A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

David Geffen School of Medicine at the University of California, Los Angeles 90095-1690,USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2008; 359(15):1543-54. DOI: 10.1056/NEJMoa0805800
Source: PubMed


Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy.
In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality.
Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure.
In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). ( number, NCT00144339.)

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    • "The safety profile of bronchodilators in COPD remains of prime importance [4] [5]. Studies such as Towards a Revolution in COPD Health (TORCH) and Understanding Longterm Impacts on Function with Tiotropium (UPLIFT) have provided the evidence that long-acting bronchodilators at therapeutic doses in stable COPD do not increase risk of the cardio-and cerebrovascular (CCV) mortality or morbidity in patients with COPD [6] [7]. "
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    ABSTRACT: Background To further assess the safety profile of the fixed-dose combination of indacaterol and glycopyrronium (QVA149) and its monocomponents; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and glycopyrronium safety databases. Methods Data from 11,404 patients with chronic obstructive pulmonary disease (COPD) were pooled from 14 clinical studies of QVA149, indacaterol and glycopyrronium of ≥3 month’s duration with at least two of the treatment groups: QVA149 110/50 μg, glycopyrronium 50 μg, indacaterol 150 μg, placebo or tiotropium 18 μg. Overall hazard ratio (HR) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction, inhaled corticosteroid use, cardiovascular risk factors, sex, age and body mass index for death, serious cases of cardio- and cerebrovascular (CCV) events, major adverse cardiovascular events (MACEs), pneumonia, COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation (AF/F). Results The HR for QVA149 versus placebo showed no significant increase in the overall risk for death (HR [95% confidence interval]: 0.93 [0.34–2.54]); CCV events (0.60 [0.29–1.24]); MACE (1.04 [0.45–2.42]); pneumonia (1.10 [0.54–2.25]); COPD exacerbations (0.60 [0.40–0.91]); and AF/F (1.03 [0.49–2.18]). Similar results were observed for indacaterol, glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups. Conclusions There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149, and it had a comparable safety profile as its monocomponents and tiotropium versus placebo.
    Respiratory Medicine 10/2014; 108(10). DOI:10.1016/j.rmed.2014.07.011 · 3.09 Impact Factor
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    • "Tiotropium is also associated with a reduction in and prolongation of time to exacerbations.148 However, there does not appear to be any reduction in the rate of decline in lung function.149 The benefits come with an increase in adverse effects such as dry mouth and urinary retention.150 "
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    ABSTRACT: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens. This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management. Both adult-onset asthma and COPD are complex diseases arising from gene-environment interactions. Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma. While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD. Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness. In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes). Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation. The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly. Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy. Each of these is associated with error due to overlap and convergence of clinical characteristics. The management of chronic stable asthma and COPD is similarly convergent. New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and risk factors. Short-acting beta-agonists provide effective symptom relief in airway diseases. Inhalers combining a long-acting beta-agonist and corticosteroid are now widely used for both asthma and COPD. Written action plans are a cornerstone of asthma management although evidence for self-management in COPD is less compelling. The current management of chronic asthma in adults is based on achieving and maintaining control through step-up and step-down approaches, but further trials of back-titration in COPD are required before a similar approach can be endorsed. Long-acting inhaled anticholinergic medications are particularly useful in COPD. Other distinctive features of management include pulmonary rehabilitation, home oxygen, and end of life care.
    International Journal of COPD 09/2014; 9:945-962. DOI:10.2147/COPD.S46761 · 3.14 Impact Factor
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    • "The long-term management of asthma by ipratropium bromide has not been fully elucidated, but global guidelines recommend shortacting anticholinergic bronchodilators, in combination with short-acting b 2 -agonists, as reliever medication for asthmatic patients [1]. The long-acting anticholinergic bronchodilator tiotropium bromide has demonstrated efficacy and tolerability as a once-daily dose in adult patients with chronic obstructive pulmonary disease [11] [12]. More recently in two proof-of-concept studies, treatment with once-daily tiotropium 5 μg (via the Respimat â SoftMistä inhaler [Boehringer Ingelheim, Ingelheim am Rhein, Germany], hereinafter referred to as tiotropium Respimat â ) for 8e16 weeks improved lung function in patients with symptomatic asthma despite receiving ICS with or without LABAs [13] [14]. "
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    ABSTRACT: Introduction: Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat(®) SoftMist™ inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment. Methods: This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 μg, 2.5 μg and 1.25 μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0-3h)). Results: From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0-3h) response for tiotropium 5 μg was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p = 0.0134) versus placebo, but not for 2.5 μg (p = 0.0975), while FEV1 area under the curve(0-3h) responses were significant for all doses (p = 0.00001-0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity. Conclusion: This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. identifier; NCT01122680.
    Respiratory Medicine 09/2014; 108(9). DOI:10.1016/j.rmed.2014.06.011 · 3.09 Impact Factor
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