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      Cost-effectiveness of roflumilast as an add-on to triple inhaled therapy vs triple inhaled therapy in patients with severe and very severe COPD associated with chronic bronchitis in the UK

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          Patients with severe COPD are at high risk of experiencing disease exacerbations, which require additional treatment and are associated with elevated mortality and increased risk of future exacerbations. Some patients continue to experience exacerbations despite receiving triple inhaled therapy (ICS plus LAMA plus LABA). Roflumilast is recommended by the Global Initiative for Chronic Obstructive Lung Disease as add-on treatment to triple inhaled therapy for these patients. This cost-effectiveness analysis compared costs and quality-adjusted life-years for roflumilast plus triple inhaled therapy vs triple inhaled therapy alone, using data from the REACT and RE 2SPOND trials.

          Patients and methods

          Patients included in the analysis had severe to very severe COPD, FEV 1 <50% predicted, symptoms of chronic bronchitis and ≥2 exacerbations per year. Our model was adapted from a previously published and validated model, and the analyses conducted from a UK National Health Service perspective. A scenario analysis considered a subset of patients who had experienced at least one COPD-related hospitalization within the previous year.


          Roflumilast as add-on to triple inhaled therapy was associated with non-significant reductions in rates of both moderate and severe exacerbations compared with triple inhaled therapy alone. The incremental cost-effectiveness ratio (ICER) for roflumilast as add-on to triple inhaled therapy was £24,976. In patients who had experienced previous hospitalization, roflumilast was associated with a non-significant reduction in the rate of moderate exacerbations, and a statistically significant reduction in the rate of severe exacerbations. The ICER for roflumilast in this population was £7,087.


          Roflumilast is a cost-effective treatment option for patients with severe or very severe COPD, chronic bronchitis, and a history of exacerbations. The availability of roflumilast as add-on treatment addresses an important unmet need in this patient population.

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          Most cited references 13

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          Reference spirometric values using techniques and equipment that meet ATS recommendations.

          Forced expiratory volumes and flows were measured in 251 healthy nonsmoking men and women using techniques and equipment that meet American Thoracic Society (ATS) recommendations. Linear regression equations using height and age alone predict spirometric parameters as well as more complex equations using additional variables. Single values for 95% confidence intervals are acceptable and should replace the commonly used method of subtracting 20% to determine the lower limit of normal for a predicted value. Our study produced predicted values for forced vital capacity and forced expiratory volume in one second that were almost identical to those predicted by Morris and associates (1) when the data from their study were modified to be compatible with the back extrapolation technique recommended by the ATS. The study of Morris and colleagues was performed at sea level in rural subjects, whereas ours was performed at an altitude of 1,400 m in urban subjects. Either the present study or the study of Morris and co-workers, modified to back extrapolation, could be recommended for predicting normal values.
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            Temporal clustering of exacerbations in chronic obstructive pulmonary disease.

            Exacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data. To assess whether exacerbations are random events, or cluster in time. A total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly. The observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948-0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (rho = 0.81; P < 0.0001). Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial excerbation.
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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.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                03 September 2018
                : 13
                : 2707-2720
                [1 ]ICON plc, Abingdon, UK
                [2 ]AstraZeneca, Barcelona, Spain, sandrine.ruiz@
                [3 ]AstraZeneca, Cambridge, UK
                [4 ]AstraZeneca, Luton, UK
                [5 ]Phastar, Manchester, UK
                Author notes
                Correspondence: Sandrine Ruiz, AstraZeneca, Avenida Diagonal 615, Floor 2, 08028 Barcelona, Spain, Tel +34 61 648 0486, Email sandrine.ruiz@
                © 2018 Kiff et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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