Cost-effectiveness of replacing versus discarding the nail in children with nail bed injury.

Every year in the UK, around 10 000 children need to have operations to mend injuries to the bed of their fingernails. Currently, most children have their fingernail placed back on the injured nail bed after the operation. The NINJA trial found that children were slightly less likely to have an infection if the nail was thrown away rather than being put back, but the difference between groups was small and could have be due to chance. This study looked at whether replacing the nail is cost-effective compared with throwing it away. Using data from the NINJA trial, we compared costs, healthcare use, and quality of life and assessed the cost-effectiveness of replacing the nail. It was found that throwing the nail away after surgery would save the National Health Service (NHS) £75 (€85) per operation compared with placing the nail back on the nail bed. Changing clinical practice could save the NHS in England £720 000 (€819 000) per year.

Lifetime cost-effectiveness simulation of once-weekly exenatide in type 2 diabetes: A cost-utility analysis based on the EXSCEL trial.

AIMS: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial assessed once-weekly exenatide (EQW) vs. placebo, added to usual care in 14,752 patients with type 2 diabetes mellitus (Clinicaltrials.gov: NCT01144338). We assessed the lifetime cost-effectiveness of adding EQW vs. usual care alone from a healthcare perspective. METHODS: Medical resource use and EQ-5D utilities were collected throughout the study. Within-trial results were extrapolated to a lifetime horizon using the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2), predicting predict cardiovascular and microvascular events. Cost-effectiveness was evaluated separately for US and UK settings, with outcomes measured in quality-adjusted life-years (QALYs). RESULTS: EQW plus usual care gained 0.162 QALYs at an additional cost of $41,545/patient, compared with usual care in a US setting. The incremental cost-effectiveness ratio (ICER) was $259,223/QALY. In a UK setting, the QALY gain was 0.151 at an additional cost of £6357: an ICER of £42,589/QALY. Sensitivity analyses ranged between $34,369-$269,571 and £3430-£46,560 per QALY gained. CONCLUSIONS: In a lifetime extrapolation, adding EQW to usual care increased QALYs and costs compared with usual care alone. The base-case ICERs exceeded the commonly-cited cost-effectiveness thresholds of $100,000/QALY and £20,000/QALY. However, ICERs were considerably lower in some subgroups, and in sensitivity analyses.

Statistical and health economic analysis plan for a randomized controlled trial of surgical fixation with K-wires versus plaster casting in the treatment of dorsally displaced distal radius fractures: DRAFFT2.

AIMS: Describe a statistical and economic analysis plan for the Distal Radius Acute Fracture Fixation Trial 2 (DRAFFT2) randomized controlled trial. METHODS: DRAFFT2 is a multicentre, parallel, two-arm randomized controlled trial. It compares surgical fixation with K-wires versus plaster cast in adult patients who have sustained a dorsally displaced fracture of the distal radius. The primary outcome measure is the Patient-Rated Wrist Evaluation (PRWE, a validated assessment of wrist function and pain) at 12 months post-randomization. Secondary outcomes are measured at three, six, and 12 months after randomization and include the PWRE, EuroQoL EQ-5D-5L index and EQ-VAS (visual analogue scale), complication rate, and cost-effectiveness of the treatment. RESULTS: This paper describes the full details of the planned methods of analysis and descriptive statistics. The DRAFFT2 study protocol has been published previously. CONCLUSION: The planned analysis strategy described records our intent to conduct statistical and within-trial cost-utility analyses.Cite this article: Bone Joint Open 2020;1-6:245-252.

Economic Evaluation of Factorial Trials: Cost-Utility Analysis of the Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes 2 × 2 × 2 Factorial Trial of Atorvastatin, Omega-3 Fish Oil, and Action Planning.

OBJECTIVES: We applied principles for conducting economic evaluations of factorial trials to a trial-based economic evaluation of a cluster-randomized 2 × 2 × 2 factorial trial. We assessed the cost-effectiveness of atorvastatin, omega-3 fish oil, and an action-planning leaflet, alone and in combination, from a UK National Health Service perspective. METHODS: The Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes (AFORRD) Trial randomized 800 patients with type 2 diabetes to atorvastatin, omega-3, or their respective placebos and randomized general practices to receive a leaflet-based action-planning intervention designed to improve compliance or standard care. The trial was conducted at 59 UK general practices. Sixteen-week outcomes for each trial participant were extrapolated for 70 years using the United Kingdom Prospective Diabetes Study Outcomes Model v2.01. We analyzed the trial as a 2 × 2 factorial trial (ignoring interactions between action-planning leaflet and medication), as a 2 × 2 × 2 factorial trial (considering all interactions), and ignoring all interactions. RESULTS: We observed several qualitative interactions for costs and quality-adjusted life-years (QALYs) that changed treatment rankings. However, different approaches to analyzing the factorial design did not change the conclusions. There was a ≥99% chance that atorvastatin is cost-effective and omega-3 is not, at a £20 000/QALY threshold. CONCLUSIONS: Atorvastatin monotherapy was the most cost-effective combination of the 3 trial interventions at a £20 000/QALY threshold. Omega-3 fish oil was not cost-effective, while there was insufficient evidence to draw firm conclusions about action planning. Recently-developed methods for analyzing factorial trials and combining parameter and sampling uncertainty were extended to estimate cost-effectiveness acceptability curves within a 2x2x2 factorial design with model-based extrapolation.

Who gets referred for knee or hip replacement? A theoretical model of the potential impact of evidence-based referral thresholds using data from a retrospective review of clinic records from an English musculoskeletal referral hub.

OBJECTIVES: To estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool. DESIGN: Retrospective analysis of medical records and decision tree model evaluating policy changes using local and national data. SETTING: One musculoskeletal interface clinic (hub) in England. PARTICIPANTS: 922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis. INTERVENTIONS: We assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced. MAIN OUTCOME MEASURE: OKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years. RESULTS: Of 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1-41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5-44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year. CONCLUSIONS: Musculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.

Accurately Reflecting Uncertainty When Using Patient-Level Simulation Models to Extrapolate Clinical Trial Data.

Introduction. Patient-level simulation models facilitate extrapolation of clinical trial data while allowing for heterogeneity, prior history, and nonlinearity. However, combining different types of uncertainty around within-trial and extrapolated results remains challenging. Methods. We tested 4 methods to combine parameter uncertainty (around the regression coefficients used to predict future events) with sampling uncertainty (uncertainty around mean risk factors within the finite sample whose outcomes are being predicted and the effect of treatment on these risk factors). We compared these 4 methods using a simulation study based on an economic evaluation extrapolating the AFORRD randomized controlled trial using the UK Prospective Diabetes Study Outcomes Model version 2. This established type 2 diabetes model predicts patient-level health outcomes and costs. Results. The 95% confidence intervals around life years gained gave 25% coverage when sampling uncertainty was excluded (i.e., 25% of 95% confidence intervals contained the "true" value). Allowing for sampling uncertainty as well as parameter uncertainty widened confidence intervals by 6.3-fold and gave 96.3% coverage. Methods adjusting for baseline risk factors that combine sampling and parameter uncertainty overcame the bias that can result from between-group baseline imbalance and gave confidence intervals around 50% wider than those just considering parameter uncertainty, with 99.8% coverage. Conclusions. Analyses extrapolating data for individual trial participants should include both sampling uncertainty and parameter uncertainty and should adjust for any imbalance in baseline covariates.

Within-Trial Evaluation of Medical Resources, Costs, and Quality of Life Among Patients With Type 2 Diabetes Participating in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

OBJECTIVE: To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS: Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.S. Medicare payments and wholesale acquisition costs, respectively. Secondary analyses used English costs. RESULTS: Patients were followed for an average of 3.3 years, during which time those randomized to EQW experienced 0.41 fewer inpatient days (7.05 vs. 7.46 days; relative rate ratio 0.91; P = 0.05). Rates of outpatient medical visits were similar, as were total inpatient and outpatient costs. Mean costs for nonstudy diabetes medications over the study period were ∼$1,600 lower with EQW than with placebo (P = 0.01). Total within-study costs, excluding study medication, were lower in the EQW arm than in the placebo arm ($28,907 vs. $30,914; P ≤ 0.01). When including the estimated cost of EQW, total mean costs were significantly higher in the EQW group than in the placebo group ($42,697 vs. $30,914; P < 0.01). With English costs applied, mean total costs, including exenatide costs, were £1,670 higher in the EQW group than the placebo group (£10,874 vs. £9,204; P < 0.01). There were no significant differences in EQ-5D health utilities between arms over time. CONCLUSIONS: Medical costs were lower in the EQW arm than the placebo arm, but total costs were significantly higher once the cost of branded exenatide was incorporated.

Is stratification testing for treatment of chronic obstructive pulmonary disease exacerbations cost-effective in primary care? an early cost-utility analysis.

OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) who experience acute exacerbations usually require treatment with oral steroids or antibiotics, depending on the etiology of the exacerbation. Current management is based on clinician's assessment and judgement, which lacks diagnostic accuracy and results in overtreatment. A test to guide these decisions in primary care is in development. We developed an early decision model to evaluate the cost-effectiveness of this treatment stratification test in the primary care setting in the United Kingdom. METHODS: A combined decision tree and Markov model was developed of COPD progression and the exacerbation care pathway. Sensitivity analysis was carried out to guide technology development and inform evidence generation requirements. RESULTS: The base case test strategy cost GBP 423 (USD 542) less and resulted in a health gain of 0.15 quality-adjusted life-years per patient compared with not testing. Testing reduced antibiotic prescriptions by 30 percent, potentially lowering the risk of antimicrobial resistance developing. In sensitivity analysis, the result depended on the clinical effects of treating patients according to the test result, as opposed to treating according to clinical judgement alone, for which there is limited evidence. The results were less sensitive to the accuracy of the test. CONCLUSIONS: Testing may be cost-saving in primary care, but this requires robust evidence on whether test-guided treatment is effective. High quality evidence on the clinical utility of testing is required for early modeling of diagnostic tests generally.

Partial factorial trials: comparing methods for statistical analysis and economic evaluation.

BACKGROUND: Partial factorial trials compare two or more pairs of treatments on overlapping patient groups, randomising some (but not all) patients to more than one comparison. The aims of this research were to compare different methods for conducting and analysing economic evaluations on partial factorial trials and assess the implications of considering factors simultaneously rather than drawing independent conclusions about each comparison. METHODS: We estimated total costs and quality-adjusted life years (QALYs) within 10 years of surgery for 2252 patients in the Knee Arthroplasty Trial who were randomised to one or more comparisons of different surgical types. We compared three analytical methods: an "at-the-margins" analysis including all patients randomised to each comparison (assuming no interaction); an "inside-the-table" analysis that included interactions but focused on those patients randomised to two comparisons; and a Bayesian vetted bootstrap, which used results from patients randomised to one comparison as priors when estimating outcomes for patients randomised to two comparisons. Outcomes comprised incremental costs, QALYs and net benefits. RESULTS: Qualitative interactions were observed for costs, QALYs and net benefits. Bayesian bootstrapping generally produced smaller standard errors than inside-the-table analysis and gave conclusions that were consistent with at-the-margins analysis, while allowing for these interactions. By contrast, inside-the-table gave different conclusions about which intervention had the highest net benefits compared with other analyses. CONCLUSIONS: All analyses of partial factorial trials should explore interactions and assess whether results are sensitive to assumptions about interactions, either as a primary analysis or as a sensitivity analysis. For partial factorial trials closely mirroring routine clinical practice, at-the-margins analysis may provide a reasonable estimate of average costs and benefits for the whole trial population, even in the presence of interactions. However, such conclusions will be misleading if there are large interactions or if the proportion of patients allocated to different treatments differs markedly from what occurs in clinical practice. The Bayesian bootstrap provides an alternative to at-the-margins analysis for analysing clinical or economic endpoints from partial factorial trials, which allows for interactions while making use of the whole sample. The same techniques could be applied to analyses of clinical endpoints. TRIAL REGISTRATION: ISRCTN, ISRCTN45837371 . Registered on 25 April 2003.

Associations between preoperative Oxford hip and knee scores and costs and quality of life of patients undergoing primary total joint replacement in the NHS England: an observational study.

OBJECTIVES: To assess how costs and quality of life (measured by EuroQoL-5 Dimensions (EQ-5D)) before and after total hip replacement (THR) and total knee replacement (TKR) vary with age, gender and preoperative Oxford hip score (OHS) and Oxford knee score (OKS). DESIGN: Regression analyses using prospectively collected data from clinical trials, cohort studies and administrative data bases. SETTING: UK secondary care. PARTICIPANTS: Men and women undergoing primary THR or TKR. The Hospital Episode Statistics data linked to patient-reported outcome measures included 602 176 patients undergoing hip or knee replacement who were followed up for up to 6 years. The Knee Arthroplasty Trial included 2217 patients undergoing TKR who were followed up for 12 years. The Clinical Outcomes in Arthroplasty Study cohort included 806 patients undergoing THR and 484 patients undergoing TKR who were observed for 1 year. OUTCOME MEASURES: EQ-5D-3L quality of life before and after surgery, costs of primary arthroplasty, costs of revision arthroplasty and the costs of hospital readmissions and ambulatory costs in the year before and up to 12 years after joint replacement. RESULTS: Average postoperative utility for patients at the 5th percentile of the OHS/OKS distribution was 0.61/0.5 for THR/TKR and 0.89/0.85 for patients at the 95th percentile. The difference between postoperative and preoperative EQ-5D utility was highest for patients with preoperative OHS/OKS lower than 10. However, postoperative EQ-5D utility was higher than preoperative utility for all patients with OHS≤46 and those with OKS≤44. In contrast, costs were generally higher for patients with low preoperative OHS/OKS than those with high OHS/OKS. For example, costs of hospital readmissions within 12 months after primary THR/TKR were £740/£888 for patients at the 5th percentile compared with £314/£404 at the 95th percentile of the OHS/OKS distribution. CONCLUSIONS: Our findings suggest that costs and quality of life associated with total joint replacement vary systematically with preoperative symptoms measured by OHS/OKS.

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).

BACKGROUND: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. DESIGN: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. SETTING: Twenty-three ophthalmology departments in NHS hospitals. PARTICIPANTS: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. INTERVENTIONS: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. MAIN OUTCOME MEASURES: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. RESULTS: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. CONCLUSIONS: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92166560. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.

Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial.

OBJECTIVE: To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective. DESIGN: A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial. SETTING: 23 hospital ophthalmology clinics. PARTICIPANTS: 610 patients aged ≥50 years with untreated nAMD in the study eye. INTERVENTIONS: 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years. MAIN OUTCOME MEASURES: Quality-adjusted life-years (QALYs). RESULTS: Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI -0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab. CONCLUSIONS: Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective. TRIAL REGISTRATION NUMBER: ISRCTN92166560.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of different knee prostheses: the Knee Arthroplasty Trial (KAT).

BACKGROUND: In the late 1990s, new developments in knee replacement were identified as a priority for research within the NHS. The newer forms of arthroplasty were more expensive and information was needed on their safety and cost-effectiveness. OBJECTIVES: The Knee Arthroplasty Trial examined the clinical effectiveness and cost-effectiveness of four aspects of knee replacement surgery: patellar resurfacing, mobile bearings, all-polyethylene tibial components and unicompartmental replacement. DESIGN: This study comprised a partial factorial, pragmatic, multicentre randomised controlled trial with a trial-based cost-utility analysis which was conducted from the perspective of the NHS and the patients treated. Allocation was computer generated in a 1 : 1 ratio using a central system, stratified by eligible comparisons and surgeon, minimised by participant age, gender and site of disease. Surgeons were not blinded to allocated procedures. Participants were unblinded if they requested to know the prosthesis they received. SETTING: The setting for the trial was UK secondary care. PARTICIPANTS: Patients were eligible for inclusion if a decision had been made for them to have primary knee replacement surgery. Patients were recruited to comparisons for which the surgeon was in equipoise about which type of operation was most suitable. INTERVENTIONS: Patients were randomised to receive a knee replacement with the following: patellar resurfacing or no patellar resurfacing irrespective of the design of the prosthesis used; a mobile bearing between the tibial and femoral components or a bearing fixed to the tibial component; a tibial component made of either only high-density polyethylene ('all polyethylene') or a polyethylene bearing fixed to a metal backing plate with attached stem; or unicompartmental or total knee replacement. MAIN OUTCOME MEASURES: The primary outcome was the Oxford Knee Score (OKS). Other outcomes were Short Form 12; EuroQol 5D; intraoperative and postoperative complications; additional surgery; cost; and cost-effectiveness. Patients were followed up for a median of 10 years; the economic evaluation took a 10-year time horizon, discounting costs and quality-adjusted life-years (QALYs) at 3.5% per annum. RESULTS: A total of 116 surgeons in 34 centres participated and 2352 participants were randomised: 1715 in patellar resurfacing; 539 in mobile bearing; 409 in all-polyethylene tibial component; and 34 in the unicompartmental comparisons. Of those randomised, 345 were randomised to two comparisons. We can be more than 95% confident that patellar resurfacing is cost-effective, despite there being no significant difference in clinical outcomes, because of increased QALYs [0.187; 95% confidence interval (CI) -0.025 to 0.399] and reduced costs (-£104; 95% CI -£630 to £423). We found no definite advantage or disadvantage of mobile bearings in OKS, quality of life, reoperation and revision rates or cost-effectiveness. We found improved functional results for metal-backed tibias: complication, reoperation and revision rates were similar. The metal-backed tibia was cost-effective (particularly in the elderly), costing £35 per QALY gained. CONCLUSIONS: The results provide evidence to support the routine resurfacing of the patella and the use of metal-backed tibial components even in the elderly. Further follow-up is required to assess the stability of these findings over time and to inform the decision between mobile and fixed bearings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45837371. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the orthopaedic industry. It will be published in full in Health Technology Assessment; Vol. 18, No. 19. See the NIHR Journals Library website for further project information.

A systematic review and mixed treatment comparison of the efficacy of pharmacological treatments for fibromyalgia.

OBJECTIVES: To review the literature on pharmacological treatments for fibromyalgia. METHODS: Relative efficacy was estimated in terms of outcome measures highlighted by the Outcome Measures in Rheumatology Network using a Bayesian mixed treatment comparison (MTC) meta-analysis. Randomized controlled trials reporting treatments for fibromyalgia were identified by systematically reviewing electronic databases (Cochrane Library, Medline, EMBASE; accessed February 2008) and conducting manual bibliographic searches. RESULTS: Forty-five randomized controlled trials met the prespecified inclusion criteria for the systematic review. There were limited robust clinical data for some therapeutic classes (tricyclic antidepressants, analgesics, sedative hypnotics, monoamine oxidase inhibitors) and only 21 studies met the more stringent criteria for inclusion in the MTC. The majority of studies included in the MTC assessed the anticonvulsant pregabalin (n = 5) or the serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine (n = 3) and milnacipran (n = 3). Licensed doses of pregabalin and duloxetine were significantly (P < 0.05) more efficacious than placebo in terms of absolute reduction in pain, number of "responders" (≥30% reduction in pain), or change in Fibromyalgia Impact Questionnaire score (pregabalin 450 mg/d only). There was no significant difference between licensed doses of pregabalin and duloxetine for these outcomes. However licensed doses of pregabalin produced significantly greater improvements in sleep compared with milnacipran (as measured by Medical Outcomes Study Sleep Scale). CONCLUSIONS: The current study confirms the therapeutic efficacy of pregabalin and the SNRIs, duloxetine and milnacipran, in the treatment of fibromyalgia. Given their different modes of action, combination therapy with pregabalin plus an SNRI should be investigated in future research.

Mixed treatment comparison of repeated measurements of a continuous endpoint: an example using topical treatments for primary open-angle glaucoma and ocular hypertension.

Mixed treatment comparison (MTC) meta-analyses estimate relative treatment effects from networks of evidence while preserving randomisation. We extend the MTC framework to allow for repeated measurements of a continuous endpoint that varies over time. We used, as a case study, a systematic review and meta-analysis of intraocular pressure (IOP) measurements from randomised controlled trials evaluating topical ocular hypotensives in primary open-angle glaucoma or ocular hypertension because IOP varies over the day and over the treatment course, and repeated measurements are frequently reported. We adopted models for conducting MTC in WinBUGS (The BUGS Project, Cambridge, UK) to allow for repeated IOP measurements and to impute missing standard deviations of the raw data using the predictive distribution from observations with standard deviations. A flexible model with an unconstrained baseline for IOP variations over time and time-invariant random treatment effects fitted the data well. We also adopted repeated measures models to allow for class effects; assuming treatment effects to be exchangeable within classes slightly improved model fit but could bias estimated treatment effects if exchangeability assumptions were not valid. We enabled all timepoints to be included in the analysis, allowing for repeated measures to increase precision around treatment effects and avoid bias associated with selecting timepoints for meta-analysis.The methods we developed for modelling repeated measures and allowing for missing data may be adapted for use in other MTC meta-analyses.

Cost-consequence analysis evaluating the use of botulinum neurotoxin-A in patients with detrusor overactivity based on clinical outcomes observed at a single UK centre.

OBJECTIVE(S): This study aimed to assess the resource utilisation, health benefits and cost-effectiveness of intra-detrusor injections of botulinum neurotoxin-A (BoNT/A) in patients with overactive bladder (OAB). METHODS: 101 patients with urodynamically-proven detrusor overactivity of either neurogenic (NDO; n = 63) or idiopathic (IDO; n = 38) origin received intra-detrusor injections of 200-300 units of BoNT/A in 20-30 ml saline as part of a research protocol. Twenty-nine patients received repeat injections after 7-26 months. Symptom severity and urodynamic parameters were assessed at 0, 4 and 16 weeks. The cost of therapy was quantified based on the NHS resources used by typical patients and was used to calculate the cost-effectiveness of BoNT/A compared with standard care from the perspective of the UK NHS. RESULTS: In an intent-to-treat analysis, 82% of patients showed a 25% or greater improvement in at least two out of five parameters (urinary frequency, urgency, urgency incontinence episodes, maximum cystometric capacity and maximum detrusor pressure) four weeks after treatment, reducing to 65% after 16 weeks. A 50% or greater improvement in the frequency of micturition, urgency or urgency incontinence was seen in 73% of patients at four weeks and 54% at 16 weeks. There were no significant differences between IDO and NDO patients in the proportion meeting these endpoints. Therapy cost pounds 826 per patient, with a cost-effectiveness ratio of pounds 617 per patient-year with > or = 25% clinical improvement. CONCLUSION(S): This study demonstrates that intra-detrusor BoNT/A is an effective treatment for OAB that is highly likely to be cost-effective in both idiopathic and neurogenic disease.