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      Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat ® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy


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          The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat ® FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease.


          While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat ® FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV 1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service.


          Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat ® FDC with tiotropium alone, resulted in mean incremental costs per patient of €1167 and an incremental cost-effectiveness ratio (ICER) of €7518 per additional QALY with tiotropium + olodaterol Respimat ® FDC. The lung function outcomes observed for tiotropium + olodaterol Respimat ® FDC in TOnado drove the results in terms of slightly higher mean life-years (12.24 versus 12.07) exacerbation-free months (11.36 versus 11.32) per patient and slightly fewer moderate and severe exacerbations per patient-year (0.411 versus 0.415; 0.21 versus 0.24) versus tiotropium. Probabilistic sensitivity analyses showed tiotropium + olodaterol Respimat ® FDC to be the more cost-effective treatment in 95.2% and 98.4% of 500 simulations at thresholds of €20,000 and €30,000 per QALY respectively.


          Tiotropium + olodaterol Respimat ® FDC is a cost-effective bronchodilator in the maintenance treatment of COPD for the Italian health care system.

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          Most cited references18

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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            Lung function decline in COPD

            The landmark study of Fletcher and Peto on the natural history of tobacco smoke-related chronic airflow obstruction suggested that decline in the forced expiratory volume in the first second (FEV1) in chronic obstructive pulmonary disease (COPD) is slow at the beginning, becoming faster with more advanced disease. The present authors reviewed spirometric data of COPD patients included in the placebo arms of recent clinical trials to assess the lung function decline of each stage, defined according to the severity of airflow obstruction as proposed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. In large COPD populations the mean rate of FEV1 decline in GOLD stages II and III is between 47 and 79 mL/year and 56 and 59 mL/year, respectively, and lower than 35 mL/year in GOLD stage IV. Few data on FEV1 decline are available for GOLD stage I. Hence, the loss of lung function, assessed as expiratory airflow reduction, seems more accelerated and therefore more relevant in the initial phases of COPD. To have an impact on the natural history of COPD, it is logical to look at the effects of treatment in the earlier stages.
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              COPD exacerbations .1: Epidemiology.

              The epidemiology of exacerbations of chronic obstructive pulmonary disease (COPD) is reviewed with particular reference to the definition, frequency, time course, natural history and seasonality, and their relationship with decline in lung function, disease severity and mortality. The importance of distinguishing between recurrent and relapsed exacerbations is discussed.

                Author and article information

                Ther Adv Respir Dis
                Ther Adv Respir Dis
                Therapeutic Advances in Respiratory Disease
                SAGE Publications (Sage UK: London, England )
                12 June 2016
                October 2016
                : 10
                : 5
                : 391-401
                [1-1753465816657272]Amaris Consulting, 188 York Way, 2 nd Floor, London, N7 9AS, UK
                [2-1753465816657272]Boehringer Ingelheim GmbH., Ingelheim, Germany
                [3-1753465816657272]Boehringer Ingelheim GmbH., Ingelheim, Germany
                [4-1753465816657272]Boehringer Ingelheim Ltd., Ellesfield Avenue, Bracknell, Berkshire, UK
                [5-1753465816657272]Pneumology Department, University Hospital Vall d’Hebron, Ciber of Respiratory Diseases (CIBERES), Barcelona, Spain
                [6-1753465816657272]University of Rotterdam, iMTA, Rotterdam, The Netherlands
                [7-1753465816657272]University of Rotterdam, iMTA, Rotterdam, The Netherlands
                [8-1753465816657272]University of Rotterdam, iMTA, Rotterdam, The Netherlands
                [9-1753465816657272]Boehringer Ingelheim SpA., Milan, Italy
                Author notes
                © The Author(s), 2016

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                Original Research

                bronchodilators,copd,cost-effectiveness,economic evaluation,fixed-dose combination


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