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      Impact of pre-enrolment medication use on clinical outcomes in SUMMIT

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          Abstract

          In mortality trials including patients with COPD and heightened cardiovascular risk, patients' treatments before entering the trial may affect the effects of inhaled medications during the study http://ow.ly/WRRb30nwyIE

          Abstract

          The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations.

          We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676.

          There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48–0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment.

          Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk.

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          Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.

          The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p
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            Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease

            Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD.
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              Inhaled corticosteroids in COPD: the clinical evidence.

              In this article, we focus on the scientific evidence from randomised trials supporting treatment with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), including treatment with combinations of long-acting β-agonist (LABA) bronchodilators and ICS. Our emphasis is on the methodological strengths and limitations that guide the conclusions that may be drawn. The evidence of benefit of ICS and, therefore, of the LABA/ICS combinations in COPD is limited by major methodological problems. From the data reviewed herein, we conclude that there is no survival benefit independent of the effect of long-acting bronchodilation and no effect on FEV1 decline, and that the possible benefit on reducing severe exacerbations is unclear. Our interpretation of the data is that there are substantial adverse effects from the use of ICS in patients with COPD, most notably severe pneumonia resulting in excess deaths. Currently, the most reliable predictor of response to ICS in COPD is the presence of eosinophilic inflammation in the sputum. There is an urgent need for better markers of benefit and risk that can be tested in randomised trials for use in routine specialist practice. Given the overall safety and effectiveness of long-acting bronchodilators in subjects without an asthma component to their COPD, we believe use of such agents without an associated ICS should be favoured.
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                Author and article information

                Journal
                ERJ Open Res
                ERJ Open Res
                ERJOR
                erjor
                ERJ Open Research
                European Respiratory Society
                2312-0541
                February 2019
                25 February 2019
                : 5
                : 1
                : 00203-2018
                Affiliations
                [1 ]Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
                [2 ]North West Lung Centre, Manchester University NHS Foundation Trust, Manchester, UK
                [3 ]Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA
                [4 ]Research and Development, GlaxoSmithKline, Uxbridge, UK
                [5 ]University of Michigan Health System, Ann Arbor, MI, USA
                [6 ]University of Liverpool, Dept of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK
                [7 ]Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
                [8 ]Veramed Ltd, Twickenham, UK
                [9 ]Research and Development, GlaxoSmithKline, Research Triangle Park, NC, USA
                [10 ]Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA
                [11 ]British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
                [12 ]Dept of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, Denmark
                [13 ]Medical Unit, Respiratory Section, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                Author notes
                Jørgen Vestbo, 2nd Floor, ERC Building, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK. E-mail: jorgen.vestbo@ 123456manchester.ac.uk
                Author information
                https://orcid.org/0000-0002-7266-8371
                Article
                00203-2018
                10.1183/23120541.00203-2018
                6387990
                114e01b3-8776-4766-a9db-75e1be891a7d
                Copyright ©ERS 2019

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 30 October 2018
                : 19 December 2018
                Funding
                Funded by: GlaxoSmithKline http://doi.org/10.13039/100004330
                Categories
                Original Articles
                COPD
                1

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