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      The evidence on tiotropium bromide in asthma: from the rationale to the bedside

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          Abstract

          Severe and poorly controlled asthma still accounts for a great portion of the patients affected. Disease control and future risk management have been identified by international guidelines as the main goals in patients with asthma. The need for new treatment approaches has led to reconsider anticholinergic drugs as an option for asthma treatment. Tiotropium is the first anticholinergic drug that has been approved for children and adults with poorly controlled asthma and is currently considered as an option for steps 4 and 5 of the Global Initiative for Asthma. In large randomized clinical trials enrolling patients with moderate to severe asthma, add-on therapy with tiotropium has demonstrated to be efficacious in improving lung function, decreasing risk of exacerbation and slowing the worsening of disease; accordingly, tiotropium demonstrated to be non inferior compared to long acting beta-agonists in the maintenance treatment along with medium to high inhaled corticosteroids. In view of the numerous ancillary effects acting on inflammation, airway remodeling, mucus production and cough reflex, along with the good safety profile and the broad spectrum of efficacy demonstrated in different disease phenotypes, tiotropium can represent a beneficial alternative in the therapeutic management of poorly controlled asthma. The present extensive narrative review presents the pharmacological and pathophysiological basis that guided the rationale for the introduction of tiotropium in asthma treatment algorithm, with a particular focus on its conventional and unconventional effects; finally, data on tiotropium efficacy and safety. from recent randomized clinical trials performed in all age categories will be extensively discussed.

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          Most cited references127

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          Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study.

          For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.
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            Tiotropium in asthma poorly controlled with standard combination therapy.

            Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs). In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P=0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups. In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.).
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              The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.

              To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. A 28-week, randomized, double-blind, placebo-controlled, observational study. Study subjects were seen once in the study physician's office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting beta2-agonist use were excluded. Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI. Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo. For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.
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                Author and article information

                Contributors
                danko86@hotmail.com
                pierachille.santus@unimi.it
                francesco.blasi@unimi.it
                (0039) 02 55033789 , marco.mantero@unimi.it
                Journal
                Multidiscip Respir Med
                Multidiscip Respir Med
                Multidisciplinary Respiratory Medicine
                BioMed Central (London )
                1828-695X
                2049-6958
                4 May 2017
                4 May 2017
                2017
                : 12
                : 12
                Affiliations
                [1 ]Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Pulmonary Unit, Ospedale L. Sacco, ASST Fatebenfratelli-Sacco, Milan, Italy
                [2 ]Department of Pathophysiology and Transplantation, University of Milan, Cardio-thoracic unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
                Author information
                http://orcid.org/0000-0001-7324-1217
                Article
                94
                10.1186/s40248-017-0094-3
                5420159
                4339a43c-0663-4119-995c-f37820dd46b0
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 March 2017
                : 18 April 2017
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Respiratory medicine
                airway remodeling,anticholinergic,asthma,exacerbation,forced expiratory flow,inflammation,muscarinic receptor,poor control,tiotropium

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