Maiwenn Al

One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease

The aim of this paper is to assess the health economic consequences of substituting ipratropium with the new, once-daily bronchodilator tiotropium in patients with a diagnosis of chronic obstructive pulmonary disease (COPD). This prospective cost-effectiveness analysis was performed alongside two 1‐yr randomised, double-blind clinical trials in the Netherlands and Belgium. Patients had a diagnosis of COPD and a forced expiratory volume in one second (FEV1) ≤65% predicted normal. Patients were randomised to tiotropium (18 µg once daily) or ipratropium (2 puffs of 20 µg administered four times daily) in a ratio of 2:1. The mean number of exacerbations was reduced from 1.01 in the ipratropium group (n=175) to 0.74 in the tiotropium group (n=344). The percentages of patients with a relevant improvement on the St. Georges Respiratory Questionnaire (SGRQ) were 34.6% and 51.2% respectively. Compared to ipratropium, the number of hospital admissions, hospital days and unscheduled visits to healthcare providers was reduced by 46%, 42% and 36% respectively. Mean annual healthcare costs including the acquisition cost of the study drugs were 1721 (sem 160) in the tiotropium group and 1,541 (SEM 163) in the ipratropium group (difference 180). Incremental cost-effectiveness ratios were 667 per exacerbation avoided and 1084 per patient with a relevant improvement on the SGRQ. Substituting tiotropium for ipratropium in chronic obstructive pulmonary disease patients offers improved health outcomes and is associated with increased costs of 180 per patient per year.

Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy

BACKGROUND Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects. OBJECTIVE Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. METHODS We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. RESULTS Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. CONCLUSION Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance.

The cost-utility of rotavirus vaccination with Rotarix™ (RIX4414) in the Netherlands

The objective of this study was to estimate the cost-utility of mass vaccination of 0-4-year-old children with Rotarix in the Netherlands. We used a Markov process with Dutch data on incidence, resource use and costs (GP, hospitalisation, productivity loss and household costs) to compare vaccination to conventional treatment from a societal perspective. Utility loss due to rotavirus-induced diarrhoea was measured using EQ5D, with GPs and paediatricians serving as proxies to fill out the questions. As the costs of a vaccination course ranged from 90 euro to 100 euro per child, the cost-utility ratio varied from 21,900 euro to 35,076 euro per QALY gained. Based on the current study, it is clear that mass vaccination with Rotarix against rotavirus gastroenteritis can be attractive, from an economic and a health care perspective.

Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis

BACKGROUND Patients with substantive bleeding usually require transfusion and/or (re-)operation. Red blood cell (RBC) transfusion is independently associated with a greater risk of infection, morbidity, increased hospital stay and mortality. ROTEM (ROTEM® Delta, TEM International GmbH, Munich, Germany; www.rotem.de), TEG (TEG® 5000 analyser, Haemonetics Corporation, Niles, IL, USA; www.haemonetics.com) and Sonoclot (Sonoclot® coagulation and platelet function analyser, Sienco Inc., Arvada, CO) are point-of-care viscoelastic (VE) devices that use thromboelastometry to test for haemostasis in whole blood. They have a number of proposed advantages over standard laboratory tests (SLTs): they provide a result much quicker, are able to identify what part of the clotting process is disrupted, and provide information on clot formation over time and fibrinolysis. OBJECTIVES This assessment aimed to assess the clinical effectiveness and cost-effectiveness of VE devices to assist with the diagnosis, management and monitoring of haemostasis disorders during and after cardiac surgery, trauma-induced coagulopathy and post-partum haemorrhage (PPH). METHODS Sixteen databases were searched to December 2013: MEDLINE (OvidSP), MEDLINE In-Process and Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE (OvidSP), BIOSIS Previews (Web of Knowledge), Science Citation Index (SCI) (Web of Science), Conference Proceedings Citation Index (CPCI-S) (Web of Science), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Latin American and Caribbean Health Sciences Literature (LILACS), International Network of Agencies for Health Technology Assessment (INAHTA), National Institute for Health Research (NIHR) HTA programme, Aggressive Research Intelligence Facility (ARIF), Medion, and the International Prospective Register of Systematic Reviews (PROSPERO). Randomised controlled trials (RCTs) were assessed for quality using the Cochrane Risk of Bias tool. Prediction studies were assessed using QUADAS-2. For RCTs, summary relative risks (RRs) were estimated using random-effects models. Continuous data were summarised narratively. For prediction studies, the odds ratio (OR) was selected as the primary effect estimate. The health-economic analysis considered the costs and quality-adjusted life-years of ROTEM, TEG and Sonoclot compared with SLTs in cardiac surgery and trauma patients. A decision tree was used to take into account short-term complications and longer-term side effects from transfusion. The model assumed a 1-year time horizon. RESULTS Thirty-one studies (39 publications) were included in the clinical effectiveness review. Eleven RCTs (n=1089) assessed VE devices in patients undergoing cardiac surgery; six assessed thromboelastography (TEG) and five assessed ROTEM. There was a significant reduction in RBC transfusion [RR 0.88, 95% confidence interval (CI) 0.80 to 0.96; six studies], platelet transfusion (RR 0.72, 95% CI 0.58 to 0.89; six studies) and fresh frozen plasma to transfusion (RR 0.47, 95% CI 0.35 to 0.65; five studies) in VE testing groups compared with control. There were no significant differences between groups in terms of other blood products transfused. Continuous data on blood product use supported these findings. Clinical outcomes did not differ significantly between groups. There were no apparent differences between ROTEM or TEG; none of the RCTs evaluated Sonoclot. There were no data on the clinical effectiveness of VE devices in trauma patients or women with PPH. VE testing was cost-saving and more effective than SLTs. For the cardiac surgery model, the cost-saving was £43 for ROTEM, £79 for TEG and £132 for Sonoclot. For the trauma population, the cost-savings owing to VE testing were more substantial, amounting to per-patient savings of £688 for ROTEM compared with SLTs, £721 for TEG, and £818 for Sonoclot. This finding was entirely dependent on material costs, which are slightly higher for ROTEM. VE testing remained cost-saving following various scenario analyses. CONCLUSIONS VE testing is cost-saving and more effective than SLTs, in both patients undergoing cardiac surgery and trauma patients. However, there were no data on the clinical effectiveness of Sonoclot or of VE devices in trauma patients. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005623. FUNDING The NIHR Health Technology Assessment programme.

A systematic review and economic evaluation of new-generation computed tomography scanners for imaging in coronary artery disease and congenital heart disease: Somatom Definition Flash, Aquilion ONE, Brilliance iCT and Discovery CT750 HD

BACKGROUND Computed tomography (CT) is important in diagnosing and managing many conditions, including coronary artery disease (CAD) and congenital heart disease. Current CT scanners can very accurately diagnose CAD requiring revascularisation in most patients. However, imaging technologies have developed rapidly and new-generation computed tomography (NGCCT) scanners may benefit patients who are difficult to image (e.g. obese patients, patients with high or irregular heart beats and patients who have high levels of coronary calcium or a previous stent or bypass graft). OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of NGCCT for diagnosing clinically significant CAD in patients who are difficult to image using 64-slice computed tomography and treatment planning in complex congenital heart disease. DATA SOURCES Bibliographic databases were searched from 2000 to February/March 2011, including MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) database and Science Citation Index (SCI). Trial registers and conference proceedings were searched. REVIEW METHODS Systematic review methods followed published guidance. Risk of bias was assessed using QUADAS-2. Results were stratified by patient group. Summary sensitivity and specificity were calculated using a bivariate summary receiver operating characteristic, or random effects model. Heterogeneity was assessed using the chi-squared statistic and I(2)-statistic. Cost-effectiveness of NGCCT was modelled separately for suspected and known CAD, evaluating invasive coronary angiography (ICA) only, ICA after positive NGCCT (NGCCT-ICA), and NGCCT only. The cost-effectiveness of NGCCT, compared with 64-slice CT, in reducing imaging-associated radiation in congenital heart disease was assessed. RESULTS Twenty-four studies reported accuracy of NGCCT for diagnosing CAD in difficult-to-image patients. No clinical effectiveness studies of NGCCT in congenital heart disease were identified. The pooled per-patient estimates of sensitivity were 97.7% [95% confidence interval (CI) 88.0% to 99.9%], 97.7% (95% CI 93.2% to 99.3%) and 96.0% (95% CI 88.8% to 99.2%) for patients with arrhythmias, high heart rates and previous stent, respectively. The corresponding estimates of specificity were 81.7% (95% CI 71.6% to 89.4%), 86.3% (95% CI 80.2% to 90.7%) and 81.6% (95% CI 74.7% to 87.3%), respectively. In patients with high coronary calcium scores, previous bypass grafts or obesity, only per-segment or per-artery data were available. Sensitivity estimates remained high (> 90% in all but one study). In patients with suspected CAD, the NGCCT-only strategy appeared most cost-effective; the incremental cost-effectiveness ratio (ICER) of NGCCT-ICA compared with NGCCT only was £71,000. In patients with known CAD, the most cost-effective strategy was NGCCT-ICA (highest cost saving, dominates ICA only). The ICER of NGCCT only compared with NGCCT-ICA was £726,230. For radiation exposure only, the ICER for NGCCT compared with 64-slice CT in congenital heart disease ranged from £521,000 for the youngest patients to £90,000 for adults. LIMITATIONS Available data were limited, particularly for obese patients and patients with previous bypass grafts. All studies of the accuracy of NGCCT assume that the reference standard (ICA) is 100% sensitive and specific; however, there is some evidence that ICA may sometimes underestimate the extent and severity of stenosis. Patients with more than one criterion that could contribute to difficulty in imaging were often excluded from studies; the effect on test accuracy of multiple difficult to image criteria remains uncertain. CONCLUSIONS NGCCT may be sufficiently accurate to diagnose clinically significant CAD in some or all difficult-to-image patient groups. Economic analyses suggest that NGCCT is likely to be considered cost-effective for difficult-to-image patients with CAD, at current levels of willingness to pay in the NHS. For patients with suspected CAD, NGCCT only would be most favourable; for patients with known CAD, NGCCT-ICA would be most favourable. No studies assessing the effects of NGCCT on therapeutic decision making, or subsequent patient outcomes, were identified. The ideal study to address these questions would be a large multi-centre RCT. However, one possible alternative might be to establish a multicentre tracker study. High-quality test accuracy studies, particularly in obese patients, patients with high coronary calcium, and those with previous bypass grafts are needed to confirm the findings of our systematic review. These studies should include patients with multiple difficult to image criteria. FUNDING The National Institute for Health Research Health Technology Assessment programme. This project was funded by the HTA programme, on behalf of NICE, as project number 10/107/01.

Methods to analyse cost data of patients who withdraw in a clinical trial setting

AbstractBackground: Missing data resulting from premature study withdrawal are a common problem in the analysis of longitudinal data in clinical trials. To date, this subject has received little attention in the context of economic evaluations and with regard to the analysis of cost data. Objectives: To (i) demonstrate the impact of patients who drop out during the study on the outcomes of an economic evaluation, and (ii) to compare the mean and variation in costs after applying five different methods to deal with incomplete data: multiple imputation, complete cases analysis, linear extrapolation, predicted mean and hot decking. Study design: The study was performed using cost data collected in two randomised clinical trials comparing patients with chronic obstructive pulmonary disease receiving either tiotropium bromide or ipratropium bromide. The overall dropout rate was 17%, with the daily costs of the dropouts approximately 4 times higher than the costs of the completers. Methods: Multiple imputation is a principled method that deals with missing observations by replacing each missing observation with a set of multiple plausible values. The variance between the resulting multiple datasets is combined with the variance between the datasets to take account of the extra uncertainty that results from missing data. The outcomes after multiple imputation were compared with the results of four naive methods to deal with missing observations: complete cases analysis, linear extrapolation, predicted mean and hot decking. All costs were expressed in 2001 euros. Results: In the tiotropium bromide group, mean (standard error) costs varied from €955 (137) after complete cases analysis to €1298 (198) after linear extrapolation. The corresponding estimates in the ipratropium bromide group were €970 (125) and €1561 (244), respectively. The difference in costs between treatment groups varied from -€15 (95% CI: -379 to 349) after complete cases analysis to -€402 (95% CI: -883 to 79) after predicted mean, in favour of the tiotropium bromide group. The difference in costs according to the other methods varied from -€263 (95% CI: -878 to 353) after linear extrapolation to -€265 (95% CI: -709 to 180) after multiple imputation to -€359 (95% CI: -771 to 54) after hot decking.

The ISPOR Good Practices for Quality Improvement of Cost-Effectiveness Research Task Force Report

OBJECTIVES The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Health Science Policy Council recommended and the ISPOR Board of Directors approved the formation of a Task Force to critically examine the major issues related to Quality Improvement in Cost-effectiveness Research (QICER). The Councils primary recommendation for this Task Force was that it should report on the quality of cost-effectiveness research and make recommendations to facilitate the improvement of pharmacoeconomics and health outcomes research and its use in stimulating better health care and policy. Task force members were knowledgeable and experienced in medicine, pharmacy, biostatistics, health policy and health-care decision-making, biomedical knowledge transfer, health economics, and pharmacoeconomics. They were drawn from industry, academia, consulting organizations, and advisors to governments and came from Japan, the Netherlands, Canada and the United States. METHODS Face-to-face meetings of the Task Force were held at ISPOR North American and European meetings and teleconferences occurred every few months. Literature reviews and surveys were conducted and the first preliminary findings presented at an open forum at the May 2008 ISPOR meeting in Toronto. The final draft report was circulated to the expert reviewer group and then to the entire membership for comment. The draft report was posted on the ISPOR Web site in April 2009. All formal comments received were posted to the association Web site and presented for discussion at the Task Force forum during the ISPOR 14th Annual International Meeting in May 2009. Comments and feedback from the forums, reviewers and membership were considered in the final report. Once Task Force consensus was reached, the article was submitted to Value in Health. CONCLUSIONS The QICER Task Force recommends that ISPOR implement the following: * With respect to CER guidelines, that ISPOR promote harmonization of guidelines, allowing for differences in application, regional needs and politics; evaluate available instruments or promote development of a new one that will allow standardized quantification of the impact of CER guidelines on the quality of CER studies; report periodically on those countries or regions that have developed guidelines; periodically evaluate the quality of published studies (those journals with CER guidances) or those submitted to decision-making bodies (as public transparency increases). * With respect to methodologies, that ISPOR promote publication of methodological guidelines in more applied journals in more easily understandable format to transfer knowledge to researchers who need to apply more rigorous methods; promote full availability of models in electronic format to combat space restrictions in hardcopy publications; promote consistency of methodological review for all CER studies; promote adoption of explicit best practices guidelines among regulatory and reimbursement authorities; periodically update all ISPOR Task Force reports; periodically review use of ISPOR Task Force guidelines; periodically report on statistical and methodological challenges in HE; evaluate periodically whether ISPORs methodological guidelines lead to improved quality; and support training and knowledge transfer of rigorous CER methodologies to researchers and health care decision-makers. * With respect to publications, that ISPOR develop standard CER guidances to which journals will be able to refer their authors and their reviewers; lobby to establish these guidances within the International Committee for Medical Journal Editors (ICMJE) Requirements to which most journals refer in their Author Instructions; provide support in terms of additional reviewer expertise to those journals lacking appropriate reviewers; periodically report on journals publishing CER research; periodically report on the quality of CER publications; and support training and knowledge transfer of the use of these guidelines to researchers and reviewers. * With respect to evidence-based health-care decision-making, that ISPOR recognize at its annual meetings those countries/agencies/private companies/researchers using CER well, and those practitioners and researchers supporting good patient use of CER in decision-making; and promote public presentation of case studies of applied use of CER concepts or guidelines.

Association between lung function and exacerbation frequency in patients with COPD.

Purpose: To quantify the relationship between severity of chronic obstructive pulmonary disease (COPD) as expressed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and the annual exacerbation frequency in patients with COPD. Methods: We performed a systematic literature review to identify randomized controlled trials and cohort studies reporting the exacerbation frequency in COPD patients receiving usual care or placebo. Annual frequencies were determined for total exacerbations defined by an increased use of health care (event-based), total exacerbations defined by an increase of symptoms, and severe exacerbations defined by a hospitalization. The association between the mean forced expiratory volume in one second (FEV1)% predicted of study populations and the exacerbation frequencies was estimated using weighted log linear regression with random effects. The regression equations were applied to the mean FEV1% predicted for each GOLD stage to estimate the frequency per stage. Results: Thirty-seven relevant studies were found, with 43 reports of total exacerbation frequency (event-based, n = 19; symptom-based, n = 24) and 14 reports of frequency of severe exacerbations. Annual event-based exacerbation frequencies per GOLD stage were estimated at 0.82 (95% confidence interval 0.46–1.49) for mild, 1.17 (0.93–1.50) for moderate, 1.61 (1.51–1.74) for severe, and 2.10 (1.51–2.94) for very severe COPD. Annual symptom-based frequencies were 1.15 (95% confidence interval 0.67–2.07), 1.44 (1.14–1.87), 1.76 (1.70–1.88), and 2.09 (1.57–2.82), respectively. For severe exacerbations, annual frequencies were 0.11 (95% confidence interval 0.02–0.56), 0.16 (0.07–0.33), 0.22 (0.20–0.23), and 0.28 (0.14–0.63), respectively. Study duration or type of study (cohort versus trial) did not significantly affect the outcomes. Conclusion: This study provides an estimate of the exacerbation frequency per GOLD stage, which can be used for health economic and modeling purposes.

Long term outcome and cost-effectiveness of stenting versus balloon angioplasty for acute myocardial infarction

OBJECTIVE To investigate the long term clinical outcome and cost-effectiveness of stenting compared with balloon angioplasty in patients with acute myocardial infarction. METHODS Patients with acute myocardial infarction were randomly allocated to primary stenting (112) or balloon angioplasty (115). The primary end point was the cumulative first event rate of death, non-fatal reinfarction, or target vessel revascularisation. Secondary end points were restenosis at six months and the cost-effectiveness at follow up. RESULTS After 24 months, the combined clinical end point of death/reinfarction was 4% after stenting and 11% after balloon angioplasty (p = 0.04). Subsequent target vessel revascularisation was necessary in 15 patients (13%) after stenting and in 39 (34%) after balloon angioplasty (p < 0.001). The cumulative cardiac event-free survival rate was also higher after stenting (84% v 62%, p < 0.001). The angiographic restenosis rate after stenting was less than after balloon angioplasty (12% v 34%, p < 0.001). Despite the higher initial costs of stenting (Dfl 21 484v Dfl 18 625, p < 0.001), the cumulative costs at 24 months were comparable with those of balloon angioplasty (Dfl 31 423 v Dfl 32 933, p = 0.83). CONCLUSIONS Compared with balloon angioplasty, primary stenting for acute myocardial infarction results in a better long term clinical outcome without increased cost.

Sample size calculation in economic evaluations

A simulation method is presented for sample size calculation in economic evaluations. As input the method requires: the expected difference and variance of costs and effects, their correlation, the significance level (alpha) and the power of the testing method and the maximum acceptable ratio of incremental effectiveness to incremental costs. The method is illustrated with data from two trials. The first compares primary coronary angioplasty with streptokinase in the treatment of acute myocardial infarction, in the second trial, lansoprazole is compared with omeprazole in the treatment of reflux oesophagitis. These case studies show how the various parameters influence the sample size. Given the large number of parameters that have to be specified in advance, the lack of knowledge about costs and their standard deviation, and the difficulty of specifying the maximum acceptable ratio of incremental effectiveness to incremental costs, the conclusion of the study is that from a technical point of view it is possible to perform a sample size calculation for an economic evaluation, but one should wonder how useful it is.