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The New England Journal of Medicine Sep 2017Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
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.
METHODS
In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 μg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV after bronchodilator use and the between-group difference in the annual decline in the FEV before and after bronchodilator use from day 30 to month 24.
RESULTS
Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups.
CONCLUSIONS
Tiotropium resulted in a higher FEV than placebo at 24 months and ameliorated the annual decline in the FEV after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).
Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide
PubMed: 28877027
DOI: 10.1056/NEJMoa1700228 -
International Journal of Chronic... 2006Therapy with bronchodilators forms the pharmacologic foundation of the treatment of patients with COPD. Bronchodilators can significantly lessen dyspnea, increase... (Review)
Review
Therapy with bronchodilators forms the pharmacologic foundation of the treatment of patients with COPD. Bronchodilators can significantly lessen dyspnea, increase airflow, improve quality of life, and enhance exercise performance. While bronchodilators decrease airway resistance and lessen dynamic hyperinflation in patients with COPD, they have not been shown to alter the rate of decline in FEV1 over time, or improve patient survival. Fairly recently, a long-acting, once-daily anticholinergic medication, tiotropium bromide, has been developed which may improve symptom management in COPD patients. This paper reviews anticholinergic pharmacologic therapy for patients with COPD focusing on tiotropium bromide, and discusses treatment strategies based on disease stage. It is important to recognize that while bronchodilators improve symptoms, a multimodality treatment approach including respiratory and rehabilitative therapy, nutrition services, psychosocial counseling, and surgical care, is often necessary for the best possible care of patients with COPD.
Topics: Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide
PubMed: 18046887
DOI: 10.2147/copd.2006.1.2.107 -
Drugs Jun 2019Tiotropium/olodaterol (Stiolto Respimat; Spiolto Respimat) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter... (Review)
Review
Tiotropium/olodaterol (Stiolto Respimat; Spiolto Respimat) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β-adrenergic agonist olodaterol. It is available in several countries, including the USA, Japan, China and those of the EU, where it is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy of tiotropium/olodaterol 5/5 μg/day in patients with COPD was evaluated in phase III or IV trials of 6-52 weeks' duration. Tiotropium/olodaterol improved lung function to a greater extent than each of its individual components or placebo in 12- and 52-week trials. In 6-week trials, tiotropium/olodaterol provided greater lung function benefits over 24 h than the individual components, placebo or twice-daily fluticasone propionate/salmeterol. Tiotropium/olodaterol also demonstrated beneficial effects on health-related quality of life (HR-QoL), dyspnoea, inspiratory capacity, exercise endurance and the need for rescue medication. In an 8-week open-label trial, umeclidinium/vilanterol was superior to tiotropium/olodaterol for the primary endpoint of trough forced expiratory volume in 1 s. The tolerability profile of tiotropium/olodaterol was generally similar to that of the individual components. In conclusion, tiotropium/olodaterol provides a useful option for the maintenance treatment of COPD, with the convenience of once-daily administration via a single inhaler.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome
PubMed: 31119643
DOI: 10.1007/s40265-019-01133-w -
Drugs Mar 2018Asthma is one of the most common chronic diseases in children, with a high proportion of patients demonstrating poor control despite the availability of disease... (Review)
Review
Asthma is one of the most common chronic diseases in children, with a high proportion of patients demonstrating poor control despite the availability of disease management guidelines. Global Initiative for Asthma guidelines include tiotropium as an add-on therapy option at Steps 4 and 5 in patients aged ≥ 12 years with a history of exacerbations, and tiotropium delivered via the Respimat Soft Mist™ Inhaler has recently been approved for use as once-daily maintenance therapy for children with asthma over the age of 6 years in the USA. A large clinical trial program has been conducted in children, adolescents, and adults across the spectrum of asthma severity. Findings from these clinical studies and pooled analyses in children and adolescents with symptomatic moderate or severe asthma have demonstrated that tiotropium Respimat as add-on to inhaled corticosteroids, with or without other maintenance therapies, is a well-tolerated and efficacious bronchodilator, showing improved lung function and trends towards improved asthma control, mirroring findings in adult studies. This review discusses the evidence to date for tiotropium Respimat for the management of asthma in adolescents and children with symptomatic moderate and severe asthma, and considers the challenges of asthma management in these patients. Factors affecting this population group, such as poor adherence, underreporting of symptoms, and social and psychological issues, are highlighted, along with the need for active review and management of treatment to help achieve optimal control.
Topics: Administration, Inhalation; Adolescent; Asthma; Child; Child, Preschool; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Nebulizers and Vaporizers; Tiotropium Bromide; Treatment Outcome
PubMed: 29368127
DOI: 10.1007/s40265-018-0862-1 -
Respiratory Medicine 2019Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended... (Review)
Review
OBJECTIVE
Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies.
DATA SOURCES
A search was performed in PubMed using search terms 'tiotropium' and 'asthma.' Relevant references cited in those articles were reviewed.
STUDY SELECTIONS
English language articles published from December 2008-December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included.
RESULTS
Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting.
CONCLUSIONS
An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.
Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Asthma; Bronchodilator Agents; Child; Cholinergic Antagonists; Clinical Trials as Topic; Cost-Benefit Analysis; Expectorants; Humans; Muscarinic Antagonists; Prevalence; Tiotropium Bromide; Treatment Outcome; United States; Young Adult
PubMed: 31212121
DOI: 10.1016/j.rmed.2019.06.008 -
Respiratory Care May 2020Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and... (Review)
Review
Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with complex pulmonary disease. During 2019, lung injury associated to e-cigarette or vaping was reported, including 60 casualties.
Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Electronic Nicotine Delivery Systems; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes
PubMed: 32345761
DOI: 10.4187/respcare.07738 -
Therapeutic Advances in Respiratory... 2019Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective... (Review)
Review
Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.
Topics: Administration, Inhalation; Adolescent; Adult; Aged; Animals; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Cholinergic Antagonists; Dose-Response Relationship, Drug; Glucocorticoids; Humans; Tiotropium Bromide
PubMed: 30795731
DOI: 10.1177/1753466618824010 -
Annals of Allergy, Asthma & Immunology... Mar 2020Asthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium-a long-acting muscarinic antagonist-as add-on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Asthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium-a long-acting muscarinic antagonist-as add-on therapy to an inhaled corticosteroid with or without a long-acting β-agonist provides clinical benefit with a safety profile similar to placebo.
OBJECTIVE
To review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s).
METHODS
We searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events.
RESULTS
Overall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 μg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection.
CONCLUSION
Once-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.
Topics: Adolescent; Age Factors; Asthma; Bronchodilator Agents; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Infant; Male; Publication Bias; Tiotropium Bromide; Treatment Outcome
PubMed: 31805357
DOI: 10.1016/j.anai.2019.11.030 -
American Journal of Respiratory and... Aug 2018There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations. (Randomized Controlled Trial)
Randomized Controlled Trial
Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial.
RATIONALE
There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations.
OBJECTIVES
To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD).
METHODS
This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 μg once daily) or continuation of triple therapy (tiotropium [18 μg] once daily plus combination of salmeterol/fluticasone propionate [50/500 μg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV. Moderate or severe exacerbations were predefined secondary endpoints.
MEASUREMENTS AND MAIN RESULTS
A total of 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV of -26 ml (95% confidence interval, -53 to 1 ml) with confidence limits exceeding the noninferiority margin of -50 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with ≥300 blood eosinophils/μl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups.
CONCLUSIONS
In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/μl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Treatment Outcome
PubMed: 29779416
DOI: 10.1164/rccm.201803-0405OC -
Respiratory Research Nov 2017Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD. This article analyses the evidence of efficacy and safety of the TIO/OLO combination.
METHODS
A systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator.
RESULTS
A total of 10 Randomized controlled trials (RCT) were identified (N = 10,918). TIO/OLO significantly improved trough FEV from baseline to week 12 versus TIO, OLO and LABA/ICS (0.06 L, 0.09 L and between 0.04 and 0.05 L, respectively). TIO/OLO improved transitional dyspnea index (TDI) and St. George's Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% confidence interval [CI]: [1.07, 1.28] versus TIO and RR: 1.14, 95%CI: [1.01, 1.28] versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus TIO and RR: 1.28, 95%CI: [1.18, 1.40] versus OLO). Patients treated with TIO/OLO showed a significant reduction in the use of rescue medication and no significant differences in frequency of general and serious adverse events were observed between TIO/OLO and mono-components.
CONCLUSIONS
Treatment with TIO/OLO provided significant improvements in lung function versus mono-components and LABA/ICS with more patients achieving significant improvements in dyspnea and health status. No differences in adverse events were observed compared with other active treatments.
CLINICAL TRIAL REGISTRATION
PROSPERO register of systematic reviews ( CRD42016040162 ).
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Spirometry; Tiotropium Bromide; Treatment Outcome
PubMed: 29178871
DOI: 10.1186/s12931-017-0683-x