirect consequences, for example the psychological distress experienced by wider family members. What is the implication for parents? Placing a monetary value on what is for parents a profound personal tragedy may seem unkind. It is, however, unavoidable if we are to provide policy makers with vital information on the wide-ranging consequences that could be prevented through future investments in initiatives to reduce stillbirth.

Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial.

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.

Development of a low phenolic acid diet for the management of orofacial granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) is a rare disease of unknown cause. A cinnamon- and benzoate-free diet is successful in up to 72% of patients. Phenolic acids are among the chemical constituents restricted in this diet, which avoids some but not all of these structurally similar compounds. The present study aimed to: (i) develop a novel diet low in phenolic acids; (ii) implement this in a small clinical trial; and (iii) assess its nutritional adequacy. METHODS: A literature review identified 10 papers quantifying phenolic acids from which 91 10-mg phenolic acid exchanges were devised. A phenolic acid exclusion diet with precautionary micronutrient supplementation was designed and implemented in 10 patients. Phenolic acids were excluded for 6 weeks and were reintroduced at a rate of one exchange every second day for 6 weeks. Wilcoxon matched pairs tests analysed disease outcomes measured by an oral disease severity scoring tool at weeks 0, 6 and 12. Nutritional adequacy was assessed, excluding micronutrient supplementation, at weeks 0 and 6, and compared intakes with dietary reference values. RESULTS: The diet was nutritionally inadequate for a range of micronutrients. Seven of 10 patients responded. Mean [standard deviation (SD)] severity scores improved from week 0-6 [20.8 (9.39) and 10.1 (5.72); P = 0.009] and were maintained in five patients who completed the reintroduction [6.6 (3.13) and 7.2 (5.54); P = 0.713]. CONCLUSIONS: A low phenolic acid diet with micronutrient supplementation holds promise of a novel dietary treatment for OFG. Further work is required in larger studies to determine long-term outcomes.

Review article: cinnamon- and benzoate-free diet as a primary treatment for orofacial granulomatosis.

BACKGROUND: Orofacial granulomatosis is a rare chronic granulomatous inflammatory disease of the lips, face and mouth. The aetiology remains unclear but may involve an allergic component. Improvements have been reported with cinnamon- and benzoate-free diets. AIMS: To explore the prevalence of compound and food sensitivity and examine the dietary treatments used in orofacial granulomatosis. METHODS: A comprehensive literature search was carried out and relevant studies from January 1933 to January 2010 were identified using the electronic database search engines; AGRIS 1991-2008, AMED 1985-2008, British Nursing and Index archive 1985-2008, EMBASE 1980-2008, evidence based medicine review databases (e.g. Cochrane DSR), International Pharmaceutical and Medline 1950-2008. RESULTS: Common sensitivities identified, predominantly through patch testing, were to benzoic acid (36%) food additives (33%), perfumes and flavourings (28%), cinnamaldehyde (27%), cinnamon (17%), benzoates (17%) and chocolate (11%). The cinnamon- and benzoate-free diet has been shown to provide benefit in 54-78% of patients with 23% requiring no adjunctive therapies. A negative or positive patch test result to cinnamaldehyde, and benzoates did not predict dietary outcome. The most concentrated source of benzoate exposure is from food preservatives. Use of liquid enteral formulas can offer a further dietary therapy, particularly in children with orofacial granulomatosis. CONCLUSION: Management of orofacial granulomatosis is challenging but cinnamon- and benzoate-free diets appear to have a definite role to play.

The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses.

BACKGROUND: The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). METHODS: A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. FINDINGS: For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. INTERPRETATION: To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.

Estimation and external validation of a new prognostic model for predicting recurrence-free survival for early breast cancer patients in the UK.

BACKGROUND: We aimed to estimate and externally validate a new UK-specific prognostic model for predicting the long-term risk of a first recurrent event (local recurrence, metastatic recurrence, or second primary breast cancer) in women diagnosed with early breast cancer. METHODS: Using data on the prognostic characteristics and outcomes of 1844 women treated for early breast cancer at the Churchill Hospital in Oxford, parametric regression-based survival analysis was used to estimate a prognostic model for recurrence-free survival. The model, which incorporated established prognostic factors, was externally validated using independent data. Its performance was compared with that of the Nottingham Prognostic Index (NPI) and Adjuvant! Online. RESULTS: The number of positive axillary lymph nodes, tumour grade, tumour size and patient age were strong predictors of recurrence. Oestrogen receptor (ER) positivity was shown to afford a moderate protective effect. The model was able to separate patients into distinct prognostic groups, and predicted well at the patient level, mean Brier Accuracy Score=0.17 (s.e.=0.004) and overall C=0.745 (95% CI, 0.717-0.773). Its performance diminished only slightly when applied to a second independent data set. When compared with the NPI, the model was able to better discriminate between women with excellent and good prognoses, and it did not overestimate 10-year recurrence-free survival to the extent observed for Adjuvant! Online. CONCLUSION: The model estimated here predicts well at both the individual patient and group levels, and appears transportable to patients treated at other UK hospitals. Its parametric form permits long-term extrapolation giving it an advantage over other prognostic tools currently in use. A simple point scoring system and reference table allow 5-, 10-, and 15-year predictions from the model to be quickly and easily estimated. The model is also available to download as an interactive computer program.

An investigation into the performance of the Adjuvant! Online prognostic programme in early breast cancer for a cohort of patients in the United Kingdom.

BACKGROUND: Adjuvant! Online is an internet-based computer programme providing 10-year prognosis predictions for early breast cancer patients. It was developed in the United States, has been successfully validated in Canada, and is used in the United Kingdom and elsewhere. This study investigates the performance of Adjuvant! in a cohort of patients from the United Kingdom. METHODS: Data on the prognostic factors and management of 1065 women with early breast cancer diagnosed consecutively at the Churchill Hospital in Oxford between 1986 and 1996 were entered into Adjuvant! to generate predictions of overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) at 10 years. Such predictions were compared with the observed 10-year outcomes of these patients. RESULTS: For the whole cohort, Adjuvant! significantly overestimated OS (by 5.54%, P<0.001), BCSS (by 4.53%, P<0.001), and EFS (by 3.51%, P=0.001). For OS and BCSS, overestimation persisted across most demographic, pathologic, and treatment subgroups investigated. Differences between Adjuvant! predicted and observed EFS appeared smaller, and were significant for far fewer subgroups, only 5 out of the 28. The likely explanation for such discordance is that US breast cancer mortality rates (upon which Adjuvant! is based) appear to be systematically lower than breast cancer mortality rates in the United Kingdom. Differences in survival after recurrence would seem to be one contributory factor, with data suggesting that prognosis after relapse appears poorer in the United Kingdom. This may reflect the fact that new and more effective cancer drugs are often only approved for use in the United Kingdom many years after their adoption in the United States. CONCLUSION: The use of Adjuvant! by clinicians within the UK National Health Service is increasing, under the assumption that the programme is transferrable to the United Kingdom. At least for women treated for breast cancer at the Churchill Hospital in Oxford, however, Adjuvant!'s predictions were on the whole overoptimistic. If the findings reported here could be shown to be generalisable to other areas of the United Kingdom, then thought should perhaps be given to the development of a UK-specific version of the programme.

How cost-effective is screening for abdominal aortic aneurysms?

OBJECTIVE: To provide reliable estimates of the long-term cost-effectiveness of abdominal aortic aneurysm screening in men. METHODS: A Markov health economic decision model for screening is described and extrapolated to 30 years. The strategy modelled involves a one-off scan at age 65 years, with annual and three-monthly follow-up scans for small and medium aneurysms, respectively. Referral for elective surgery occurs at an aortic diameter of 5.5 cm. Model parameters are estimated from patient-level data from the UK Multi-centre Aneurysm Screening Study. Model structure is validated on this trial's data, and input parameter uncertainty is addressed by probabilistic sensitivity analysis. Costs and life-years gained are obtained for both screening and no systematic screening strategies. RESULTS: Cost-effectiveness improves dramatically when considered over longer timescales. Taking a 30-year perspective, screening for abdominal aortic aneurysms in men is highly cost-effective at 2320 pounds per life-year gained (95% uncertainty interval: 1600 pounds to 4240 pounds). Adjusting life-years for the age-specific health-related quality of life experienced in this population gave a figure of 2970 pounds (95% uncertainty interval: 2030 pounds to 5430 pounds) per quality-adjusted life-year gained. The additional cost of screening the UK male population is estimated to be 19 m pounds per year. CONCLUSIONS: The long-term cost-effectiveness of screening for abdominal aortic aneurysms in men is highly attractive and this evidence provides further support for a national screening programme in the UK.

A UK trial-based cost--utility analysis of transmyocardial laser revascularization compared to continued medical therapy for treatment of refractory angina pectoris.

OBJECTIVE: Transmyocardial laser revascularization (TMLR) is used to treat patients with refractory angina considered unsuitable for conventional forms of revascularization. Using patient specific data from a single centre UK randomised-controlled trial, we aimed to determine whether, from a UK National Health Service (NHS) perspective, TMLR plus standard medical management is cost-effective when compared with standard medical management alone. METHODS: One hundred and eighty-eight patients assessed as having refractory angina, and not suitable for conventional forms of revascularization were randomized to receive TMLR and medical management (94) or medical management alone (94). Costs to the UK NHS of TMLR (where appropriate), and all secondary sector health care contacts and cardiac-related medication in the 12 months following randomization, were collected. Patient utility as measured using the EuroQol EQ-5D questionnaire was combined with 12-month survival data to generate quality adjusted life years (QALYs). RESULTS: The mean cost per patient over the year from hospitalization for TMLR was 11,470 pounds sterling and for medical management alone was 2586 pounds sterling, giving a cost difference of 8901 pounds sterling (95% confidence interval (CI) 7502 pounds sterling--10,008 pounds sterling: P < 0.0001). The mean QALY difference, in favour of TMLR was 0.039 (95% CI -0.033 to 0.113: P = 0.268). This gives an incremental cost per QALY of over 228,000 pounds sterling. Analysis of stochastic uncertainty and of sensitivity to gross changes in key parameters consistently produces very high costs per QALY. CONCLUSIONS: The policy implications are clear: for such patients TMLR is an inefficient use of UK health service resources. This conclusion would not be changed by considerable improvements in effectiveness or reductions in cost.

Muscarinic subtype selectivity of tetrahydroaminoacridine: possible relationship to its capricious efficacy.

Tetrahydroaminoacridine discriminated slightly in its potency to displace [3H]N-methylscopolamine ([3H]NMS) binding from different muscarinic receptor subtypes (M2 greater than M1 greater than M3) and to allosterically decelerate ligand binding (M2 greater than or equal to M1 greater than M3). The steep displacement curves suggest that marked changes in receptor occupancy may occur within a relatively narrow dose range. Thus, individual inter-patient variability and inconsistent results in clinical studies may be related to blockade of muscarinic receptors, which would oppose the beneficial effects resulting from acetylcholinesterase inhibition.