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Background and Objective:Background and Objective: Epilepsy is one of the most common neurological disorders, affecting more than 3 million people in Europe. This paper reviews the published evidence regarding the cost effectiveness of second-generation antiepileptic drugs (AEDs). Abstract: Methods:Methods: A systematic literature search was performed, using the databases Academic Search Complete, Econlit, EMBASE and MEDLINE. Health economic evaluations of newer (second-generation) AEDs, published as full-length journal articles, were searched for. We focused on evaluations of newer AEDs as treatment for partial-onset seizures. 470 studies were initially identified and 19 were finally included. Information regarding (i) AEDs studied, (ii) cost effectiveness, and (iii) a variety of health economic modelling specifics was extracted from each study. Then, the included studies were summarized and a quality assessment was performed, according to the British Medical Journal's guidelines for economic studies. Abstract: Results:Results: The results were as follows: (i) the cost per additional QALY for newer AEDs used as adjunctive treatment, compared with standard therapy, ranged between $US19 139 (levetiracetam) and $US57 210 (pregabalin) [year 2010 values]; no cost-effectiveness evidence was identified for felbamate, eslicarbazepine, oxcarbazepine or tiagabine; and (ii) all studies met at least 60% of the British Medical Journal's guidelines criteria, and seven studies were found to satisfy more than 80% of the criteria. Guidelines criteria not met involve inadequate reporting of input data and modelling details, including validation and availability of models used for cost-effectiveness calculations. Abstract: Conclusions:Conclusions: Although failure to meet good practice guidelines influences the reliability of the presented evidence adversely, a sufficient number of the included studies were found to comply enough with the guidelines in order for the qualitative content of the cost-effectiveness results - that some of the newer AEDs are cost effective - to be reliable. In fact, this conclusion is likely to be relatively robust, since the effect of improved seizure control on labour market performance was not included in the base-case results in any of the included studies and improved seizure control need only to have a moderate effect on sickness absenteeism in order for the corresponding treatment to be cost effective even when willingness to pay for an additional QALY is low. However, the cost effectiveness of newer AEDs has only been studied for a small number of settings, and hence future studies incorporating additional settings are needed.

Background:Background: Preliminary studies have revealed an association between cultural competence and an improvement in the quality of healthcare services, increased patient satisfaction, and increased effectiveness of services. Abstract: Objective:Objective: This study examined factors that helped to explain patients' perceptions of their providers' interpersonal sensitivity - one component of cultural competence. Abstract: Methods and Participants:Methods and Participants: The respondents were 2075 racially/ethnically diverse adults, aged 50 years and older, who responded to a national telephone survey. Abstract: Results:Results: Results indicate that one of the main factors predicting interpersonal sensitivity is self-rated physical health: those who reported better health were more likely to see their provider as exhibiting higher levels of sensitivity. This was true for Hispanic/Latino patients. The results also suggest that having a provider of the same race/ethnicity was a significant factor only for Hispanic/Latino patients. Abstract: Conclusion:Conclusion: Despite findings from previous research, racial/ethnic concordance may not be universally effective in improving interpersonal sensitivity in healthcare settings for all racial/ethnic groups.

This article provides an overview of the clinical profile of oral dabigatran etexilate (Pradaxa, Pradax™) [hereafter referred to as dabigatran] when used for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), followed by a review of cost-utility analyses of dabigatran in this patient population. Dabigatran (110 or 150 mg twice daily) demonstrated noninferiority versus adjusted-dose warfarin with regard to the prevention of stroke and systemic embolism (primary endpoint) in patients with AF in the RE-LY trial, and the 150 mg twice-daily dosage was significantly more effective than warfarin for this endpoint, as well as most other efficacy endpoints. The incidence of major bleeding was generally similar in patients receiving dabigatran 150 mg twice daily or warfarin, but was lower in patients receiving dabigatran 110 mg twice daily. With regard to other bleeding endpoints, dabigatran was generally associated with lower rates than warfarin, except for gastrointestinal major bleeding. Dabigatran (both dosages) was associated with a higher incidence of dyspepsia than warfarin. Results of modelled cost-utility analyses from several countries from the perspective of a healthcare payer over a lifetime (or 20-year) time horizon and primarily based on data from the RE-LY trial were generally consistent. All but one analysis demonstrated that twice-daily dabigatran 150 mg (or age-adjusted, sequential dosing) was cost effective with regard to the incremental cost per QALY gained relative to adjusted-dose warfarin in the prevention of stroke and systemic embolism in AF patients, as the results were below generally accepted cost-effectiveness thresholds. In contrast, the incremental cost per QALY gained for dabigatran 110 mg twice daily versus warfarin exceeded cost-effectiveness thresholds in all studies except one. Sensitivity analyses suggested that the cost utility of dabigatran versus warfarin was generally robust to variations in the majority of parameters. However, the incremental cost per QALY gained for dabigatran versus warfarin improved when levels of international normalized ratio control in warfarin recipients decreased and when the baseline level of risk of stroke increased.

Background:Background: Preference-based health state utilities are required for many health economic evaluations. When the direct evidence of such is lacking and only condition-specific scores are available, establishing a 'mapping' relationship between instruments can be useful. Abstract: Objective:Objective: Our objective was to map the 11-point Pain Intensity Numerical Rating Scale (PI-NRS-11), a pain-specific instrument ranging from 0 ('no pain') to 10 ('pain as bad as you can imagine'), to the EQ-5D, a preference-based generic instrument. Abstract: Methods:Methods: We used web survey data collected from adult US respondents who (i) had ≥3 months of neuropathic pain (NP), either painful diabetic peripheral neuropathy (pDPN) or post-herpetic neuralgia (PHN); (ii) were receiving medications treating NP; and (iii) had completed the EQ-5D and PI-NRS-11. We explored indirect and direct mapping approaches. The indirect method took a probabilistic approach using ordered logistic models (OLMs) predicting response levels for each EQ-5D item via repeated Monte Carlo simulations before computing utilities. The direct approach simply predicted EQ-5D utilities directly using ordinary least squares (OLS). Categorical scores of PI-NRS-11 were used as the predictors. Patient age, gender, and pain duration were additionally controlled in the full model specification. Seventy percent of the data were used for estimation and 30% for prediction. Mean square errors (MSEs) and 95% confidence intervals (CIs) of prediction errors were reported. Abstract: Results:Results: A total of 2719 respondents were included. Mean (SD) age was 55.48 (10.65) years and 56.23% were female. Average NP duration was 61 months and 58% gave scores ≥6 on the PI-NRS-11. The clinical pain scores were significantly associated with all EQ-5D items, especially with the 'pain/discomfort' item (p < 0.001). The observed mean (SD) EQ-5D index was 0.594 (0.22). Predicted utilities and responses showed good representation of the observed ones. The reduced model showed comparable results with the full model while imposing minimum data collection burden. From the reduced model, the predicted mean (SD) EQ-5D index was 0.594 (0.11) from direct estimation and 0.588 (0.19) from indirect estimation. All estimated utilities discriminated health gains/losses along the PI-NRS-11. Lower MSEs and prediction errors were found for EQ-5D >0.2. Abstract: Conclusions:Conclusions: Findings suggest that EQ-5D utilities or item responses could be estimated on the basis of NP scores. Independent testing of the external validity of the mapping algorithms developed herein is encouraged.

Background and Objective:Background and Objective: Patient-centered care, which is dependent on knowing each patient as an individual, has been identified as a critical aspect of healthcare. The most effective and efficient methods to get to know patients as individuals have not been defined. Our aim was to identify questions and phrases that can be used by physicians to get to know their patients. Abstract: Methods:Methods: We surveyed 15 physicians who have been formally recognized for their clinical excellence to determine what questions or phrases they use when interviewing patients to get to know them as individuals. Abstract: Results:Results: A total of 28 questions or phrases were received from 13 physicians and were qualitatively analyzed and grouped into six major themes: (i) appreciation of the patient's concerns; (ii) personal relationships; (iii) hobbies and pleasurable activities; (iv) open-ended questions to learn about the patient; (v) work; and (vi) the patient's perspective on the patient-physician relationship. Abstract: Conclusion:Conclusion: This work identifies questions and phrases used by clinically excellent physicians to get to know their patients as people. Future work should focus on obtaining the perspectives of patients, and on examining whether using the identified questions and phrases results in an improved patient experience as demonstrated by improved satisfaction ratings, ratings on the quality of physician-patient interaction, or patient outcomes.

Objective:Objective: The aim of the study was to evaluate the quality of pharmacoeconomic studies based in India. Abstract: Methods:Methods: A literature search was conducted using PubMed, MEDLINE, EconLit, PsycInfo and Google Scholar to identify published work on pharmacoeconomics studies based in India. Articles were included if they were original studies that evaluated pharmaceuticals, were based in India and were conducted between 1990 and 2010. Two reviewers independently reviewed the articles using a subjective 10-point quality scale in addition to the 100-point Quality of Health Economic Studies (QHES) questionnaire. Abstract: Results:Results: Twenty-nine articles published between 1998 and May 2010 were included in the review. The included articles were published in 23 different journals. Each article was written by an average of five authors. The mean subjective quality score of the 29 articles was 7.8 (standard deviation &lsqb;SD&rsqb; - 1.3) and the mean QHES scores for the complete pharmacoeconomic studies (n - 24) was 86 (SD - 6). The majority of authors resided in India (62%) at the time of publication and had a medical background (90%). The quality score was significantly (p ≤ 0.05) related to the country of residence of the primary author (non-India - higher) and the study design (randomized controlled trials - higher). Abstract: Conclusion:Conclusion: Although the overall quality scores were comparable to (e.g. Nigeria) or higher than (e.g. Zimbabwe) similar studies in other developing countries, key features such as an explicit study perspective and the use of sensitivity analyses were missing in about 40% of the articles. The need for economic evaluation of pharmaceuticals is imperative, especially in developing countries such as India as this helps decision makers allocate scarce resources in a justifiable manner.

Background:Background: Measurement of consumers' satisfaction in psychiatric settings is important because it has been correlated with improved clinical outcomes and administrative measures of high-quality care. These consumer satisfaction measurements are actively used as performance measures required by the accreditation process and for quality improvement activities. Abstract: Objectives:Objectives: Our objectives were (i) to re-evaluate, through exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), the structure of an instrument intended to measure consumers' satisfaction with care in psychiatric settings and (ii) to examine and publish the psychometric characteristics, validity and reliability, of the Inpatient Consumer Survey (ICS). Abstract: Methods:Methods: To psychometrically test the structure of the ICS, 34 878 survey results, submitted by 90 psychiatric hospitals in 2008, were extracted from the Behavioral Healthcare Performance Measurement System (BHPMS). Basic descriptive item-response and correlation analyses were performed for total surveys. Two datasets were randomly created for analysis. A random sample of 8229 survey results was used for EFA. Another random sample of 8261 consumer survey results was used for CFA. This same sample was used to perform validity and reliability analyses. Abstract: Results:Results: The item-response analysis showed that the mean range for a disagree/agree five-point scale was 3.10-3.94. Correlation analysis showed a strong relationship between items. Six domains (dignity, rights, environment, empowerment, participation, and outcome) with internal reliabilities between good to moderate (0.87-0.73) were shown to be related to overall care satisfaction. Overall reliability for the instrument was excellent (0.94). Results from CFA provided support for the domains structure of the ICS proposed through EFA. Abstract: Conclusion:Conclusion: The overall findings from this study provide evidence that the ICS is a reliable measure of consumer satisfaction in psychiatric inpatient settings. The analysis has shown the ICS to provide valid and reliable results and to focus on the specific concerns of consumers of psychiatric inpatient care. Scores by item indicate that opportunity for improvement exists across healthcare organizations.

Background:Background: Atherothrombosis represents a leading cause of morbidity and mortality worldwide. Given the prominent role of platelet aggregation in atherothrombosis, antiplatelet therapy forms the cornerstone of treatment, with proven efficacy in the secondary prevention of atherothrombotic events. Although clopidogrel seems to be superior to aspirin in terms of risk reduction for an atherothrombotic event, whether this clinical advantage is cost effective in Greece is unknown. Abstract: Objective:Objective: The aim of this study was to conduct a cost-effectiveness analysis comparing clopidogrel with aspirin in the secondary prevention of atherothrombotic events in patients with peripheral artery disease, a recent stroke or a recent myocardial infarction, from the third-party-payer perspective in Greece. Abstract: Methods:Methods: A Markov model with a 6-month cycle length was developed. Transition probabilities used in the model were obtained from the event rates reported in the CAPRIE trial. The effect of clopidogrel was applied only during the first 2 years of the model. Utility data were used to estimate quality-adjusted life-years (QALYs). Costs (for the year 2012) assigned to each health state included antiplatelet treatment cost, cost for the management of adverse events related to antiplatelet therapy and the direct healthcare cost of patients (i.e. concomitant medication, hospitalization, outpatient visits, rehabilitation, laboratory and imaging diagnostic examinations as well as interventions) in the acute and follow-up phase, separately. The incremental cost-effectiveness ratio (ICER) was calculated for life-years (LYs) and QALYs, separately. A probabilistic sensitivity analysis was conducted in order to evaluate the impact of the variation that characterizes the majority of model parameters to the cost-effectiveness results. Abstract: Results:Results: The Markov analysis revealed that the discounted survival was 11.83 (95% CI 11.40, 12.22) years and 12.17 (95% CI 11.75, 12.55) years in the aspirin and clopidogrel treatment groups, respectively, a difference of 0.34 (95% CI 0.09, 0.618) LYs. The corresponding discounted QALYs were 8.63 (95% CI 8.34, 8.90) and 8.84 (95% CI 8.54, 9.10), respectively, a difference of 0.21 (95% CI 0.05, 0.37) QALYs. The cumulated lifetime costs per patient were &U20AC;20 678 (95% CI 19 675, 21 724) and &U20AC;21 688 (95% CI 20 649, 22 773), for aspirin and clopidogrel treatment arm, respectively. The ICER for clopidogrel was calculated to be &U20AC;4038 (95% CI 2743, 7837) for each LY saved and &U20AC;5518 (95% CI 3358, 12 921) for each QALY saved. Abstract: Conclusion:Conclusion: The analysis indicates that clopidogrel is cost effective for the secondary prevention of atherothrombotic events in the Greek setting. These findings are in line with those reported in other European countries.

Background:Background: Smoking is probably the most important among preventable health risks. Health economic evaluation of smoking-cessation interventions, applying a lifetime perspective, is made possible by available epidemiological knowledge. The well established method of performing cost-effectiveness analyses of smoking-cessation interventions involves mathematical modelling (both deterministic and stochastic) of future events important for cost effectiveness. Abstract: Objectives:Objectives: This study surveys cost-effectiveness analyses of smoking cessation, with a particular focus on the mathematical modelling and simulation analyses performed. Abstract: Data Sources:Data Sources: A systematic literature search was performed using the databases MEDLINE, Econlit and Academic Search Complete. Abstract: Study Selection:Study Selection: Health economic evaluations, published as full-length journal articles, were searched for. Abstract: Results:Results: 423 studies were identified and 78 were finally included, of which 30 were assessed as being highly relevant, based on the application of simulation modelling. Abstract: Conclusions:Conclusions: In general, studies are well performed as regards modelling. Common weaknesses include reporting of modelling details; validation of used simulation models; and the handling of structural uncertainty and different types of heterogeneity.

Background:Background: Little is known about the real-world treatment patterns and costs of patients with chronic low back pain (CLBP) who are treated with duloxetine compared with those receiving other non-surgical treatments. Abstract: Objective:Objective: Our objective was to compare the real-world treatment patterns and costs between patients with CLBP who initiated duloxetine and matched controls who initiated another non-surgical treatment. Abstract: Methods:Methods: The study sample was selected from a US privately insured claims database (2004-8). Selected patients were aged 18-64 years, and had a low back pain (LBP) diagnosis (per Healthcare Effectiveness Data and Information Set &lsqb;HEDIS&rsqb; specifications) with a subsequent CLBP-qualifying diagnosis recorded ≥90 days after the initial LBP diagnosis. Duloxetine-treated patients had ≥1 duloxetine prescription within 6 months after CLBP diagnosis, no prior duloxetine claim, and continuous eligibility ≥12 months before first LBP diagnosis and ≥6 months after index duloxetine prescription (study period). Because duloxetine patients had higher rates of co-morbidities, 553 duloxetine-treated patients were matched to 553 control patients who initiated another non-surgical LBP treatment based on propensity score and time from first LBP diagnosis to treatment initiation. A subset (n - 103 each) of matched employees with disability data was also analysed to assess work loss. Main outcomes measures included study period treatment rates and direct (medical and drug) costs from a third-party payer perspective and employee indirect (work-loss) costs. McNemar tests were used to compare LBP treatment rates. Bias-corrected bootstrapping t-tests were used to compare costs. Abstract: Results:Results: After matching, the two groups had balanced baseline characteristics including demographics, LBP diagnostic categories, co-morbidity profiles, resource use, treatment patterns and mean direct costs. During the 6-month study period, matched duloxetine-treated patients had significantly lower rates of other pharmacological therapy (e.g. 56.2% vs 64.9% narcotic opioids, p - 0.0024; 34.9% vs 49.5% NSAIDs, p < 0.0001) and non-invasive therapy (28.8% vs 38.5% chiropractic therapy, p - 0.0007; 25.5% vs 35.4% physical therapy, p - 0.0004; 17.5% vs 28.4% exercise therapy, p < 0.0001) than controls. Duloxetine-treated patients versus controls had similar back surgery rates (2.2% vs 3.8%; p - 0.1127) and similar direct costs (&dollar;US7658 vs &dollar;US7439; p - 0.8119). Among CLBP employees, duloxetine-treated employees versus controls had lower rates of other non-surgical therapy, similar back surgery rates (0.0% vs 3.9%; p - 0.1250), lower total direct and indirect costs (&dollar;US5227 vs &dollar;US7299; p - 0.0418), and similar indirect costs (&dollar;US1806 vs &dollar;US2664; p - 0.0528). Abstract: Conclusions:Conclusions: Duloxetine treatment in CLBP patients/employees versus other non-surgical treatment was associated with reduced rates of non-surgical therapies and similar back surgery rates, without increased costs.

Background:Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1.5 million people in the US. Tumour necrosis factor (TNF)-α inhibitors have been shown to effectively treat and maintain remission in patients with moderately to severely active RA compared with conventional agents. The high acquisition cost of TNF-α inhibitors prohibits access, which mandates economic investigations into their affordability. The lack of head-to-head comparisons between these agents makes it difficult to determine which agent is the most cost effective. Abstract: Objective:Objective: This study aimed to determine which TNF-α inhibitor was the most cost-effective agent for the treatment of moderately to severely active RA from the US healthcare payer's perspective. Abstract: Methods:Methods: A Markov model was constructed to analyse the cost utility of five TNF-α inhibitors (in combination with methotrexate &lsqb;+MTX&rsqb;) versus MTX monotherapy using Bayesian methods for evidence synthesis. The model had a cycle length of 3 months and an overall time horizon of 5 years. Transition probabilities and utility scores were based on published studies. Total direct costs were adjusted to year 2009 &dollar;US using the medical component of the Consumer Price Index. All costs and QALYs were discounted at a rate of 3% per year. Patient response to the different strategies was determined by the American College of Rheumatology (ACR)50 criteria. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case scenario. The base-case scenario was changed to ACR20 criteria (scenario 1) and ACR70 criteria (scenario 2) to determine the model's robustness. Cost-effectiveness acceptability curves and cost-effectiveness frontiers were used to estimate the cost-effectiveness probability of each treatment strategy. A willingness-to-pay (WTP) threshold was defined as three times the US GDP per capita (&dollar;US139 143 per additional QALY gained). Primary results were presented as incremental cost-effective ratios (ICERs). Abstract: Results:Results: Etanercept+MTX was the most cost-effective treatment strategy in the base-case scenario up to a WTP threshold of &dollar;US546 449 per QALY gained. At a WTP threshold of greater than &dollar;US546 499 per QALY gained, certolizumab+MTX was the most cost-effective treatment strategy. One-way analyses showed that the base-case scenario was sensitive to the probability of achieving ACR50 criteria for MTX and each TNF-α inhibitor, and changes in the utility score for patients who achieved the ACR50 criteria. With the exception of infliximab, all of the TNF-α inhibitors were sensitive to drug cost per cycle. In the scenario analyses, certolizumab+MTX was a dominant treatment strategy using ACR20 criteria, but etanercept+MTX was a dominant treatment strategy using ACR70 criteria. Abstract: Conclusions:Conclusions: Etanercept+MTX was a cost-effective treatment strategy in the base-case scenario; however, the model was sensitive to parameter uncertainties and ACR response criteria. Although Bayesian methods were used to determine transition probabilities, future studies will need to focus on head-to-head comparisons of multiple TNF-α inhibitors to provide valid comparisons.

Background:Background: Bipolar disorder has a significant impact upon a patient's quality of life, imposing a considerable economic burden on the individual, family members and society as a whole. Several medications are indicated for the acute treatment of mania and depression associated with bipolar disorder as well as for maintenance therapy; however, these have varying efficacy, tolerability and costs. Abstract: Objective:Objective: The objective of this study was to develop a new discrete-event simulation model to analyse the long-term consequences of pharmacological therapy for the management of bipolar I and II disorders (acute treatment of episodes of mania and depression as well as maintenance therapy). Abstract: Methods:Methods: Probabilities of remission and relapse were obtained from clinical trial data and meta-analyses. Costs (year 2011 values) were assessed from a UK healthcare payer's perspective, and included pharmacological therapy and resource use associated with the treatment of mood events and selected adverse events. The health effects were measured in terms of QALYs. Abstract: Results:Results: For a patient starting with acute depression or in remission at 40 years of age (which was the average age in the clinical trials), quetiapine 300 mg/day was a cost-effective strategy compared with olanzapine 15 mg/day over a 5-year time frame. With acute bipolar depression as a starting episode, the 5-year medical costs were £323 higher and QALYs were 0.038 higher for quetiapine compared with olanzapine, corresponding to a cost-effectiveness ratio of £8600 per QALY gained. Abstract: Conclusion:Conclusion: Compared with olanzapine, the results suggest that quetiapine is cost effective as a maintenance treatment for bipolar depression.

Background:Background: Osteoporosis is a common condition and the economic burden of osteoporosis-related fractures is significant. While studies have reported the incremental or attributable costs of osteoporosis-related fracture, data on the economic impact of osteoporosis-related fractures in commercial health plan populations are limited. Abstract: Objective:Objective: To estimate the direct costs of osteoporosis-related fractures among pharmacologically treated patients in a large, commercially insured population between 2005 and 2008. Abstract: Methods:Methods: In this retrospective cohort study, patients were identified from a large, commercially insured population with integrated pharmacy and medical claims. Inclusion criteria were age 45-64 years; one or more osteoporosis medication claim(s) with first (index) claim between 1 January 2005 and 30 April 2008; and continuous insurance coverage for ≥12 months pre-index and ≥6 months post-index. Patients with pre-index Paget's disease or malignant neoplasm; skilled nursing facility stay; combination therapy at index; or fracture ≤6 months post-index were excluded. A generalized linear model compared differences in 6-month pre-/post-event costs for patients with and without fracture. Propensity score weighting was used to ensure comparability of fracture and non-fracture patients. Generalized estimating equations accounted for repeated measures. Abstract: Results:Results: The study included 49 680 patients (2613 with fracture) with a mean (SD) age of 56.4 (4.7) years; 95.9% were female. Mean differences between pre- and post-event direct costs were &dollar;US14 049 (95% CI 7670, 20 428) for patients with vertebral fractures, &dollar;US16 663 (95% CI 11 690, 21 636) for patients with hip fractures, and &dollar;US7582 (95% CI 6532, 8632) for patients with other fractures. After adjusting for covariates, osteoporosis-related fractures were associated with an additional &dollar;US9996 (95% CI 8838, 11 154; p < 0.0001) in direct costs per patient across all fracture types during the 6 months following fracture. Abstract: Conclusion:Conclusion: Patients with osteoporosis-related fractures were found to incur nearly &dollar;US10 000 in estimated additional direct healthcare costs in the 6 months post-fracture, compared with patients with no fracture. Reduced fracture risk may lower associated direct healthcare costs.

Background and Objectives: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. Abstract: Methods: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. Abstract: Results: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 £2099 and £1355 per QALY, respectively, from trial-based incremental cost-effectiveness ratio estimates of £8290 and £7721 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. Abstract: Conclusions: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.

Background:Background: Underuse of controller therapy among Medicaid-enrolled children is common and leads to more emergency department (ED) visits and hospitalizations. However, there is little evidence about the relationship between medication adherence, outcomes and costs once controller therapy is initiated. Abstract: Objective:Objective: This study examined the relationship between adherence to two commonly prescribed anti-inflammatory medications, inhaled corticosteroids (ICS) and leukotriene inhibitors (LI), and healthcare utilization and expenditures among children enrolled in Medicaid and the Children's Health Insurance Program in Florida and Texas in the US. Abstract: Methods:Methods: The sample for this retrospective observational study consisted of 18 456 children aged 2-18 years diagnosed with asthma, who had been continuously enrolled for 24 months during 2004-7 and were on monotherapy with ICS or LI. State administrative enrolment files were linked to medical claims data. Children were grouped into three adherence categories based on the percentage of days per year they had prescriptions filled (medication possession ratio). Bivariate and multivariable regression analyses that adjusted for the children's demographic and health characteristics were used to examine the relationship between adherence and ED visits, hospitalizations, and expenditures. Abstract: Results:Results: Average adherence was 20% for ICS-treated children and 28% for LI-treated children. Children in the highest adherence category had lower odds of an ED visit than those in the lowest adherence category (p < 0.001). We did not detect a statistically significant relationship between adherence and hospitalizations; however, only 3.7% of children had an asthma-related hospitalization. Overall asthma care expenditures increased with greater medication adherence. Abstract: Conclusions:Conclusions: Although greater adherence was associated with lower rates of ED visits, higher medication expenditures outweighed the savings. The overall low adherence rates suggest that quality improvement initiatives should continue to target adherence regardless of the class of medication used. However, low baseline hospitalization rates may leave little opportunity to significantly decrease costs through better disease management, without also decreasing medication costs.

Background:Background: A recent health reform proposal in South Africa proposes universal access to a comprehensive package of healthcare services in the public sector, through the implementation of a national health insurance (NHI) scheme. Implementation of the scheme is likely to involve the introduction of a payroll tax. It is implied that the introduction of the payroll tax will significantly reduce the size of the private health insurance market. Abstract: Objective:Objective: The objective of this study was to estimate the impact of an NHI payroll tax on the demand for private health insurance in South Africa, and to explore the broader implications for health policy. Abstract: Methods:Methods: The study applies probit regression analysis on household survey data to estimate the change in demand for private health insurance as a result of income shocks arising from the proposed NHI. Abstract: Results:Results: The introduction of payroll taxes for the proposed NHI was estimated to result in a reduction to private health insurance membership of 0.73%. This suggests inelasticity in the demand for private health insurance. In the literature on the subject, this inelasticity is usually due to quality differences between alternatives. In the South African context, there may be other factors at play. Abstract: Conclusion:Conclusion: An NHI tax may have a very small impact on the demand for private health insurance. Although additional financial resources will be raised through a payroll tax under the proposed NHI reform, systemic problems within the South African health system can adversely affect the ability of the NHI to translate additional finances into better quality healthcare. If these systemic challenges are not adequately addressed, the introduction of a payroll tax could introduce inefficiencies within the South African health system.

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

Background and Objective:Background and Objective: A probabilistic patient-level Markov model was previously developed to simulate lifetime clinical and economic outcomes of cinacalcet treatment in secondary hyperparathyroidism (SHPT) patients using local data from Italy. The present study extends the application of the model to four other European countries - Spain, Portugal, Switzerland and the Czech Republic - in order to assess the consistency of results. Abstract: Methods:Methods: Cinacalcet influences the levels of parathyroid hormone, serum calcium and phosphorous. Our simulation was based on data from the OPTIMA (Open-Label, Randomized Study Using Cinacalcet to Improve Achievement of KDOQI Targets in Patients with End-Stage Renal Disease) randomized controlled trial and from published correlations between bone-metabolism parameters, mortality and morbidity (cardiovascular &lsqb;CV&rsqb; events, fractures and parathyroidectomy). Local epidemiological and cost data for dialysis, drugs and event management were incorporated into the model. The simulation horizon was patient lifetime; standard treatment for SHPT (vitamin D sterols and phosphate binders) and cinacalcet plus standard treatment were compared. Effectiveness was measured in terms of life expectancy (LE) and quality-adjusted life expectancy (QALE). Health utility indexes derived from published literature took into account dialysis, CV events and fractures. Abstract: Results:Results: The simulated mean LE extension in patients receiving cinacalcet was 1.20 life-years (LY) in Italy, 1.10 LY in Spain, 1.18 LY in Portugal, 1.10 LY in the Czech Republic and 1.40 LY in Switzerland. QALE increase was 0.89, 0.82, 0.89, 0.80 and 1.01 QALY in the same countries, respectively. The incremental cost-effectiveness ratio (ICER) result was &U20AC;23 500/LY and &U20AC;31 600/QALY in Italy, &U20AC;21 800/LY and &U20AC;29 300/QALY in Spain, &U20AC;23 700/LY and &U20AC;31 200/QALY in Portugal, &U20AC;29 700/LY and &U20AC;40 800/QALY in the Czech Republic and &U20AC;24 700/LY and &U20AC;34 200/QALY in Switzerland. Including dialysis costs as a part of the total costing doubled the ICER, from a minimum of &U20AC;42 800/LY in Spain to a maximum of &U20AC;82 800/LY in Switzerland and in the range from &U20AC;57 500/QALY (Spain) to &U20AC;114 700/QALY (Switzerland). Abstract: Conclusion:Conclusion: Taking into consideration the limited clinical, epidemiological and health economics data available, cinacalcet treatment showed a relatively good cost-effectiveness profile in all the countries analysed, despite the differences in their healthcare systems and economic wealth.

In 1997, we published a review in PharmacoEconomics about quality of life (QOL) measurement in patients with schizophrenia. The objective of this article is to provide an update, as well as to revisit the development of the construct of QOL and its measurement as applied to schizophrenia. Since our previous article, there has been significant growth in the number of publications about QOL in schizophrenia. Unfortunately, alongside this significant increase in research interest, a number of concerns have also risen about the limitations and lack of impact the concept of QOL has on clinical care and health-policy decision making. A number of concerns previously outlined (such as lack of consensus on a uniform definition of QOL) continue to be an issue. However, we believe that a uniform definition may not be possible, and instead, it may be preferable to have several definitions, which may enrich the concept and broaden its usefulness. Some of the scales we reviewed in 1997 continue to be in use, while others are now rarely or never used. New scales with better psychometrics have been introduced, but most are without theoretical or conceptual foundation. On the other hand, the field of scaling in general has been changing over the past few years and is moving towards a new approach for scale development, based on item response theory, item banks and computer adaptive testing. Unfortunately, this has not extended to QOL in schizophrenia. There continues to be a dearth of theoretical and conceptual models for QOL in schizophrenia, which seems to create the perception that the construct lacks a good theoretical and scientific foundation. One of the major gaps identified in this review is the recognized lack of impact of QOL measurements on clinical management or policy decision making. The majority of publications continue to focus on measurement rather than what to do with the data. The lack of strategies to integrate QOL data in clinical care, as well as the failure to contribute to policy decisions, particularly in cost analysis or resource allocations, has created the perception that the construct of QOL in schizophrenia is not that useful. It is evident that, for QOL in schizophrenia to regain its promise, researchers must take the ultimate next step beyond measurement: to develop credible strategies for integrating QOL data in clinical practice. Additionally, more focused research is needed to demonstrate the role of QOL, not only as an outcome in itself but also as a contributor to other outcomes, such as adherence to medications, more satisfaction, less resource utilization and so on. Since self-appraisal of QOL does not happen in a vacuum but relates to the total human experience in all its biological, psychosocial and environmental aspects, particular attention must also be focused on important neurobiological dimensions such as affect and cognition. Both are significantly affected by the illness itself and its treatment.

Background: Shared decision making is the process in which a healthcare choice is made jointly by the health professional and the patient. Little is known about what patients view as effective or ineffective strategies to implement shared decision making in routine clinical practice. Objective: This systematic review evaluates the effectiveness of interventions to improve health professionals’ adoption of shared decision making in routine clinical practice, as seen by patients. Data Sources: We searched electronic databases (PubMed, the Cochrane Library, EMBASE, CINAHL, and PsycINFO) from their inception to mid-March 2009. We found additional material by reviewing the reference lists of the studies found in the databases; systematic reviews of studies on shared decision making; the proceedings of various editions of the International Shared Decision Making Conference; and the transcripts of the Society for Medical Decision Making’s meetings. Study Selection: In our study selection, we included randomized controlled trials, controlled clinical trials, controlled before-and-after studies, and interrupted time series analyses in which patients evaluated interventions to improve health professionals’ adoption of shared decision making. The interventions in question consisted of the distribution of printed educational material; educational meetings; audit and feedback; reminders; and patient-mediated initiatives (e.g. patient decision aids). Study Appraisal: Two reviewers independently screened the studies and extracted data. Statistical analyses considered categorical and continuous process measures. We computed the standardized effect size for each outcome at the 95% confidence interval. The primary outcome of interest was health professionals’ adoption of shared decision making as reported by patients in a self-administered questionnaire. Results: Of the 6764 search results, 21 studies reported 35 relevant comparisons. Overall, the quality of the studies ranged from 0% to 83%. Only three of the 21 studies reported a clinically significant effect for the primary outcome that favored the intervention. The first study compared an educational meeting and a patient-mediated intervention with another patient-mediated intervention (median improvement of 74%). The second compared an educational meeting, a patient-mediated intervention, and audit and feedback with an educational meeting on an alternative topic (improvement of 227%). The third compared an educational meeting and a patient-mediated intervention with usual care (p = 0.003). All three studies were limited to the patient-physician dyad. Limitations: To reduce bias, future studies should improve methods and reporting, and should analyze costs and benefits, including those associated with training of health professionals. Conclusions: Multifaceted interventions that include educating health professionals about sharing decisions with patients and patient-mediated interventions, such as patient decision aids, appear promising for improving health professionals’ adoption of shared decision making in routine clinical practice as seen by patients.

Background:Background: Patients are vulnerable to issues that emerge after discharge from the hospital, and this susceptibility is compounded as patients attempt to navigate complex healthcare organizations. Post-discharge clinic appointments may provide the opportunity to mitigate risks posed to patients during this vulnerable time. Abstract: Objective:Objective: Our aim was to determine whether actively engaging patients in scheduling post-discharge appointments before leaving the hospital affects the rate of patients seeing an ambulatory care physician. Abstract: Methods:Methods: This was a prospective cohort pilot study from May to July 2007 with a historical convenience control from 2003. The setting was an inpatient academic tertiary care referral center in the US. Study participants had been discharged from a general medicine hospitalist service during the study time period. Patients, or their designated caregivers, were contacted in hospital rooms to schedule a post-discharge appointment before discharge. The primary outcome was rate of attendance at post-discharge appointments, determined a priori. Abstract: Results:Results: Eighty-three patients with 115 scheduled appointments in the intervention group were compared with 306 patients with 398 appointments in the historical control group. The attendance rate was 59.5% in the control group versus 78.3% in the study group (p < 0.0001). Patients received 1.3 discharge appointments per discharge in both the historical and study group. In a limited evaluation, the study group had a trend towards a lower return rate to the emergency department within 3 days of discharge (1.2% vs 3.8%, nonsignificant), and a lower readmission rate within 14 days of discharge (10.8% vs 11.8%, nonsignificant). Abstract: Conclusion:Conclusion: Our patient-centered process for helping patients arrange their post-discharge appointments before discharge improved the attendance rate at those appointments.

Background:Background: Major orthopaedic surgery, such as total hip replacement (THR) and total knee replacement (TKR), is associated with an increased risk of venous thromboembolism (VTE). Abstract: Objective:Objective: Clinical trials have demonstrated the efficacy of rivaroxaban, a once-daily, orally administered Factor Xa inhibitor, for the prevention of VTE in patients undergoing THR or TKR. This analysis evaluated the cost effectiveness of rivaroxaban compared with enoxaparin, from a US payer's perspective. Abstract: Methods:Methods: A decision-analytic model was developed to compare the costs and outcomes associated with rivaroxaban and enoxaparin for the prevention of VTE. The model replicated short-term clinical outcomes from the phase III RECORD trials. RECORD1 and RECORD2 compared rivaroxaban 10 mg daily (qd), given for 35 days, with enoxaparin 40 mg qd, given for 35 days or 10 to 14 days, respectively, in patients undergoing THR. RECORD3 compared 10 mg of rivaroxaban qd for 10 to 14 days versus 40 mg of enoxaparin qd for 10 to 14 days in patients undergoing TKR. The decision-analytic model also included data on long-term complications and sequelae as captured in observational studies and databases. It also included direct year 2010 medical costs over 1-year and 5-year time horizons. A series of sensitivity analyses were performed to determine the impact of different factors on the results of the model. Results of the cost-effectiveness analysis were reported in terms of symptomatic VTE events avoided. Abstract: Results:Results: Rivaroxaban was associated with cost savings of &dollar;US511.93 per patient and prevented an average of 0.0145 symptomatic VTE events per patient in the THR population, compared with enoxaparin. For a TKR population, 10 to 14 days of rivaroxaban prophylaxis was associated with cost savings of &dollar;US465.74 and prevented an average 0.0193 symptomatic VTE events per patient. Sensitivity analysis suggested that the results of the model were robust, with cost savings ranging from &dollar;US133.96-629.57 in the THR population and &dollar;US293.01-848.68 in the TKR population, depending on the variables used. Sensitivity analysis also suggested that the economic profile of rivaroxaban is improved when the time horizon of the model is extended from 1 year to 5 years. A probabilistic sensitivity analysis confirmed the findings of baseline results, showing that rivaroxaban was less costly and more effective in all model simulations for both populations. Abstract: Conclusions:Conclusions: This decision-analytic model analysis, from the US payer's perspective, concluded that rivaroxaban may be cost saving in both the THR and the TKR populations, when compared with enoxaparin in the US.

Background:Background: In spite of the important progress made in the abortive treatment of acute migraine episodes since the introduction of triptans, reduction of pain and associated symptoms is in many cases still not as effective nor as fast as would be desirable. Recent research pays more attention to the timing of the treatment, and taking triptans early in the course of an attack when pain is still mild has been found more efficacious than the usual strategy of waiting for the attack to develop to a higher pain intensity level. Abstract: Objective:Objective: To investigate the cost effectiveness of early versus non-early intervention with almotriptan in acute migraine. Abstract: Methods:Methods: An economic evaluation was conducted from the perspectives of French society and the French public health system based on patient-level data collected in the AwM (Act when Mild) study, a placebo-controlled trial that compared the response to early and non-early treatment of acute migraine with almotriptan. Incremental cost-effectiveness ratios (ICERs) were determined in terms of QALYs, migraine hours and productive time lost. Costs were expressed in Euros (year 2010 values). Bootstrapping was used to derive cost-effectiveness acceptability curves. Abstract: Results:Results: Early treatment has shown to lead to shorter attack duration, less productive time lost, better quality of life, and is, with 92% probability, overall cost saving from a societal point of view. In terms of drug costs only, however, non-early treatment is less expensive. From the public health system perspective, the (bootstrap) mean ICER of early treatment amounts to &U20AC;0.38 per migraine hour avoided, &U20AC;1.29 per hour of productive time lost avoided, and &U20AC;14 296 per QALY gained. Considering willingness-to-pay values of approximately &U20AC;1 to avoid an hour of migraine, &U20AC;10 to avoid the loss of a productive hour, or &U20AC;30 000 to gain one QALY, the approximate probability that early treatment is cost effective is 90%, 90% and 70%, respectively. These results remain robust in different scenarios for the major elements of the economic evaluation. Abstract: Conclusions:Conclusions: Compared with non-early treatment, a strategy of early treatment of acute migraine with almotriptan when pain is still mild is, with high probability, cost saving from the French societal perspective and can be considered cost effective from the public health system point of view.

Objectives:Objectives: Our objective was to evaluate the potential usefulness of the Kano conceptual model to assess expectations of patients and neurologists in Spain regarding symptomatic migraine treatment. Abstract: Methods:Methods: We performed a multicenter, cross-sectional study in adult migraine patients with at least 1 year of disease evolution and at least one prescription of anti-migraine drugs within the last year. Data collection was performed using questionnaires that included sociodemographic and treatment expectations. Using Kano's methodology, treatment attributes were classified as the following: Must-be; One-dimensional; Attractive; Indifferent; Reverse; or Questionable. Abstract: Results:Results: A total of 204 migraine patients (mean age 39.2 years &lsqb;SD 11.9&rsqb;; 84.6% women) and 68 neurologists (mean age 44 years &lsqb;SD 8.8&rsqb;; 63.2% men) were surveyed. None of the treatment attributes evaluated by the patients showed a dominant Must-be feature. Among patients and neurologists, the attributes that led to a greater dissatisfaction when absent and that were ranked as the three most important attributes were those related to treatment safety (absence of long-term adverse effects), efficacy (pain relief achievement), and quality of life (possibility of resuming occupational or academic activities). Differences in attributes' classification were noted among patients and neurologists. The attribute that was considered most important by the patients was achievement of total disappearance of pain, whereas for neurologists the most important attribute was absence of long-term adverse effects. Abstract: Conclusions:Conclusions: Kano's methodology is a useful tool to analyze differences in migraine treatment expectations among patients and neurologists. The main difference between patients and neurologists related to basic priorities. Therefore, when selecting treatment for migraine, physicians should invite the patient to participate in the decision making of which treatment is more appropriate.

Background:Background: Vertebral compression fractures (VCFs) can be treated by nonsurgical management or by minimally invasive surgical treatment including vertebroplasty and balloon kyphoplasty. Abstract: Objective:Objective: The purpose of the present study was to characterize the cost to Medicare for treating VCF-diagnosed patients by nonsurgical management, vertebroplasty, or kyphoplasty. We hypothesized that surgical treatments for VCFs using vertebroplasty or kyphoplasty would be a cost-effective alternative to nonsurgical management for the Medicare patient population. Abstract: Methods:Methods: Cost per life-year gained for VCF patients in the US Medicare population was compared between operated (kyphoplasty and vertebroplasty) and non-operated patients and between kyphoplasty and vertebroplasty patients, all as a function of patient age and gender. Life expectancy was estimated using a parametric Weibull survival model (adjusted for comorbidities) for 858 978 VCF patients in the 100% Medicare dataset (2005-2008). Median payer costs were identified for each treatment group for up to 3 years following VCF diagnosis, based on 67 018 VCF patients in the 5% Medicare dataset (2005-2008). A discount rate of 3% was used for the base case in the cost-effectiveness analysis, with 0% and 5% discount rates used in sensitivity analyses. Abstract: Results:Results: After accounting for the differences in median costs and using a discount rate of 3%, the cost per life-year gained for kyphoplasty and vertebroplasty patients ranged from &dollar;US1863 to &dollar;US6687 and from &dollar;US2452 to &dollar;US13 543, respectively, compared with non-operated patients. The cost per life-year gained for kyphoplasty compared with vertebroplasty ranged from -&dollar;US4878 (cost saving) to &dollar;US2763. Abstract: Conclusions:Conclusions: Among patients for whom surgical treatment was indicated, kyphoplasty was found to be cost effective, and perhaps even cost saving, compared with vertebroplasty. Even for the oldest patients (85 years of age and older), both interventions would be considered cost effective in terms of cost per life-year gained.

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE's single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer's cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11,111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Background: Patients with gallbladder and common bile duct stones are generally treated by pre-operative endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (POES). Recently, a meta-analysis has shown that intra-operative ES during laparoscopic cholecystectomy (IOES) results in fewer complications than POES, with similar efficacy. The cost effectiveness of IOES versus POES is unknown. Objective: The objective of this study was to compare the cost effectiveness of IOES versus POES from the UK NHS perspective. Methods: A decision-tree model estimating and comparing costs to the UK NHS and QALYs gained following a policy of either IOES or POES was developed with a time horizon of 3 years. Uncertainty was investigated with probabilistic sensitivity analysis, and the expected value of perfect information (EVPI) and partial information (EVPPI) were also calculated. Results: IOES was less costly than POES (approximately -£623 per patient &lsqb;year 2008 values&rsqb;) and resulted in similar quality of life (+0.008 QALYs per patient) as POES. Given a willingness-to-pay threshold of £20 000 per QALY gained, there was a 92.9% probability that IOES is cost effective compared with POES. Full implementation of IOES could save the NHS £2.8 million per annum. At a willingness to pay of £20 000 per QALY gained, the 10-year population EVPI was estimated at £0.6 million. Conclusions: IOES appears to be cost effective compared with POES.

Background:Background: Patient and public participation in health technology assessment (HTA) of medicines has been cited as an important component of the decision-making structure; however, how to actually achieve meaningful involvement is less understood. Abstract: Objectives:Objectives: Our objectives were to conduct a pilot study to form the basis of future research and to gain insight into how to practically and meaningfully advance patient and public input in HTAs for medicines. Abstract: Methods:Methods: Semi-structured interviews (n - 13) with informants in Australia (n - 7), Canada (n - 3), and the UK (n - 3) were conducted across agencies and experts (n - 9), as well as patient and advocacy groups (n - 4). Abstract: Results:Results: This pilot study identified through structured interviews three areas for further consideration. Advancement area 1 indicates that industry could help bring the patient perspective into the HTA process through incorporating patient experiences early in the drug development process and by including qualitative research on patient experiences in HTA dossiers. Advancement area 2 involves recognizing and supporting the role of patient advocacy groups, and making use of their access to the genuine patient perspective and experience of living with the condition in question. Finally, advancement area 3 is the continuous development of HTA systems and processes to better facilitate involvement, increasing transparency and feedback, exploring new options for reaching patients, and focusing on creating an active and informed health consumer. Abstract: Conclusions:Conclusions: The HTA process is becoming increasingly transparent to patients and the public; however, more effort is required to fully engage patients in the decision-making processes for medicine HTAs. This pilot study identified three key areas for further advancement in this field, and recognized a need for further research in the areas of measuring the impact of patient engagement on decision making in medicine HTAs, as well as the best methods to better prepare patient advocacy groups through HTA education and training. These research recommendations will form the basis of a future study with a larger, more comprehensive sample.

Background:Background: Assessment of health state and health-related quality of life (HR-QOL) are limited by a child's age and cognitive ability. Parent-proxy reports are known to differ from children's reports. Simultaneous assessment using a parent-child dyad is an alternative approach. Abstract: Objective:Objective: Our objective was to assess the validity, reliability and responsiveness of a parent-child dyad approach to utility and HR-QOL assessment of paediatric asthma health states. Abstract: Methods:Methods: The setting was specialist care in a hospital-based asthma clinic. Participants were 91 girls and boys with asthma aged 8 to 17 years and 91 parents. The intervention employed was parent-child dyad administration of the Health Utilities Index (HUI) 2 and 3, the Pediatric Quality of Life Inventory™ (PedsQL™) Core and Asthma modules, and the Pediatric Asthma Quality of Life Questionnaire (PAQLQ). Questionnaires were administered by interview to children and parents separately and then together as a dyad to assess the child's health state. The dyad interview was repeated at the next clinic visit. Dyad-child agreement was measured by intra-class correlation (ICC) coefficient; Spearman correlations were used to assess convergent validity. Test-retest reliability was assessed in 28 children who remained clinically stable between visits with a two-way ICC coefficient. Responsiveness to change from baseline was assessed with Spearman coefficients in 30 children who demonstrated clinical change between visits. Abstract: Results:Results: There was no significant agreement between parent and child for the HUI2 or HUI3 whereas agreement between dyad and child was 0.55 (95% confidence interval &lsqb;CI&rsqb; 0.36, 0.69) for the HUI2 and 0.74 (95% CI 0.61, 0.82) for the HUI3 overall. With respect to dyad performance characteristics, both HUI2 and HUI3 overall scores demonstrated moderate convergent validity with the generic PedsQL™ Core domains (range r - 0.30-0.52; p < 0.01). Dyad HUI2 attributes demonstrated moderate convergent validity with the generic PedsQL™ Core domains of similar constructs (range r - 0.35-0.43; p < 0.001) and weaker convergent validity with disease-specific domains (range r - 0.13-0.32). Dyad HUI3 attributes demonstrated weaker convergent validity compared with the HUI2. For the assessment of test-retest reliability, significant agreement between baseline and follow-up was observed for dyad HUI2 total (r - 0.53), dyad PedsQL™ Core summary (r - 0.70) and select dyad disease-specific domains. Significant responsiveness (r > 0.4; p < 0.05) was observed for dyad HUI2 total score change over time as correlated with dyad HUI3, dyad PedsQL™ Core summary and select disease-specific domains. Abstract: Conclusions:Conclusions: The parent-child dyad approach demonstrated moderate to strong performance characteristics in generic and disease-specific questionnaires suggesting it may be a valuable alternative to relying on parent proxies for assessing children's utility and HR-QOL. Future research in additional paediatric populations, younger children and a population-based sample would be useful.

Osteoporotic fractures are costly in terms of both the dollar amount and healthcare utilization. The objective of this review was to systematically synthesize published evidence regarding direct costs associated with the treatment of osteoporosis-related fractures in the US. We conducted a systematic literature review of published studies that used claims databases and economic studies reporting costs associated with osteoporosis-related fractures in the US. Studies published between 1990 and 2011 were systematically searched in PubMed (primary source), Ovid HealthSTAR, EMBASE and the websites of large agencies. Data concerning study design, patient population and cost components assessed were extracted with qualitative assessment of study methods, limitations and conclusions. Cost assessment included direct medical and hospitalization (inpatient) costs. The cost differences by age and gender were examined. Of the 33 included studies, 26 reported an estimated total medical cost and hospital resource use associated with osteoporotic fractures. These studies indicated that, in the year following a fracture, medical and hospitalization costs were 1.6-6.2 higher than pre-fracture costs and 2.2-3.5 times higher than those for matched controls. Analysis of the hospitalization costs by osteoporotic fracture type resulted in hip fractures identified as the most expensive fracture type (unit cost range &dollar;US8358-32 195), while wrist and forearm fractures were the least expensive (unit cost range &dollar;US1885-12 136). Although incremental fracture costs were generally lower in the elderly than in the younger population, total costs were highest for the older (≥65 years of age) population. Total healthcare costs for fractures were highest for the older female population, but unit fracture costs in women were not consistently found to be higher than for men. The qualitative assessment of the included studies demonstrated that the design and reporting of individual studies were of good quality. However, the findings of this review and comparisons across studies were limited by differences in methodologies used by the different studies to derive costs, the populations included in the studies used and the fracture assessment. Despite the variability in estimates, the literature indicates that osteoporosis-related fractures are associated with high total medical and hospitalization costs in the US. The variability in the cost estimates highlights the importance of comparing the methodologies and the types of costs used when choosing an appropriate unit cost for economic modelling.

Background:Background: Male circumcision (MC) has become an important weapon in the fight against HIV/AIDS in many Sub-Saharan African countries. The successful implementation of a national MC program requires the design of circumcision services that are attractive to young men of various ages. For many potential clients, mothers and/or fathers will play an important role in the decision to be circumcised, and hence services will need to be designed with the preferences of mothers, fathers, and sons in mind. Abstract: Objective:Objective: Our objective was to value multiple design characteristics of potential community-based MC services from the perspectives of mothers, fathers, and sons in Johannesburg, South Africa, and to test for concordance between their values for the design characteristics. Abstract: Methods:Methods: Potential design characteristics of MC services were identified through open-ended interviews with key informants (n - 25). Preferences were estimated using conjoint analysis implemented as part of a cluster randomized household survey. Each participant was randomized to receive one of two possible blocks of conjoint analysis, each consisting of six forced-choice tasks comparing two possible MC services varying on 11 design characteristics. With only two levels for each attribute, our experimental design utilized a main effects orthogonal array. Data were analyzed using linear probability models, with tests of concordance of values using Wald tests generated from stratified estimates calculated using restricted least square estimation. Abstract: Results:Results: A racially and geographically diverse sample consisting of 204 fathers, 204 mothers, and 237 sons completed the survey. In aggregate, requiring a follow-up visit was the most valued design factor (p < 0.001), followed by having a lower infection rate (p < 0.001), having less pain (p - 0.001), and a private waiting room (p - 0.001). Based on stratified analysis, sons also valued having the risks and benefits of MC explained (p - 0.01) and mothers valued requiring an HIV test as part of the procedure. Requiring an HIV test was the most significant difference between the respondents (p - 0.03), with sons finding it somewhat repulsive (p - 0.30). Abstract: Conclusion:Conclusion: Our findings suggest that valuation of aspects of MC clinic design can diverge by decision maker. To better ensure utilization of services, these variations should be taken into account to prior to implementation of a national strategy in South Africa.

Background:Background: With growing emphasis on patient involvement in health technology assessment, there is a need for scientific methods that formally elicit patient preferences. Analytic hierarchy process (AHP) and conjoint analysis (CA) are two established scientific methods - albeit with very different objectives. Abstract: Objective:Objective: The objective of this study was to compare the performance of AHP and CA in eliciting patient preferences for treatment alternatives for stroke rehabilitation. Abstract: Methods:Methods: Five competing treatments for drop-foot impairment in stroke were identified. One survey, including the AHP and CA questions, was sent to 142 patients, resulting in 89 patients for final analysis (response rate 63%). Standard software was used to calculate attribute weights from both AHP and CA. Performance weights for the treatments were obtained from an expert panel using AHP. Subsequently, the mean predicted preference for each of the five treatments was calculated using the AHP and CA weights. Differences were tested using non-parametric tests. Furthermore, all treatments were rank ordered for each individual patient, using the AHP and CA weights. Abstract: Results:Results: Important attributes in both AHP and CA were the clinical outcome (0.3 in AHP and 0.33 in CA) and risk of complications (about 0.2 in both AHP and CA). Main differences between the methods were found for the attributes 'impact of treatment' (0.06 for AHP and 0.28 for two combined attributes in CA) and 'cosmetics and comfort' (0.28 for two combined attributes in AHP and 0.05 for CA). On a group level, the most preferred treatments were soft tissue surgery (STS) and orthopedic shoes (OS). However, STS was most preferred using AHP weights versus OS using CA weights (p < 0.001). This difference was even more obvious when interpreting the individual treatment ranks. Nearly all patients preferred STS according to the AHP predictions, while >50% of the patients chose OS instead of STS, as most preferred treatment using CA weights. Abstract: Conclusion:Conclusion: While we found differences between AHP and CA, these differences were most likely caused by the labeling of the attributes and the elicitation of performance judgments. CA scenarios are built using the level descriptions, and hence provide realistic treatment scenarios. In AHP, patients only compared less concrete attributes such as 'impact of treatment.' This led to less realistic choices, and thus overestimation of the preference for the surgical scenarios. Several recommendations are given on how to use AHP and CA in assessing patient preferences.

Background:Background: Discrete choice experiments (DCEs) and the Juster scale are accepted methods for the prediction of individual purchase probabilities. Nevertheless, these methods have seldom been applied to a social decision-making context. Abstract: Objective:Objective: To gain an overview of social decisions for a decision-making population through data triangulation, these two methods were used to understand purchase probability in a social decision-making context. Abstract: Methods:Methods: We report an exploratory social decision-making study of pharmaceutical subsidy in Australia. A DCE and selected Juster scale profiles were presented to current and past members of the Australian Pharmaceutical Benefits Advisory Committee and its Economic Subcommittee. Abstract: Results:Results: Across 66 observations derived from 11 respondents for 6 different pharmaceutical profiles, there was a small overall median difference of 0.024 in the predicted probability of public subsidy (p - 0.003), with the Juster scale predicting the higher likelihood. While consistency was observed at the extremes of the probability scale, the funding probability differed over the mid-range of profiles. There was larger variability in the DCE than Juster predictions within each individual respondent, suggesting the DCE is better able to discriminate between profiles. However, large variation was observed between individuals in the Juster scale but not DCE predictions. Abstract: Conclusions:Conclusions: It is important to use multiple methods to obtain a complete picture of the probability of purchase or public subsidy in a social decision-making context until further research can elaborate on our findings. This exploratory analysis supports the suggestion that the mixed logit model, which was used for the DCE analysis, may fail to adequately account for preference heterogeneity in some contexts.

Background: Around 0.4 million cases of multidrug-resistant tuberculosis (MDR-TB) occur each year. Only a small fraction of these cases are treated according to international guidelines. Evidence relevant to decisions about whether to scale-up treatment for MDR-TB includes cost and cost-effectiveness data. Up to 2010, no systematic review of this evidence has been available. Objective: Our objective was to conduct a systematic review of the cost and cost effectiveness of treatment for MDR-TB and synthesize the available data. Methods: We searched for papers published or prepared for publication in peer-review journals and grey literature using search terms in five languages: English, French, Portuguese, Russian and Spanish. From an initial set of 420 studies, four were included, from Peru, the Philippines, Estonia and Tomsk Oblast in the Russian Federation. Results on costs, effectiveness and cost effectiveness were extracted. Assessment of the quality of each economic evaluation was guided by two existing checklists around which there is broad consensus. Costs were adjusted to a common year of value (2005) to remove distortions caused by inflation, and calculated in two common currencies: &dollar;US and international dollars (I&dollar;), to standardize for purchasing power parity. Data from the four identified studies were then synthesized using probabilistic sensitivity analysis, to appraise the likely cost and cost effectiveness of MDR-TB treatment in other settings, relative to WHO benchmarks for assessing whether or not an intervention is cost effective. Best estimates are provided as means, with 5th and 95th percentiles of the distributions. Results: The cost per patient for MDR-TB treatment in Estonia, Peru, the Philippines and Tomsk was &dollar;US10 880, &dollar;US2423, &dollar;US3613 and &dollar;US14 657, respectively. Best estimates of the cost per disability-adjusted life-year (DALY) averted were &dollar;US598 (I&dollar;960), &dollar;US163 (I&dollar;291), &dollar;US143 (I&dollar;255) and &dollar;US745 (I&dollar;1059), respectively. The main influences on costs were (i) the model of care chosen (the extent to which hospitalization or ambulatory care were relied upon) and (ii) the second-line drugs included in the treatment regimen. When extrapolated to other settings, the best estimate of the cost of treatment varied from US3401 to US195 078, depending on the region and model of care. The cost per DALY averted was lower than GDP per capita in all 14 WHO sub-regions considered, with better cost effectiveness for outpatient versus inpatient models of care. Conclusions: Treatment for MDR-TB can be cost effective in low- and middle-income countries. Evidence about the relative cost effectiveness of outpatient versus inpatient models of care is limited and more data are needed from Africa and Asia - especially India and China, which have the largest number of cases. Unless there is strong evidence that hospitalization is necessary to achieve high rates of adherence to treatment, patients with MDR-TB should be treated using mainly ambulatory care.

Background:Background: Many statistical analyses, clinical trials and cost-utility analyses designed to measure the impact of a particular disease on utility scores often overlook the important influence of co-morbidity burden. Abstract: Objectives:Objectives: This study aims to examine the impact of co-morbidity burden on EQ-5D index scores in a nationally representative sample of the US. Abstract: Methods:Methods: The pooled 2001 and 2003 Medical Expenditure Panel Survey was used. The total number of chronic conditions for each individual was calculated based on Clinical Classification Categories codes. Spline regression was used to identify nonlinear age effects: individuals were separated into four quartiles based on age. Censored least absolute deviation was used to regress EQ-5D index scores on age and chronic co-morbidity, controlling for income, gender, race, ethnicity, education, physical activity and smoking status. Interactions between age and chronic conditions were also explored. Abstract: Results:Results: The coefficients for chronic co-morbidities were highly statistically significant with large magnitudes for those with two or more chronic conditions (coefficient two chronic conditions - -0.16; coefficient nine chronic conditions - -0.28). After controlling for chronic co-morbidities and other confounders, age was not statistically significant except for those aged >58 years and the magnitude of this coefficient was very small (coefficient aged >58 years - -0.0006). The interactions between age and chronic co-morbidity were significant, but the deleterious impact of their interaction was largely dominated by the existence and number of chronic conditions. Abstract: Conclusions:Conclusions: Chronic conditions have a significant deleterious impact on EQ-5D index scores that is much more pronounced than age and other sociodemographic and behavioural characteristics. Future analyses and cost-utility models should incorporate the impact of multiple morbidity.

While no single type of model can provide adequate answers under all circumstances, any modelling endeavour should incorporate three fundamental considerations in any decision-making question: the target population, the disease and the intervention characteristics. A target population is likely to be characterized by various types of heterogeneity and a dynamic evolution over time. It is therefore important to adequately capture these population effects on the results of a model. There are essentially two different approaches in modelling a population over time: a cohort-based approach and a population-based approach. In a cohort-based model, a closed group of individuals who have at least one specific characteristic or experience in common over a defined period of time is run through a state transition process. The cohort is generally composed of a hypothetical number of representative or 'average' individuals (i.e. the target population is considered to be a homogeneous group). The population-based approach projects the evolution of the estimated prevalent target population and intends to reflect as much as possible the demographic, epidemiological and clinical characteristics of the prevalent target population relevant for the decision problem. A cohort-based approach is generally used in most published healthcare decision models. However, this choice is rarely discussed by modellers. In this article, we challenge this assumption. To address the underlying decision problem, we affirm it is crucial that modellers consider the characteristics of the target population. Then, they could opt for using the most appropriate approach. Decision makers should also understand the impact on the results of both types of models in order to make informed healthcare decisions.

Background:Background: The monoclonal antibody rituximab has shown clinical effectiveness in combination with chemotherapy for the treatment of non-Hodgkin's lymphoma (NHL) in several randomized controlled studies. Rituximab maintenance therapy is associated with significant improvement in progression-free and overall survival in patients with NHL. However, treatment with rituximab causes considerable costs for healthcare systems. Abstract: Objective:Objective: This article provides an overview of economic evaluations of rituximab and appraises their methodological quality. Abstract: Methods:Methods: A systematic literature search of cost-effectiveness studies on rituximab was carried out in nine electronic databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR), the German Agency of Health Technology Assessment (DAHTA) database, German Institute for Quality Improvement (DIQ)-Literatur, DIQ-Projekte, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessments (HTA) database and Sozialmedizin (SOMED) &lsqb;languages: English, German, Dutch, French, Spanish and Italian; publication period: 1998 to 2010&rsqb;. Based on pre-specified inclusion criteria, cost-effectiveness studies were identified that compared standard chemotherapy with standard chemotherapy plus rituximab in patients with a subtype of NHL. The methodological quality of the studies was assessed using a quality checklist. Abstract: Results:Results: Fourteen economic evaluations from seven different countries were included in the review. All economic evaluations reported incremental cost-effectiveness ratios (ICERs) for the add-on therapy with rituximab that were below the country-specific thresholds. The studies differed significantly in their characteristics and methodological rigour. Most studies lacked transparency regarding identification and justification of data. In several studies, the rationale for the model structure was not described appropriately. Abstract: Conclusion:Conclusion: Adding rituximab to standard chemotherapy is considered a cost-effective treatment option for NHL. However, the results of the analyses should be interpreted with caution due to methodological limitations.

Background:Background: The credibility of contingent valuation studies has been questioned because of the potential occurrence of scope insensitivity, i.e. that respondents do not react to higher quantities or qualities of a good. Abstract: Objective:Objective: The aim of this study was to examine the extent of scope insensitivity and to assess the relevance of potential explanations that may help to shed light on how to appropriately handle this problem in contingent valuation studies. Abstract: Methods:Methods: We surveyed a sample of 2004 men invited for cardiovascular disease screening. Each respondent had three contingent valuation tasks from which their sensitivity to larger risk reductions (test 1) and to change in travel costs associated with participation (test 2) could be assessed. Participants were surveyed while waiting for their screening session. Non-participants were surveyed by postal questionnaire. Abstract: Results:Results: The sample was overall found to be sensitive to scope, testing at the conventional sample-mean level. At the individual respondent level, however, more than half of the respondents failed the tests. Potential determinants for failing the tests were examined in alternative regression models but few consistent relationships were identified. One exception was the influence of more detailed information, which was positively associated with willingness to pay and negatively associated with scope sensitivity. Abstract: Conclusion:Conclusion: Possible explanations for scope insensitivity are discussed; if cognitive limitations, emotional load and mental budgeting explain scope insensitivity there are grounds for rejecting valuations, whereas other factors such as the alternative theoretical framework of regret theory may render insensitivity to scope a result of rational thinking. It is concluded that future contingent valuation studies should focus more on extracting the underlying motives for the stated preferences in order to appropriately deal with responses that are seemingly irrational, and which may lead to imprecise welfare estimates.

Previous application of value-of-information methods to optimal clinical trial design have predominantly taken a societal decision-making perspective, implicitly assuming that healthcare costs are covered through public expenditure and trial research is funded by government or donation-based philanthropic agencies. In this paper, we consider the interaction between interrelated perspectives of a societal decision maker (e.g. the National Institute for Health and Clinical Excellence &lsqb;NICE&rsqb; in the UK) charged with the responsibility for approving new health interventions for reimbursement and the company that holds the patent for a new intervention. We establish optimal decision making from societal and company perspectives, allowing for trade-offs between the value and cost of research and the price of the new intervention. Given the current level of evidence, there exists a maximum (threshold) price acceptable to the decision maker. Submission for approval with prices above this threshold will be refused. Given the current level of evidence and the decision maker's threshold price, there exists a minimum (threshold) price acceptable to the company. If the decision maker's threshold price exceeds the company's, then current evidence is sufficient since any price between the thresholds is acceptable to both. On the other hand, if the decision maker's threshold price is lower than the company's, then no price is acceptable to both and the company's optimal strategy is to commission additional research. The methods are illustrated using a recent example from the literature.

Background:Background: Hereditary angioedema (HAE) is a rare, debilitating, potentially life-threatening condition characterized by recurrent acute attacks of edema of the skin, face/upper airway, and gastrointestinal and urogenital tracts. During a laryngeal attack, people with HAE may be at risk of suffocation, while other attacks are often associated with intense pain, disfigurement, disability, and/or vomiting. The intensity of some symptoms is known only to the person experiencing them. Thus, interview studies are needed to explore such experience and patient-reported outcome measures (PROMs) are required for systematic assessment of symptoms in the clinical setting and in clinical trials of treatments for acute HAE attacks. Abstract: Objective:Objective: The aim of this interview study was to assess the content validity and suitability of four visual analog scale (VAS) instruments for use in clinical studies. The VAS instruments were designed to assess symptoms at abdominal, oro-facial-pharyngeal-laryngeal, peripheral, and urogenital attack locations. This is the first known study to report qualitative data about the patient's experience of the rare disorder, HAE. Abstract: Methods:Methods: Semi-structured exploratory and cognitive debriefing interviews were conducted with 27 adults with a confirmed clinical/laboratory diagnosis of HAE (baseline plasma level of functional plasma protein C1 esterase inhibitor &lsqb;C1INH&rsqb

Background:Background: Granulocyte-colony stimulating factor (G-CSF) reduces the risk of severe neutropenia associated with chemotherapy, but its cost implications following chemotherapy are unknown. Abstract: Objective:Objective: Our objective was to examine associations between G-CSF use and medical costs after initial adjuvant chemotherapy in early-stage (stage I-III) breast cancer (ESBC). Abstract: Methods:Methods: Women diagnosed with ESBC from 1999 to 2005, who had an initial course of chemotherapy beginning within 180 days of diagnosis and including ≥1 highly myelosuppressive agent, were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare claims were used to describe the initial chemotherapy regimen according to the classes of agents used: anthracycline (&lsqb;A&rsqb;: doxorubicin or epirubicin); cyclophosphamide (C); taxane (&lsqb;T&rsqb;: paclitaxel or docetaxel); and fluorouracil (F). Patients were classified into four study groups according to their G-CSF use: (i) primary prophylaxis, if the first G-CSF claim was within 5 days of the start of the first chemotherapy cycle; (ii) secondary prophylaxis, if the first claim was within 5 days of the start of the second or subsequent cycles; (iii) G-CSF treatment, if the first claim occurred outside of prophylactic use; and (iv) no G-CSF. Patients were described by age, race, year of diagnosis, stage, grade, estrogen (ER) and progesterone (PR) receptor status, National Cancer Institute (NCI) Co-morbidity Index, chemotherapy regimen and G-CSF use. Total direct medical costs (&dollar;US, year 2009 values) to Medicare were estimated from 4 weeks after the last chemotherapy administration up to 48 months. Medical costs included those for ESBC treatment and all other medical services received after chemotherapy. Least squares regression, using inverse probability weighting (IPW) to account for censoring within the cohort, was used to evaluate adjusted associations between G-CSF use and costs. Abstract: Results:Results: A total of 7026 patients were identified, with an average age of 72 years, of which 63% had stage II disease, and 59% were ER and/or PR positive. Compared with no G-CSF, those receiving G-CSF primary prophylaxis were more likely to have stage III disease (30% vs 16%; p < 0.0001), to be diagnosed in 2003-5 (87% vs 26%; p < 0.0001), and to receive dose-dense AC-T (26% vs 1%; p < 0.0001), while they were less likely to receive an F-based regimen (12% vs 42%; p < 0.0001). Overall, the estimated average direct medical cost over 48 months after initial chemotherapy was &dollar;US42 628. In multivariate analysis, stage II or III diagnosis (compared with stage I), NCI Co-morbidity Index score 1 or ≥2 (compared with 0), or FAC or standard AC-T (each compared with AC) were associated with significantly higher IPW 48-month costs. Adjusting for patient demographic and clinical factors, costs in the G-CSF primary prophylaxis group were not significantly different from those not receiving primary prophylaxis (the other three study groups combined). In an analysis that included four separate study groups, G-CSF treatment was associated with significantly greater costs (incremental cost - &dollar;US2938; 95% CI 285, 5590) than no G-CSF. Abstract: Conclusions:Conclusions: Direct medical costs after initial chemotherapy were not statistically different between those receiving G-CSF primary prophylaxis and those receiving no G-CSF, after adjusting for potential confounders.

This paper investigates the contribution of pharmaceutical innovation to recent longevity growth in Germany and France. The effect of the vintage of prescription drugs (and other variables) on the life expectancy and age-adjusted mortality rates of residents of Germany is examined, using longitudinal, annual, state-level data during the period 2001-7. The estimates imply that about one-third of the 1.4-year increase in German life expectancy during the period 2001-7 was due to the replacement of older drugs by newer drugs. The effect of the vintage of chemotherapy treatments on age-adjusted cancer mortality rates of residents of France is also investigated, using longitudinal, annual, cancer-site-level data during the period 2002-6. The estimates imply that chemotherapy innovation accounted for at least one-sixth of the decline in French cancer mortality rates, and may have accounted for as much as half of the decline.

Background:Background: The benefit of unfractionated heparin (UFH) added to aspirin in patients with acute coronary syndromes (ACS) was described more than 20 years ago. Ever since, a wide variety of anticoagulant drugs have become available for clinical use, including low-molecular-weight heparins (LMWH), direct thrombin inhibitors and selective factor Xa inhibitors. Abstract: Objective:Objective: The aim of this study was to critically review the available evidence on the cost and incremental cost effectiveness of anticoagulants in patients with ACS. Abstract: Methods:Methods: Studies were identified using specialist databases (UK NHS Economic Evaluation Database &lsqb;NHS EED&rsqb; and Cost-Effectiveness Analysis &lsqb;CEA&rsqb; Registry), PubMed and the reference lists of recovered articles. Only studies based on randomized controlled trials were considered for inclusion. Finally, 22 studies were included in the review. Abstract: Results:Results: Enoxaparin is the only LMWH that has been shown to reduce the risk of death or myocardial infarction in patients with non-ST-elevation ACS (NSTE-ACS). In economic studies based on the ESSENCE trial conducted in the late 1990s, enoxaparin was consistently associated with a lower risk of coronary events, a reduction in the number of revascularization procedures and a lower cost per patient than UFH. However, these results refer to patients managed conservatively, with little use of thienopyridines and glycoprotein IIb/IIIa inhibitors, and the results are difficult to extrapolate to moderate-to-high-risk patients managed with the present day early invasive strategy. Available studies of LMWH in ACS with persistent elevation of ST-segment (STE-ACS) are limited to patients treated with thrombolysis. In this scenario, enoxaparin was shown to be a dominant alternative compared with UFH in a study based on the ASSENT-3 study and was considered an economically attractive alternative in three studies based on the ExTRACT-TIMI 25 study. However, these results should be interpreted cautiously due to the heterogeneity of the supportive randomized trials and the possible underestimation of bleeding costs. The effectiveness and safety of bivalirudin, a direct thrombin inhibitor, were evaluated in the ACUITY study (NSTE-ACS patients managed invasively) and the HORIZONS-AMI study (STE acute myocardial infarction patients planned for primary percutaneous coronary intervention). Bivalirudin monotherapy was not inferior to heparin plus a glycoprotein IIb/IIIa inhibitor and reduced the risk of major bleeding. The economic evaluations based on these studies suggest that bivalirudin is an attractive alternative to heparin plus a glycoprotein-IIb/IIIa inhibitor. In the OASIS-5 trial, compared with enoxaparin, fondaparinux reduced the mortality in patients with NSTE-ACS, probably because of a reduced risk of bleeding. In three economic evaluations of fondaparinux versus enoxaparin based on this trial, fondaparinux was the dominant strategy in two of them, and still economically attractive in a third. Taken as a whole, the usefulness of economic studies of anticoagulants in patients with ACS is undermined by the quality of the evidence about their effectiveness and safety; the narrow spectrum of the analysed scenarios; the lack of economic evaluations based on systematic reviews; the limitations of sensitivity analyses reported by the available economic evaluations; and their substantial risk of commercial bias. Abstract: Conclusions:Conclusions: The available studies suggest that enoxaparin is an economically attractive alternative compared with UFH in patients with NSTE-ACS treated conservatively and STE-ACS patients treated with thrombolysis. Bivalirudin in patients with ACS treated invasively is cost effective compared with heparin plus a glycoprotein IIb/IIIa inhibitor. In patients with NSTE-ACS, fondaparinux is cost effective compared with enoxaparin. The usefulness of these results for decision making in contemporary clinical practice is limited due to problems of internal and external validity.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of bevacizumab (Roche Products) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with metastatic colorectal cancer (mCRC), as part of the Institute's Single Technology Appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology provided within the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a phase III, multicentre, multinational, two-arm, randomized, open-label study with the primary objective of confirming the non-inferiority of oxaliplatin plus capecitabine (XELOX) compared with oxaliplatin plus 5-fluorouracil and folinic acid (FOLFOX-4) in adult patients with histologically confirmed mCRC who had not previously been treated. The ERG considered that the NO16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free and overall survival when bevacizumab is added to either XELOX or FOLFOX-4. The ERG considered that the size of the actual treatment effect of bevacizumab was uncertain due to trial design limitations, imbalance of a known prognostic factor, relatively short treatment duration compared with that allowed within the trial protocol, and interpretation of the statistical analyses. The manufacturer's submission included a de novo economic evaluation using a cost-effectiveness model built in Microsoft® Excel. The ERG believed that the modelling structure employed was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratios (ICERs). The areas of uncertainty identified by the ERG included whether chemotherapy would be administered continuously or intermittently, patient access scheme (PAS) costs and uptake, survival that was dependent on the statistical analyses used, and the likely duration of continued treatment with bevacizumab after cessation of oxaliplatin and the efficacy associated with continuation. The STA described here highlighted the challenges in appraising interventions with a complex PAS. Based on the analyses that include a discount to the list price of oxaliplatin, the ERG concluded that the ICERs for the addition of bevacizumab to XELOX or FOLFOX were both over £50 000. The NICE Appraisal Committee concluded that bevacizumab in combination with oxaliplatin and either 5-fluorouracil plus folinic acid or capecitabine (i.e. FOLFOX or XELOX) was not recommended for the treatment of mCRC.

Comparative effectiveness research is expected to play an important role in future clinical and policy decision making in the US; however, the application of comparative effectiveness methodologies to child health requires special attention to aspects of health and healthcare that are specific to children. These special considerations include the role of parent/caregiver as joint decision maker and co-participant in many types of interventions, how the effectiveness of an intervention varies by age and developmental stage, and the difficulties in translating short-term data from childhood into projected effectiveness over the lifespan. Each aspect of comparative effectiveness, such as conducting new studies, synthesizing existing evidence, emphasizing real-world settings, considering multiple decision makers, and measuring patient-relevant outcomes, will require expanded definitions when considered in the context of child health. This paper discusses how comparative effectiveness methods and concepts will differ when applied to child health and suggests a potential role for decision analysis as a method to synthesize data and project long-term outcomes. The initiation of comparative effectiveness studies for children represents an exciting opportunity to provide evidence that can guide clinical and policy decisions for child health.

Depression is the most common mental health disorder and is recognized as a chronic disease characterized by multiple acute episodes/relapses. Although modelling techniques play an increasingly important role in the economic evaluation of depression interventions, comparatively little attention has been paid to issues around modelling studies with a focus on potential biases. This, however, is important as different modelling approaches, variations in model structure and input parameters may produce different results, and hence different policy decisions. This paper presents a critical review of literature on recently published model-based cost-utility studies of depression. Taking depression as an illustrative example, through this review, we discuss a number of specific issues in relation to the use of decision-analytic models including the type of modelling techniques, structure of models and data sources. The potential benefits and limitations of each modelling technique are discussed and factors influencing the choice of modelling techniques are addressed. This review found that model-based studies of depression used various simulation techniques. We note that a discrete-event simulation may be the preferred technique for the economic evaluation of depression due to the greater flexibility with respect to handling time compared with other individual-based modelling techniques. Considering prognosis and management of depression, the structure of the reviewed models are discussed. We argue that a few reviewed models did not include some important structural aspects such as the possibility of relapse or the increased risk of suicide in patients with depression. Finally, the appropriateness of data sources used to estimate input parameters with a focus on transition probabilities is addressed. We argue that the above issues can potentially bias results and reduce the comparability of economic evaluations.

Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in &dollar;US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE disutility was modelled over time. While the field of cost-effectiveness analysis in solid tumours other than breast cancer is still evolving, outcomes will likely continue to be driven by drug cost and assumptions regarding treatment benefits. Although considerations such as adverse events and administration costs are important, they were not found to influence cost-effectiveness estimates greatly. As zoledronic acid will lose patent protection in 2013 and subsequently be greatly reduced in price, it is likely that the field of cost effectiveness will change with regard to SRE-limiting agents. Meanwhile, research should be conducted to improve our understanding of the impact on quality of life and medical costs of preventing SREs.

Background:Background: Relapses are a common feature of relapsing-remitting multiple sclerosis (RRMS) and increasing severity has been shown to be associated with higher healthcare costs, and to result in transient increases in disability. Increasing disability likely impacts work and leisure productivity, and lowers quality of life. Abstract: Objective:Objective: The objective of this study was to characterize from the patient's perspective the impact of a multiple sclerosis (MS) relapse in terms of the economic cost, work and leisure productivity, functional ability, and health-related quality of life (HR-QOL), for a sample of patients with RRMS in the US treated with immunomodulatory agents. Abstract: Methods:Methods: A cross-sectional, web-based, self-report survey was conducted among members of MSWatch.com, a patient support website now known as Copaxone.com. Qualified respondents in the US had been diagnosed with RRMS and were using an immunomodulatory agent. The survey captured costs of RRMS with questions about healthcare resource utilization, use of community services, and purchased alterations and assistive items related to MS. The Work and Leisure Impairment instrument and the EQ-5D were used to measure productivity losses and HR-QOL (health utility), respectively. The Goodin MS neurological impairment questionnaire was used to measure functional disability; questions were added about relapses in the past year. Abstract: Results:Results: Of 711 qualified respondents, 67% reported having at least one relapse during the last year, with a mean of 2.2 ± 2.3 relapses/year. Respondents who experienced at least one relapse had significantly higher mean annual direct and indirect costs compared with those who did not experience a relapse (&dollar;US38 458 vs &dollar;US28 669; p - 0.0004) &lsqb;year 2009 values&rsqb;. Direct health-related costs accounted for the majority of the increased cost (&dollar;US5201; 53%) and were mainly due to increases in hospitalizations, medications, and ambulatory care. Indirect costs, including informal care and productivity loss, accounted for the additional 47% of increased cost (&dollar;US4588). Accounting for the mean number of relapses associated with these increased costs, the total economic cost of one relapse episode could be estimated at about &dollar;US4449, exclusive of intangible costs. The mean self-reported Expanded Disability Status Scale (EDSS) score, derived from the Goodin MS questionnaire, was significantly higher with relapse than with a clinically stable state (EDSS 4.3 vs 3.7; p < 0.0001), while the mean health utility score was significantly lower with relapse compared with a clinically stable state (0.66 vs 0.75; p - 0.0001). The value of these intangible costs of relapse can be estimated at &dollar;US5400. The overall burden (direct, indirect, and intangible costs) of one relapse in patients treated with immunomodulatory agents is therefore estimated conservatively at &dollar;US9849. Abstract: Conclusions:Conclusions: This study shows that from a patient's perspective an MS relapse is associated with a significant increase in the economic costs as well as a decline in HR-QOL and functional ability.

Background:Background: Obesity is a well-known risk factor for sick leave, disability pension and premature death. Obesity is therefore presumably related to increased productivity losses. Abstract: Objective:Objective: The aim of this study was to estimate the lifetime productivity losses to society associated with obesity status. Abstract: Methods:Methods: This study was based on a 38-year follow-up of a nationwide cohort of 45 920 Swedish men performing mandatory military conscription tests at age 18.7 ± 0.5 years. Body mass index (BMI) based on measured height and weight at the time of military conscription tests was used to define underweight (