Cost-Effectiveness Analysis of Antimicrobial Prescribing in the Treatment of Clostridioides Difficile Infection in England.

BACKGROUND: An economic model was developed with guidance from the National Institute for Health and Care Excellence (NICE) 'Managing Common Infections' (MCI) Committee to evaluate the cost effectiveness of different antibiotic treatment sequences for treating Clostridioides difficile infection (CDI) in England. METHODS: The model consisted of a 90-day decision tree followed by a lifetime cohort Markov model. Efficacy data were taken from a network meta-analysis and published literature, while cost, utility and mortality data were taken from published literature. A treatment sequence was defined as a first-line intervention or a different second-line intervention, and used constant third- and fourth-line interventions. The possible first- and second-line interventions were vancomycin, metronidazole, teicoplanin and fidaxomicin (standard and extended regimens). Total costs and quality-adjusted life-years (QALYs) were calculated and were used to run a fully incremental cost-effectiveness analysis. Threshold analysis was conducted around pricing. RESULTS: Sequences including teicoplanin, fidaxomicin (extended regimen) and second-line metronidazole were excluded based on recommendations from the committee. The final pairwise comparison was between first-line vancomycin and second-line fidaxomicin (VAN-FID), and the reverse (FID-VAN). The incremental cost-effectiveness ratio for FID-VAN compared with VAN-FID was £156,000 per QALY gained, and FID-VAN had a 0.2% likelihood of being cost effective at a £20,000 threshold. CONCLUSION: First-line vancomycin and second-line fidaxomicin was the most cost-effective treatment sequence at the NICE threshold for treating CDI in England. The main limitation of this study was that the initial cure and recurrence rates of each intervention were applied constantly across each line of treatment and each round of recurrence.

Assessing the cost-effectiveness of HPV vaccination strategies for adolescent girls and boys in the UK.

BACKGROUND: Human papillomavirus (HPV) is the most widespread sexually transmitted infection worldwide. It causes several health consequences, in particular accounting for the majority of cervical cancer cases in women. In the United Kingdom, a vaccination campaign targeting 12-year-old girls started in 2008; this campaign has been successful, with high uptake and reduced HPV prevalence observed in vaccinated cohorts. Recently, attention has focused on vaccinating both sexes, due to HPV-related diseases in males (particularly for high-risk men who have sex with men) and an equity argument over equalising levels of protection. METHODS: We constructed an epidemiological model for HPV transmission in the UK, accounting for nine of the most common HPV strains. We complemented this with an economic model to determine the likely health outcomes (healthcare costs and quality-adjusted life years) for individuals from the epidemiological model. We then tested vaccination with the three HPV vaccines currently available, vaccinating either girls alone or both sexes. For each strategy we calculated the threshold price per vaccine dose, i.e. the maximum amount paid for the added health benefits of vaccination to be worth the cost of each vaccine dose. We calculated results at 3.5% discounting, and also 1.5%, to consider the long-term health effects of HPV infection. RESULTS: At 3.5% discounting, continuing to vaccinate girls remains highly cost-effective compared to halting vaccination, with threshold dose prices of £56-£108. Vaccination of girls and boys is less cost-effective (£25-£53). Compared to vaccinating girls only, adding boys to the programme is not cost-effective, with negative threshold prices (-£6 to -£3) due to the costs of administration. All threshold prices increase when using 1.5% discounting, and adding boys becomes cost-effective (£36-£47). These results are contingent on the UK's high vaccine uptake; for lower uptake rates, adding boys (at the same uptake rate) becomes more cost effective. CONCLUSIONS: Vaccinating girls is extremely cost-effective compared with no vaccination, vaccinating both sexes is less so. Adding boys to an already successful girls-only programme has a low cost-effectiveness, as males have high protection through herd immunity. If future health effects are weighted more heavily, threshold prices increase and vaccination becomes cost-effective.

Preferences for portable ultrasound devices: a discrete choice experiment among abdominal aortic aneurysm surveillance patients and general ultrasound patients in England.

OBJECTIVE: To undertake an assessment of preferences as to how, where and by whom ultrasounds (US) should be performed in: (1) patients undergoing surveillance of abdominal aortic aneurysm (AAA) size (AAA group); and (2) patients being scanned for general abdominal conditions (general group). DESIGN: A discrete choice experiment (DCE) questionnaire was administered to patients attending US appointments. Analysis of questionnaire responses used conditional logit models and included validity checks. SETTING: West Midlands, England. PARTICIPANTS: 524 patients (223 in the AAA group and 301 in the general group) were recruited from the US outpatient department at University Hospital Coventry and Warwickshire. OUTCOME MEASURES: Coefficients for attributes in relation to their reference levels. RESULTS: The AAA group preferred to have their US performed in hospital while the general group had a preference for portable US at general practice surgeries. All patients had a strong preference for scanning by specialists, devices with a lower risk of underdiagnosis and receiving their results at the appointment where the scan takes place. The general group had a strong preference for the person performing the scan to know their medical history. CONCLUSIONS: Patients being scanned for general abdominal conditions prefer to be scanned in a general practice by practitioners who know their medical history. Patients undergoing surveillance of AAA size prefer to be scanned in a hospital setting. Both groups would prefer to be informed of the scan results as soon as possible. Further research is required to explore the clinical scenarios in which targeted scanning by community practitioners would be of benefit to patients.

Comparing Generic and Condition-Specific Preference-Based Measures in Epilepsy: EQ-5D-3L and NEWQOL-6D.

BACKGROUND: There is debate about the psychometric characteristics of the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L) for use in epilepsy. In response to the concerns, an epilepsy-specific preference-based measure (NEWQOL-6D) was developed. The psychometric characteristics of the NEWQOL-6D, however, have not been assessed. OBJECTIVES: To investigate the validity and responsiveness of the EQ-5D-3L and the Quality of Life in Newly Diagnosed Epilepsy Instrument-six dimensions (NEWQOL-6D) for use in the assessment of treatments for newly diagnosed focal epilepsy. METHODS: The analysis used data from the Standard And New Antiepileptic Drugs trial including patients with focal epilepsy. We assessed convergent validity using correlations, and known-group validity across different epilepsy and general health severity indicators using analysis of variance and effect sizes. The responsiveness of the measures to change over time was assessed using standardized response means. We also assessed agreement between the measures. RESULTS: There was some level of convergence and agreement between the measures in terms of utility score but divergence in the concepts measured by the descriptive systems. Both instruments displayed known-group validity, with significant differences between severity groups, and generally slightly larger effect sizes for the NEWQOL-6D across the epilepsy-specific indicators. Evidence for responsiveness was less clear, with small to moderate standardized response means demonstrating different levels of change across different indicators. CONCLUSIONS: There was an overall tendency for the NEWQOL-6D to better reflect differences across groups, but this does not translate into large absolute utility differences. Both the EQ-5D-3L and the NEWQOL-6D show some evidence of validity for providing utility values for economic evaluations in newly diagnosed focal epilepsy.

Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis.

BACKGROUND: Timely and accurate identification of people with latent tuberculosis infection (LTBI) is important for controlling Mycobacterium tuberculosis (TB). There is no gold standard for diagnosis of LTBI. Screening tests such as interferon gamma release assays (IGRAs) and tuberculin skin test (TST) provide indirect and imperfect information. This systematic review compared two types of IGRAs QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT.TB with TST for identification of LTBI by predicting progression to a diagnosis of active TB in three subgroups: children, immunocompromised people, and those recently arrived from countries with high TB burden. METHODS: Cohort studies were eligible for inclusion. We searched MEDLINE, EMBASE, the Cochrane Library and other databases from December 2009 to June 2015. One reviewer screened studies, extracted data, and assessed risk of bias with cross checking by a second reviewer. Strength of association between test results and incidence of TB was summarised using cumulative incidence ratios (CIRs with 95% CIs). Summary effect measures: the ratio of CIRs (R-CIR) with 95% CIs. R-CIRs, were pooled using a random-effects model. Heterogeneity was assessed using Chi-squared and I2 statistics. RESULTS: Seventeen studies, mostly of moderate or high risk of bias (five in children, 10 in immunocompromised people, and two in those recently arrived) were included. In children, while in two studies, there was no significant difference between QFT-GIT and TST (≥5 mm) (pooled R-CIR = 1.11, 95% CI: 0.71, 1.74), two other studies showed QFT-GIT to outperform TST (≥10 mm) in identifying LTBI. In immunocompromised people, IGRA (T-SPOT.TB) was not significant different from TST (≥10 mm) for identifying LTBI, (pooled R-CIR = 1.01, 95% CI: 0.65, 1.58). The forest plot of two studies in recently arrived people from countries with high TB burden demonstrated inconsistent findings (high heterogeneity; I2 = 92%). CONCLUSIONS: Prospective studies comparing IGRA testing against TST on the progression from LTBI to TB were sparse, and these results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity. Population-based studies with adequate sample size and follow-up are required to adequately compare the performance of IGRA with TST in people at high risk of TB.

Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.

BACKGROUND: The surfaces of the bones in the knee are covered with articular cartilage, a rubber-like substance that is very smooth, allowing frictionless movement in the joint and acting as a shock absorber. The cells that form the cartilage are called chondrocytes. Natural cartilage is called hyaline cartilage. Articular cartilage has very little capacity for self-repair, so damage may be permanent. Various methods have been used to try to repair cartilage. Autologous chondrocyte implantation (ACI) involves laboratory culture of cartilage-producing cells from the knee and then implanting them into the chondral defect. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ACI in chondral defects in the knee, compared with microfracture (MF). DATA SOURCES: A broad search was done in MEDLINE, EMBASE, The Cochrane Library, NHS Economic Evaluation Database and Web of Science, for studies published since the last Health Technology Assessment review. REVIEW METHODS: Systematic review of recent reviews, trials, long-term observational studies and economic evaluations of the use of ACI and MF for repairing symptomatic articular cartilage defects of the knee. A new economic model was constructed. Submissions from two manufacturers and the ACTIVE (Autologous Chondrocyte Transplantation/Implantation Versus Existing Treatment) trial group were reviewed. Survival analysis was based on long-term observational studies. RESULTS: Four randomised controlled trials (RCTs) published since the last appraisal provided evidence on the efficacy of ACI. The SUMMIT (Superiority of Matrix-induced autologous chondrocyte implant versus Microfracture for Treatment of symptomatic articular cartilage defects) trial compared matrix-applied chondrocyte implantation (MACI®) against MF. The TIG/ACT/01/2000 (TIG/ACT) trial compared ACI with characterised chondrocytes against MF. The ACTIVE trial compared several forms of ACI against standard treatments, mainly MF. In the SUMMIT trial, improvements in knee injury and osteoarthritis outcome scores (KOOSs), and the proportion of responders, were greater in the MACI group than in the MF group. In the TIG/ACT trial there was improvement in the KOOS at 60 months, but no difference between ACI and MF overall. Patients with onset of symptoms < 3 years' duration did better with ACI. Results from ACTIVE have not yet been published. Survival analysis suggests that long-term results are better with ACI than with MF. Economic modelling suggested that ACI was cost-effective compared with MF across a range of scenarios. LIMITATIONS: The main limitation is the lack of RCT data beyond 5 years of follow-up. A second is that the techniques of ACI are evolving, so long-term data come from trials using forms of ACI that are now superseded. In the modelling, we therefore assumed that durability of cartilage repair as seen in studies of older forms of ACI could be applied in modelling of newer forms. A third is that the high list prices of chondrocytes are reduced by confidential discounting. The main research needs are for longer-term follow-up and for trials of the next generation of ACI. CONCLUSIONS: The evidence base for ACI has improved since the last appraisal by the National Institute for Health and Care Excellence. In most analyses, the incremental cost-effectiveness ratios for ACI compared with MF appear to be within a range usually considered acceptable. Research is needed into long-term results of new forms of ACI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013083. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review of economic models used to assess the cost-effectiveness of strategies for identifying latent tuberculosis in high-risk groups.

BACKGROUND: Timely diagnosis and treatment of latent tuberculosis infection (LTBI) through screening remains a key public health priority. Although globally it is recommended to screen people at high risk of developing TB, the economic evidence underpinning these recommendations is limited. This review critically appraised studies that had used a decision-analytical modelling framework to estimate the cost-effectiveness of interferon gamma release assays (IGRAs) compared to tuberculin skin test (TST) for detecting LTBI in high risk populations. METHODS: A comprehensive search of MEDLINE, EMBASE, NHS-EED was undertaken from 2009 up to June 2015. Studies were screened and extracted by independent reviewers. The study quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and the Philips' checklist, respectively. A narrative synthesis of the included studies was undertaken. RESULTS: Ten studies were included in this review. Two economic evaluations were conducted in a child population, six in an immunocompromised population and two in a recently arrived population from a country with a high incidence of TB. Most studies (n = 7) used a decision tree structure with Markov nodes. In general, all models were clearly described in terms of reporting quality, but were subject to limitations to structure and model inputs. Models have not elaborated on their setting or the perspective of the studies was not consistent with their analyses. Other concerns were related to derivation of prevalence, test accuracy and transition probabilities. CONCLUSION: Current methods available highlight limitations in the clinical effectiveness literature, model structures and assumptions, which impact on the robustness of the cost-effectiveness results. These models available are useful, but limited on the information that can be used to inform on future cost-effectiveness analysis. Until consideration is given on deriving the performance of tests used to identify LTBI that progresses to active TB, and the development of more comprehensive models, the economic benefit of LTBI testing with TST/IGRAs in high risk populations will remain unanswered.

Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation.

BACKGROUND: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) [(Zopf 1883) Lehmann and Neumann 1896], is a major cause of morbidity and mortality. Nearly one-third of the world's population is infected with MTB; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths worldwide. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of screening tests [interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs)] in latent tuberculosis infection (LTBI) diagnosis to support National Institute for Health and Care Excellence (NICE) guideline development for three population groups: children, immunocompromised people and those who have recently arrived in the UK from high-incidence countries. All of these groups are at higher risk of progression from LTBI to active TB. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, The Cochrane Library and Current Controlled Trials were searched from December 2009 up to December 2014. REVIEW METHODS: English-language studies evaluating the comparative effectiveness of commercially available tests used for identifying LTBI in children, immunocompromised people and recent arrivals to the UK were eligible. Interventions were IGRAs [QuantiFERON(®)-TB Gold (QFT-G), QuantiFERON(®)-TB Gold-In-Tube (QFT-GIT) (Cellestis/Qiagen, Carnegie, VA, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK)]. The comparator was TST 5 mm or 10 mm alone or with an IGRA. Two independent reviewers screened all identified records and undertook a quality assessment and data synthesis. A de novo model, structured in two stages, was developed to compare the cost-effectiveness of diagnostic strategies. RESULTS: In total, 6687 records were screened, of which 53 unique studies were included (a further 37 studies were identified from a previous NICE guideline). The majority of the included studies compared the strength of association for the QFT-GIT/G IGRA with the TST (5 mm or 10 mm) in relation to the incidence of active TB or previous TB exposure. Ten studies reported evidence on decision-analytic models to determine the cost-effectiveness of IGRAs compared with the TST for LTBI diagnosis. In children, TST (≥ 5 mm) negative followed by QFT-GIT was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of £18,900 per quality-adjusted life-year (QALY) gained. In immunocompromised people, QFT-GIT negative followed by the TST (≥ 5 mm) was the most cost-effective strategy, with an ICER of approximately £18,700 per QALY gained. In those recently arrived from high TB incidence countries, the TST (≥ 5 mm) alone was less costly and more effective than TST (≥ 5 mm) positive followed by QFT-GIT or T-SPOT.TB or QFT-GIT alone. LIMITATIONS: The limitations and scarcity of the evidence, variation in the exposure-based definitions of LTBI and heterogeneity in IGRA performance relative to TST limit the applicability of the review findings. CONCLUSIONS: Given the current evidence, TST (≥ 5 mm) negative followed by QFT-GIT for children, QFT-GIT negative followed by TST (≥ 5 mm) for the immunocompromised population and TST (≥ 5 mm) for recent arrivals were the most cost-effective strategies for diagnosing LTBI that progresses to active TB. These results should be interpreted with caution given the limitations identified. The evidence available is limited and more high-quality research in this area is needed including studies on the inconsistent performance of tests in high-compared with low-incidence TB settings; the prospective assessment of progression to active TB for those at high risk; the relative benefits of two-compared with one-step testing with different tests; and improved classification of people at high and low risk for LTBI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014009033. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cost Effectiveness of HPV Vaccination: A Systematic Review of Modelling Approaches.

BACKGROUND: A large number of economic evaluations have been published that assess alternative possible human papillomavirus (HPV) vaccination strategies. Understanding differences in the modelling methodologies used in these studies is important to assess the accuracy, comparability and generalisability of their results. OBJECTIVES: The aim of this review was to identify published economic models of HPV vaccination programmes and understand how characteristics of these studies vary by geographical area, date of publication and the policy question being addressed. METHODS: We performed literature searches in MEDLINE, Embase, Econlit, The Health Economic Evaluations Database (HEED) and The National Health Service Economic Evaluation Database (NHS EED). From the 1189 unique studies retrieved, 65 studies were included for data extraction based on a priori eligibility criteria. Two authors independently reviewed these articles to determine eligibility for the final review. Data were extracted from the selected studies, focussing on six key structural or methodological themes covering different aspects of the model(s) used that may influence cost-effectiveness results. RESULTS: More recently published studies tend to model a larger number of HPV strains, and include a larger number of HPV-associated diseases. Studies published in Europe and North America also tend to include a larger number of diseases and are more likely to incorporate the impact of herd immunity and to use more realistic assumptions around vaccine efficacy and coverage. Studies based on previous models often do not include sufficiently robust justifications as to the applicability of the adapted model to the new context. CONCLUSIONS: The considerable between-study heterogeneity in economic evaluations of HPV vaccination programmes makes comparisons between studies difficult, as observed differences in cost effectiveness may be driven by differences in methodology as well as by variations in funding and delivery models and estimates of model parameters. Studies should consistently report not only all simplifying assumptions made but also the estimated impact of these assumptions on the cost-effectiveness results.

Economic and Health-Related Quality of Life Outcomes of Whiplash Associated Disorders.

STUDY DESIGN: This study examines the links between severity of whiplash associated disorder and costs and health outcomes. OBJECTIVE: The study aims to estimate the economic costs and health-state utilities associated with disability levels and recovery trajectories after acute whiplash injury. SUMMARY OF BACKGROUND DATA: Data used were from the Managing Injuries of the Neck Trial, which collected information on 3851 people over a 12-month period after acute whiplash injury. METHODS: Effects of whiplash associated disorder severity on economic costs (measured from a societal perspective and separately from a health and personal social services perspective) were estimated using two-part regression models, comprising probability of incurring a cost and the total cost, given one was incurred. Effects on health-state utilities (measured using the EQ-5D and SF-6D) were estimated using ordinary least squares regression, and two-part models as for costs. RESULTS: There was a direct relationship between severity of disability after acute whiplash injury and economic costs. Between baseline and 4 months, average societal costs for those with no disability were £99.55 (UK£, 2009 prices), increasing to £668.53 for those with complete disability. Average societal costs for the whole sample were £234.15 over the first 4 months, decreasing to £127.51 between 8 and 12 months. Conversely, utility scores decreased with increased disability. The average EQ-5D utility score was 0.934 at 4 months for those with no disability, decreasing to 0.033 for those with complete disability. The average EQ-5D utility score for the whole sample increased from 0.587 immediately post-injury to 0.817 at 12 months. Relative costs and disutilities generated by the multivariate models are also presented by disability level and recovery trajectory. CONCLUSION: These results provide estimates of the costs and health-state utilities associated with disability levels and recovery trajectories after acute whiplash injury. They can be used to inform estimates of the cost-effectiveness of interventions targeting whiplash-associated disorders. LEVEL OF EVIDENCE: 3.

Psychometric properties of Patient Reported Outcome Measures (PROMs) in patients diagnosed with Acute Respiratory Distress Syndrome (ARDS).

BACKGROUND: The aim of this study was to assess the psychometric properties of the EQ-5D-3 L, the SF-12 v2 and its preference based derivative the SF-6D, and the St Georges Respiratory Questionnaire (SGRQ), in patients diagnosed with Acute Respiratory Distress Syndrome (ARDS). METHODS: Data from the Oscillation in ARDS (OSCAR) randomised unblinded clinical trial of 795 patients diagnosed with ARDS provided the foundation of this secondary psychometric analysis. The three source patient reported outcome measures (PROMs) (EQ-5D-3 L, SF-12 and SGRQ) were collected at both 6 and 12 months post randomisation. All measures were tested for acceptability, reliability, internal consistency, validity and responsiveness. Data from responders at 6 months was used to test for acceptability, reliability, known groups validity and internal responsiveness. Data from patients who responded at both 6 and 12 months was used to test for convergent validity and external responsiveness. RESULTS: Rates of response at both 6 and 12 months post randomisation were 89.88 % for the EQ-5D-3 L, 77.38 % for the SF-6D, 71.43 % for both the physical and mental components of the SF-12 and 38.10 % for the SGRQ. All measures had a Cronbach's Alpha statistic higher than 0.7. For known group's validity, there was no difference in mean summary or utility scores between known groups for all PROMs with minimal effect sizes. All three source measures showed strong convergent and discriminant validity. There was consistent evidence that the SF-6D is an empirically valid and efficient alternative to the EQ-5D-3 L. The EQ-5D-3 L and SGRQ were more responsive compared to the SF-12 and SF-6D with the EQ-5D-3 L generating greater effect sizes than the SGRQ. CONCLUSION: The PROMs explored in this study displayed varying psychometric properties in the context of ARDS. Further research should focus on shortening the SGRQ whilst still maintaining its psychometric properties and mapping between the SGRQ and preference-based measures for future application within economic evaluations of respiratory focused interventions. The selection ofa preferred PROM for evaluative studies within the ARDS context should ultimately depend on the relative importance placed on individual psychometric properties and the importance placed on generation of health utilities for economic evaluation purposes.

Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.

BACKGROUND: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. OBJECTIVES: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. DESIGN: FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. SETTINGS: Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool. PARTICIPANTS: Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. INTERVENTIONS: Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. MAIN OUTCOME MEASURES: Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use. RESULTS: Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%). CONCLUSIONS: The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37558856. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Properties of patient-reported outcome measures in individuals following acute whiplash injury.

BACKGROUND: The aim of this study was to assess the acceptability, reliability, validity and responsiveness of the Short-Form Health Survey (SF-12) and its preference-based derivative (SF-6D), the EQ-5D and the Neck Disability Index (NDI) in patients recovering from acute whiplash injury. METHODS: Data from the Managing Injuries of the Neck Trial of 3,851 patients with acute whiplash injury formed the basis of this empirical investigation. The EQ-5D and SF-12 were collected at baseline, and all three outcome measures were then collected at 4 months, 8 months and 12 months post-randomisation. The measures were assessed for their acceptability (response rates), internal consistency, validity (known groups validity and discriminant validity) and their internal and external responsiveness. RESULTS: Response rates were broadly similar across the measures, with evidence of a floor effect for the NDI and a ceiling effect for the EQ-5D utility measure. All measures had Cronbach's α statistics of greater than 0.7, indicating acceptable internal consistency. The NDI and EQ-5D utility score correlated more strongly with the physical component scale of the SF-12 than the mental component scale, whilst this was reversed for the SF-6D utility score. The smaller standard deviations in SF-6D utility scores meant there were larger effect sizes for differences in utility score between patients with different injury severity at baseline than for the EQ-5D utility measure. However, the EQ-5D utility measure and NDI were both more responsive to longitudinal changes in health status than the SF-6D. CONCLUSIONS: There was no evidence of differences between the EQ-5D utility measure and NDI in terms of their construct validity, discriminant validity or responsiveness in patients with acute whiplash injury. However, both demonstrated superior responsiveness to longitudinal health changes than the SF-6D.

First steps: study protocol for a randomized controlled trial of the effectiveness of the Group Family Nurse Partnership (gFNP) program compared to routine care in improving outcomes for high-risk mothers and their children and preventing abuse.

BACKGROUND: Evidence from the USA suggests that the home-based Family Nurse Partnership program (FNP), extending from early pregnancy until infants are 24 months, can reduce the risk of child abuse and neglect throughout childhood. FNP is now widely available in the UK. A new variant, Group Family Nurse Partnership (gFNP) offers similar content but in a group context and for a shorter time, until infants are 12 months old. Each group comprises 8 to 12 women with similar expected delivery dates and their partners. Its implementation has been established but there is no evidence of its effectiveness. METHODS/DESIGN: The study comprises a multi-site randomized controlled trial designed to identify the benefits of gFNP compared to standard care. Participants (not eligible for FNP) must be either aged < 20 years at their last menstrual period (LMP) with one or more previous live births, or aged 20 to 24 at LMP with low educational qualifications and no previous live births. 'Low educational qualifications' is defined as not having both Maths and English Language GCSE at grade C or higher or, if they have both, no more than four in total at grade C or higher. Exclusions are: under 20 years and previously received home-based FNP and, in either age group, severe psychotic mental illness or not able to communicate in English. Consenting women are randomly allocated (minimized by site and maternal age group) when between 10 and 16 weeks pregnant to either to the 44 session gFNP program or to standard care after the collection of baseline information. Researchers are blind to group assignment.The primary outcomes at 12 months are child abuse potential based on the revised Adult-Adolescent Parenting Inventory and parent/infant interaction coded using the CARE Index based on a video-taped interaction. Secondary outcomes are maternal depression, parenting stress, health related quality of life, social support, and use of services. DISCUSSION: This is the first study of the effectiveness of gFNP in the UK. Results should inform decision-making about its delivery alongside universal services, potentially enabling a wider range of families to benefit from the FNP curriculum and approach to supporting parenting. TRIAL REGISTRATION: ISRCTN78814904.

Mechanism-based approach to the economic evaluation of pharmaceuticals: pharmacokinetic/pharmacodynamic/pharmacoeconomic analysis of rituximab for follicular lymphoma.

BACKGROUND AND OBJECTIVES: Economic value is an important consideration during all phases of the drug development process. We previously published an article in PharmacoEconomics in which we described a mechanism-based economic modelling approach that incorporates data obtained during phase II clinical studies on the relationships between dose, exposure and response. We now describe case studies of rituximab for the treatment of follicular non-Hodgkin's lymphoma based on this methodology. METHODS: We utilized a population pharmacokinetic and pharmacodynamic model linking serum rituximab concentration to progression-free survival, to simulate the effectiveness of rituximab in various clinical contexts. These served as inputs to economic models of follicular lymphoma, based on National Institute for Health and Clinical Excellence (NICE) appraisals, to assess the cost effectiveness of rituximab. Our results were compared with trial-based estimates from the NICE appraisals. In a further analysis, we simulated the results of an ongoing trial to generate predictions of cost effectiveness. RESULTS: Our analyses suggest an acceptable degree of concordance between simulation- and trial-based estimates of cost effectiveness. For first-line and maintenance therapy, deviations of £2,099 and £1,355 per QALY, respectively, from trial-based incremental cost-effectiveness ratio estimates of £8,290 and £7,721 per QALY gained would not affect reimbursement decisions. The probability of rituximab-containing regimens being cost effective at £20,000 and £30,000 per QALY thresholds was 1 for both first-line and maintenance therapy in both simulated and trial-based analyses. CONCLUSIONS: Our analyses demonstrate the feasibility of mechanism-based economic analyses, which may have applications during drug development to the following: (i) directing future research based on the cost of reducing uncertainty; (ii) assessing subgroups, dosing schedules and protocol deviations; and (iii) informing strategic research and development and pricing decisions.

Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses.

OBJECTIVES: To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom. DESIGN: Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon. SETTING: UK National Health Service. Population Cohorts of 50,000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS(2) (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1. MAIN OUTCOME MEASURES: Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin. RESULTS: Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range -0.083 to 0.267) and 0.146 (-0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23,082 (€26,700; $35,800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS(2) score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42,386 per QALY gained. CONCLUSIONS: This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only for patients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.