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:: BPCO E TERAPIA BRONCODILATATRICE INALATORIA (ANTI-COLINERGICI)
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Tiotropium bromide, a new, once-daily inhaled anticholinergic bronchodilator for chronic-obstructive pulmonary disease
ZuWallackAR, ZuWallack RL
- St.FrancisHospital and MedicalCenter, Hartford, CT06105, USA. rzuwalla@stfranciscare.org
Tiotropium bromide is a quaternary ammonium compound structurally related to ipratropium and has recently been approved in the US for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic-obstructive pulmonary disease (COPD). It is available in a dry powder form, where 18 mg of the drug is inhaled once-daily through a device, the HandiHaler). The potency and long duration of effect of this anticholinergic bronchodilator result primarily from a prolonged blockade of the M1 and M3 muscarinic receptors in the airways and a relatively more rapid dissociation from the M2 receptor (which provides inhibitory feedback). Multiple studies of up to a duration of 1 year have demonstrated its effectiveness as a bronchodilator for COPD, with a trough increase (measured approximately 24 h after administration of the drug) in forced expiratory volume in 1 s of approximately 0.12 l and a peak increase of approximately 0.25 l. Tiotropium inhalation also leads to a significant reduction in static lung volumes in hyperinflated patients with COPD; this probably contributes to the reduction in dyspnoea that is associated with long-term use of this maintenance bronchodilator. Regular use of the drug was associated with clinically meaningful increases in the Transitional Dyspnoea Index, which indicate reductions in dyspnoea associated with daily activities. Improvement in the respiratory-specific health status questionnaire, the St George's Respiratory Questionnaire component and total scores was also documented. Finally, pooled data from two 1-year studies and two 6-month studies documented 20 and 28% reductions in the number of exacerbations per patient per year. Side effects have been relatively minimal, with dry mouth the most common symptom, ranging 6 - 16% of patients and rarely leading to discontinuation of the study drug. Limited comparisons of efficacy with other bronchodilators are available. Once-daily tiotropium has been demonstrated to be clearly superior to ipratropium four times daily as a bronchodilator for COPD. Combined results from two studies comparing once-daily tiotropium to twice-daily inhalation of standard doses of salmeterol, indicate a magnitude of the bronchodilator response similar in the two drugs early in the study. However, by 6 months, the bronchodilator effect of tiotropium was somewhat greater than that of the long-acting beta-agonist. Preliminary data suggest that combining tiotropium with long-acting beta-agonists may produce additional bronchodilator action in COPD.
PMID: 15264997 [PubMed - in process]
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The role of long-acting bronchodilators in the management of stable COPD
Tashkin DP, Cooper CB
- Division of Pulmonary and Critical Care Medicine and the UCLA Pulmonary Function and Exercise Physiology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA. DTashkin@mednet.ucla.edu
Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (> or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.
Publication Types:
• Review
• Review, Tutorial
PMID: 14718448 [PubMed - indexed for MEDLINE]
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Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD.
McNicholas WT, Calverley PM, Lee A, Edwards JC; Tiotropium Sleep Study in COPD Investigators.
- Dept of Respiratory Medicine, St. Vincent's UniversityHospital, ElmPark, Dublin 4, Ireland. walter.mcnicholas@ucd.ie
Oxygen desaturation occurs during sleep in severe chronic obstructive pulmonary disease (COPD), especially during rapid eye movement (REM) sleep, due to hypoventilation and ventilation-perfusion mismatching, but the possible contribution of airflow limitation is unclear. In a randomised, placebo-controlled, double-blind study of severe, stable COPD patients, the authors compared 4 weeks treatment with a long-acting inhaled anticholinergic agent (tiotropium), taken in the morning (tiotropium-AM), or in the evening (tiotropium-PM), on sleeping arterial oxygen saturation (Sa,O2) and sleep quality. Overnight polysomnography was performed at baseline and after 4 weeks treatment. A total of 95 patients with awake resting arterial oxygen tension < or = 9.98 kPa (75 mmHg) were randomised, with a mean age of 66.4 yrs and mean forced expiratory volume in one second (FEV1) of 32% predicted. A total of 80 patients completed the study, of which 56 fulfilled the polysomnographic criterion of at least 2 h sleep in both sleep study nights and represent the group analysed. Tiotropium significantly improved spirometry compared with placebo. Both tiotropium-AM and tiotropium-PM groups had higher Sa,O2 during REM than placebo (+2.41% and +2.42%, respectively, and both pooled and tiotropium-PM groups had higher Sa,O2 during total sleep time (+2.49% and +3.06%, respectively). End-of-treatment FEV1 correlated with Sa,O2 during REM sleep, however, tiotropium did not change sleep quality. Sustained anticholinergic blockade improves sleeping arterial oxygen saturation without affecting sleep quality.
Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial
PMID: 15218993 [PubMed - indexed for MEDLINE]
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The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD
Hasani A, Toms N, Agnew JE, Sarno M, Harrison AJ, Dilworth P.
- Department of Medical Physics, Royal Free Hampstead NHS Trust and Royal Free and UniversityCollegeMedicalSchool, London, UK. amer.alhasani@royalfree.nhs.uk
STUDY OBJECTIVE: To assess the effects of tiotropium on lung mucociliary clearance in COPD. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Outpatients of an urban-area university teaching hospital. PATIENTS: Thirty-four patients with COPD aged 40 to 75 years classified equally into two groups. INTERVENTION: Single (18 microg) daily dose of tiotropium inhalation capsules or of placebo for 21 days. METHODS: Six-hour tracheobronchial clearance of inhaled 99mTc-labeled polystyrene particles using a 48-h retention measurement to determine the "nontracheobronchial" deposition fraction. RESULTS: Test radioaerosol penetration into the lungs increased significantly (p < 0.003) as did FEV1 (p < 0.006) in the tiotropium-treated patients, but measured mucociliary clearance was not significantly changed despite the increased pathway length for clearance (mean +/- SE area under the tracheobronchial retention curve changed from 442 +/- 22 to 453 +/- 20%/h). Smaller (nonsignificant) decreases of radioaerosol penetration and FEV1 occurred in the placebo group together with a small (nonsignificant) decrease in the area under the retention curve. CONCLUSION: Twenty-one days of inhaled tiotropium, 18 microg/d, as a dry powder does not retard mucus clearance from the lungs.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 15136383 [PubMed - indexed for MEDLINE]
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One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease
Oostenbrink JB, Rutten-van Molken MP, Al MJ, Van Noord JA, Vincken W
- Erasmus Medical Centre, Institute for Medical Technology Assessment, ErasmusUniversity, Rotterdam, The Netherlands. oostenbrink@bmg.eur.nl
The aim of this paper is to assess the health economic consequences of substituting ipratropium with the new, once-daily bronchodilator tiotropium in patients with a diagnosis of chronic obstructive pulmonary disease (COPD). This prospective cost-effectiveness analysis was performed alongside two 1-yr randomised, double-blind clinical trials in the Netherlands and Belgium. Patients had a diagnosis of COPD and a forced expiratory volume in one second (FEV1) < or = 65% predicted normal. Patients were randomised to tiotropium (18 microg once daily) or ipratropium (2 puffs of 20 microg administered four times daily) in a ratio of 2:1. The mean number of exacerbations was reduced from 1.01 in the ipratropium group (n = 175) to 0.74 in the tiotropium group (n = 344). The percentages of patients with a relevant improvement on the St. George's Respiratory Questionnaire (SGRQ) were 34.6% and 51.2%, respectively. Compared to ipratropium, the number of hospital admissions, hospital days and unscheduled visits to healthcare providers was reduced by 46%, 42% and 36% respectively. Mean annual healthcare costs including the acquisition cost of the study drugs were 1721 Euro (SEM 160) in the tiotropium group and 1,541 Euro (SEM 163) in the ipratropium group (difference 180 Euro). Incremental cost-effectiveness ratios were 667 Euro per exacerbation avoided and 1084 Euro per patient with a relevant improvement on the SGRQ. Substituting tiotropium for ipratropium in chronic obstructive pulmonary disease patients offers improved health outcomes and is associated with increased costs of 180 Euro per patient per year.
Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial
PMID: 14979498 [PubMed - indexed for MEDLINE]
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Tiotropium bromide: a long-acting anticholinergic bronchodilator for the treatment of patients with chronic obstructive pulmonary disease
Joos GF, Brusselle G, Derom E, Pauwels R
- Department of Respiratory Diseases, Ghent University Hospital, Belgium.
Prevention and relief of symptoms by regular use of bronchodilators is central to the management of patients with chronic obstructive pulmonary disease (COPD). The bronchodilators in use are beta2-agonists, anticholinergics and theophylline. Since the 1970s the anticholinergic ipratropium bromide has been widely used for the treatment of patients with regular symptoms, but because it has a relatively short duration of action, it needs to be administered four times a day. Tiotropium bromide is a long-acting anticholinergic suitable for once daily administration. It has been developed as a dry powder inhaler for the treatment of patients with COPD. Large clinical trials with administration of the drug for one year have now been published. Compared with placebo and ipratopium bromide, significant and long-lasting bronchodilatation was observed, which was maintained over the year. The bronchodilator effect of tiotropium bromide was accompanied by improvements in other health outcomes. A significant decrease in dyspnoea, improvement in health-related quality of life, and a reduction in the number of COPD exacerbations and hospitalisations were noted. In this review we summarise the clinical development of this compound.
Publication Types:
• Review
• Review, Tutorial
PMID: 14712894 [PubMed - indexed for MEDLINE]
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Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes
Celli B, ZuWallack R, Wang S, Kesten S
- Pulmonary and Critical Care Division, St. Elizabeth's MedicalCenter, Boston, MA02135, USA. bcelli@cchcs.org
BACKGROUND: In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium. METHODS: To evaluate the effect of tiotropium, 18 micro g/d, on IC, a 4-week, randomized, double-blind, placebo-controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV(1), FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (- 60 and - 15 min) and after study drug (30 min, 60 min, 120 min, and 180 min). RESULTS: Mean age was 64 years; 62% were men. Mean baseline FEV(1) was 1.12 L (43% predicted). The mean differences (tiotropium - placebo) in FEV(1) trough (morning before drug), peak, and area under the curve over 3 h values (adjusted for baseline and center differences) at week 4 were 0.16 L, 0.22 L, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22 L, 0.35 L, and 0.30 L (p < 0.01 for all). Differences in TGV were - 0.54 L, - 0.60 L, and - 0.70 L, respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV(1) and lung volumes (FEV(1), 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%). CONCLUSIONS: Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 14605043 [PubMed - indexed for MEDLINE]
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Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease
Calverley PM, Lee A, Towse L, van Noord J, Witek TJ, Kelsen S
- Department of Medicine, University of Liverpool, Liverpool, UK. pmacal@liverpool.ac.uk
BACKGROUND: In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV1) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD. We hypothesised that tiotropium would modify the overnight change in FEV1, and this would be unaffected by the timing of drug administration. METHODS: A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV1=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment. RESULTS: There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV1 (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV1 (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p minor 0.01). FEV1 before morning or evening dosing was similar, while the peak FEV1 moved later in the day with active treatment. The mean percentage change in FEV1 from 09.00 hours to 03.00 hours (the nocturnal decline in FEV1) was -2.8% in the morning group, -1.0% in the evening group, and -12.8% in the placebo group. The magnitude of the peak to trough change in FEV1 was not statistically different. CONCLUSIONS: Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre.
Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial
PMID: 14514937 [PubMed - indexed for MEDLINE]
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Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses
Tashkin D, Kesten S
- Pulmonary Division, DavidGeffenSchool of Medicine at the University of California at Los Angeles, 90095, USA. DTashkin@mednet.ucla.edu
OBJECTIVES: To determine whether long-term symptomatic improvement occurs in COPD patients with maintenance bronchodilator therapy despite a nonsignificant short-term improvement in FEV(1) following bronchodilator inhalation obtained at a single time point. METHODS: Data obtained during two identical 1-year, placebo-controlled trials of tiotropium, 18 micro g once daily, were analyzed retrospectively to determine the associations of long-term improvements in lung function and patient health status with short-term improvements in FEV(1), as measured on the first day of treatment. Based on the presence or absence of a short-term improvement in FEV(1) of > or = 12% and > or = 200 mL, respectively, patients who had been treated with tiotropium were characterized as being responsive to tiotropium (TIO-R) or poorly responsive to tiotropium (TIO-PR). RESULTS: Baseline characteristics were similar other than baseline FEV(1), which was higher in the TIO-R group than in both the TIO-PR and placebo groups (p < 0.05). Baseline FEV(1) was 1.08 L in the TIO-R group (n = 263), 0.95 L in the TIO-PR (n = 255), and 0.99 L in the placebo group (n = 328). The mean (+/- SD) morning predose FEV(1) at 1 year significantly (p < 0.001) improved in patients in both of the tiotropium treatment subgroups (TIO-R group, 212 +/- 17 mL; TIO-PR group, 94 +/- 17 mL) relative to those treated with placebo. Statistically significant improvements in both tiotropium-treated groups also were noted over 1 year for dyspnea (p < 0.001), as assessed by the transition dyspnea index (TDI) [TIO-R group, 1.36 +/- 0.23 L; TIO-PR group, 0.86 +/- 0.23 L] relative to the placebo group. Patient health status assessed by the St. George Respiratory Questionnaire (SGRQ) showed statistically significant improvements over placebo for the TIO-R and TIO-PR groups (-3.96 +/- 0.99 and -3.05 +/- 1.00 L, respectively; p < 0.005). There was a significant correlation of the first-dose short-term FEV(1) response to the end-of-trial trough response (r = 0.43), but there was only a weak correlation to TDI focal score (r = 0.17) or SGRQ total score (r= -0.12). CONCLUSIONS: Tiotropium was effective in the treatment of patients with COPD, irrespective of the presence or absence of a short-term response on the first day of treatment. The short-term bronchodilator response should not be used as a definitive criterion for prescribing long-term treatment with inhaled bronchodilators.
PMID: 12740259 [PubMed - indexed for MEDLINE]
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Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S
- Facolta di Medicina e Chirurgia, Universita di Genova, Genova, Italy. brusasco@dism.unige.it
BACKGROUND: A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos. METHODS: Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 micro g once daily via HandiHaler or salmeterol 50 micro g twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry. RESULTS: 1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0-3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo. CONCLUSIONS: Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 12728159 [PubMed - indexed for MEDLINE]
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Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?
Tennant RC, Erin EM, Barnes PJ, Hansel TT
- Clinical Studies Unit, National Heart and Lung Institute, ImperialCollege, London, UK
Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.
Publication Types:
• Review
• Review, Tutorial
PMID: 12810191 [PubMed - indexed for MEDLINE]
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Bronchodilating
effect of oxitropium bromide in heart disease patients
with exacerbations of COPD: double-blind, randomized,
controlled study.
Centanni S, Santus P, Casanova F, Carlucci P, Boveri
B, Castagna F, Di MF, Cazzola M.
- Institute of Lung Disease, Respiratory Unit, San
Paolo Hospital, University of Milan, Itlay.
Anti-cholinergic agents are considered the bronchodilator
therapy of first-choice in the treatment of patients
with stable chronic obstructive pulmonary disease
(COPD) associated with heart disease since they may
be as effective or more effective than inhaled beta2-agonists
and, moreover, they do not interact with cardiac beta-adrenoceptors.
The aim of our study was to evaluate the bronchodilator
activity of oxitropium bromide in outpatients suffering
from exacerbations of COPD associated with heart diseases
(ischaemic heart disease and/or arrhythmias). We recruited
50 consecutive outpatients (33 males and 17 females,
mean age 68.6 years, 15 current smokers and 35 ex-smokers).
Each patient performed body plethismography in basal
condition and 30 min after inhalation of 200 microg
metered dose inhaler (MDI) oxitropium bromide administered
by a device (Fluspacer). FEV1, FVC, MMEF25-75, sRaw
and tRaw were evaluated. Thirty minutes after 200
microg oxitropium bromide administration, we observed
a significant improvement in FEV1 11.6% +/- 1 (mean
+/- SEM) (P<0.01); FVC, MMEF25-75 sRaw variation
was respectively: 9.2% +/- 0.6, 31.4 +/- 2.9, -19.9
+/- 1.1. Placebo did not significantly change pulmonary
function. Our data suggest that oxitropium bromide
bronchodilator activity is effective in exacerbations
of COPD.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 11905547 [PubMed - indexed for MEDLINE]
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Anti-cholinergic bronchodilators
versus beta2-sympathomimetic agents for acute exacerbations
of chronic obstructive pulmonary disease (Cochrane
Review)
McCrory DC, Brown CD.
Center for Clinical Health Policy Research, Duke University
Medical Center, 2200 W. Main St., Suite 230, Durham,
NC, USA, 27705. douglas.mccrory@duke.edu
BACKGROUND: Inhaled brocnhodilators form the mainstay
of treatment for acute exacerbations of COPD. Two
types of agent are used routinely, either singly or
in combination: anticholinergic agents and beta2-sympathomimetic
agonists. OBJECTIVES: To assess the effect of anti-cholinergic
agents on lung function and dyspnea in patients with
acute exacerbations of COPD, compared with placebo
or short-acting beta-2 agonists. SEARCH STRATEGY:
A comprehensive search of the literature was carried
out on MEDLINE, EMBASE, CINAHL and the Cochrane COPD
Trials Register, using the terms: bronchodilator*
OR ipratropium OR oxitropium. References listed in
each included trial were searched for additional trial
reports. SELECTION CRITERIA: Studies were included
if the participants were adult patients with a known
diagnosis of COPD and had symptoms consistent with
criteria for acute exacerbation of COPD. All randomized
controlled trials that compared inhaled ipratropium
bromide or oxitropium bromide to appropriate controls
were considered. Appropriate control treatments included
placebo, other bronchodilating agents, or combination
therapies. Studies of acute asthma or ventilated patients
were excluded. DATA COLLECTION AND ANALYSIS: All trials
that appeared to be relevant were assessed by two
reviewers who independently selected trials for inclusion.
Differences were resolved by consensus. MAIN RESULTS:
Four trials compared the short-term effects of ipratropium
bromide vs. a beta2-agonist. Short-term changes in
FEV1 (up to 90 minutes) showed no significant difference
between beta2-agonist and ipratropium bromide treated
patients. The differences were similar among the studies
and when combined: Weighted Mean Difference (WMD)
0.0 liters (95% Confidence Interval (95% CI) -0.19,
0.19). There was no significant additional increase
in change in FEV1 on adding ipratropium to beta2-agonist:
WMD 0.02 liter (95% CI -0.08, 0.12). Long-term effects
(24 hours) of the ipratropium bromide and beta2-agonist
treatment combination were similar: WMD 0.05 liters
(95%CI -0.14, 0.05). Neither of two studies found
significant changes in PaO2, either short- or long-term,
with ipratropium vs. beta-agonist, although one showed
an increase in PaO2 in subjects receiving ipratropium
bromide at 60 minutes. Adverse drug reactions included
dry mouth and tremor. REVIEWER'S CONCLUSIONS: There
was no evidence that the degree of bronchodilation
achieved with ipratropium bromide was greater than
that using a short-acting beta2-agonist. The combination
of a beta2-agonist and ipratropium did not appear
to increase the effect on FEV1 more than either used
alone.
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A 6-month, placebo-controlled
study comparing lung function and health status changes
in COPD patients treated with tiotropium or salmeterol.
Donohue JF, van Noord JA, Bateman ED, Langley SJ,
Lee A, Witek TJ Jr, Kesten S, Towse L.
Division of Pulmonary Medicine, University of North
Carolina, Chapel Hill, NC 27599-7020, USA. jdonohue@med.unc.edu
BACKGROUND: Tiotropium, a once-daily anticholinergic,
and salmeterol represent two inhaled, long-acting
bronchodilators from different pharmacologic classes.
A trial was designed to examine the efficacy and safety
of both compounds with multiple outcome measures,
including lung function, dyspnea, and health-related
quality of life (HRQoL) in patients with COPD. METHODS:
A 6-month, randomized, placebo-controlled, double-blind,
double-dummy, parallel-group study of tiotropium,
18 microg once daily via dry-powder inhaler, compared
with salmeterol, 50 microg bid via metered-dose inhaler,
was conducted in patients with COPD. Efficacy was
assessed by 12-h monitoring of spirometry, transition
dyspnea index (TDI), and the St. George's Respiratory
Questionnaire (SGRQ). RESULTS: A total of 623 patients
participated (tiotropium, n= 209; salmeterol, n =
213; and placebo, n = 201). The groups were similar
in age (mean, 65 years), gender (75% men), and baseline
FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted,
40 +/- 12% [+/- SD]). Compared with placebo treatment,
the mean predose morning FEV(1) following 6 months
of therapy increased significantly more for the tiotropium
group (0.14 L) than the salmeterol group (0.09 L;
p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium
was statistically superior to salmeterol (difference,
0.08 L; p < 0.001). Tiotropium improved TDI focal
score by 1.02 U compared with placebo (p = 0.01),
whereas there was no significant change in TDI focal
score with salmeterol (0.24 U). Tiotropium was superior
to salmeterol in improving TDI focal score (p <
0.05). At 6 months, the mean improvement in SGRQ total
score vs baseline was tiotropium, - 5.14 U (p <
0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs
placebo); and placebo, - 2.43 U. A statistically higher
proportion of patients receiving tiotropium achieved
at least a 4-U change in SGRQ score compared to patients
receiving placebo. Both active drugs reduced the need
for rescue albuterol (p < 0.0001). CONCLUSIONS:
Tiotropium once daily produces superior bronchodilation,
improvements in dyspnea, and proportion of patients
achieving meaningful changes in HRQoL compared to
twice-daily salmeterol in patients with COPD.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 12114338 [PubMed - indexed for MEDLINE]
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Pharmacodynamic steady state of
tiotropium in patients with chronic obstructive pulmonary
disease.
van Noord JA, Smeets JJ, Custers FL, Korducki L,
Cornelissen PJ.
Dept of Respiratory Diseases, Atrium Medical Centre,
Heerlen, The Netherlands. longarts.om@wolmail.nl
Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic
that has its effect through prolonged muscarinic (M)3
receptor antagonism. It has a clinically documented,
long duration of action with once-daily dosing in
chronic obstructive pulmonary disease (COPD). A single-centre,
double-blind, ipratropium-controlled study was conducted
in order to characterize the onset of pharmacodynamic
steady state of tiotropium in patients with COPD.
Thirty-one patients (25 male, six female) with a mean
age of 62 yrs and a mean forced expiratory volume
in one second (FEV1) of 1.13 L (38% of predicted)
were randomly assigned to receive either tiotropium
18 microg once-daily from a dry-powder inhaler (HandiHaler,
20 patients), or ipratropium 40 microg four-times
daily from a pressurized metered-dose inhaler (11
patients) for a period of 1 week. FEV1 and forced
vital capacity (FVC) were measured 1 h prior to, and
just before inhalation (mean value of the two measurements
on test-day 1 was the baseline value, while on all
other test days it was the trough value), and 0.5,
1, 2, 3, 4, 5, and 6 h after inhalation of the morning
dose of the study drug (one capsule and two puffs)
on days 1, 2, 3, and 8. Trough FEV1 following 8 days
of tiotropium was 0.19 L (18%) above baseline. Approximately
90% of this increase was achieved within 24 h of the
first dose (0.17 L, 16%). Trough FVC increased 0.67
L (27%) on test-day 8. Approximately 70% of the improvement
was observed after two tiotropium doses (0.47 L, 19%).
Achievement of FVC steady state was delayed compared
to FEV1. Ipratropium performed typically with an onset
of action within 30 min, a peak response between 1-2
h postdosing and a duration of action of approximately
4 h. It was concluded that forced expiratory volume
in one second steady state with tiotropium is reached
within 48 h, while continued improvements in forced
vital capacity can be expected over or beyond the
first week of therapy. The continued increases in
forced vital capacity beyond 48 h suggests that maintenance
bronchodilator therapy is required to achieve maximal
changes in hyperinflation.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 11998992 [PubMed - indexed for MEDLINE]
-
Comment in:
Improved health outcomes in patients
with COPD during 1 yr's treatment with tiotropium.
Vincken W, van Noord JA, Greefhorst AP, Bantje
TA, Kesten S, Korducki L, Cornelissen PJ; Dutch/Belgian
Tiotropium Study Group.
Respiratory Division, AZ VUB (Academic Hospital University
of Brussels), Belgium.
Tiotropium, a novel once-daily inhaled anticholinergic,
has been shown to improve lung function over a 24-h
period. In order to extend these findings, health-outcomes
were evaluated over 1 yr in chronic obstructive pulmonary
disease (COPD) patients. Spirometric results, peak
expiratory flow rate (PEFR), salbutamol use and effects
on dyspnoea, health-related quality of life and COPD
exacerbations were assessed in two identical 1-yr
randomized double-blind double-dummy studies of tiotropium
18 microg once daily (n=356) compared with ipratropium
40 microg q.i.d. (n=179). Screening forced expiratory
volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7%
of the predicted value) (tiotropium) and 1.18+/-0.37
L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at
1 yr improved by 0.12+/-0.01 L with tiotropium and
declined by 0.03+/-0.02 L with ipratropium (p<0.001).
Significant improvement in PEFR, salbutamol use, Transition
Dyspnea Index focal score, and the St George's Respiratory
Questionnaire total and impact scores were seen with
tiotropium (p<0.01). Tiotropium reduced the number
of exacerbations (by 24%, p<0.01), and increased
time to first exacerbation (p<0.01) and time to
first hospitalization for a COPD exacerbation (p<0.05)
compared with ipratropium. Apart from an increased
incidence of dry mouth in the tiotropium group, adverse
events were similar between treatments. Tiotropium
was effective in improving dyspnoea, exacerbations,
health-related quality of life and lung function in
patients with chronic obstructive pulmonary disease,
and exceeds the benefits seen with ipratropium. The
data support the use of tiotropium once-daily as first-line
maintenance treatment in patients with chronic obstructive
pulmonary disease.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 11871363 [PubMed - indexed for MEDLINE]
-
Comment in:
A long-term evaluation of once-daily
inhaled tiotropium in chronic obstructive pulmonary
disease.
Casaburi R, Mahler DA, Jones PW, Wanner A, San
PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr.
Harbor-UCLA Research and Education Institute, Torrance,
CA 90502, USA.
Currently available inhaled bronchodilators used as
therapy for chronic obstructive pulmonary disease
(COPD) necessitate multiple daily dosing. The present
study evaluates the long-term safety and efficacy
of tiotropium, a new once-daily anticholinergic in
COPD. Patients with stable COPD (age 65.2+/-8.7 yrs
(mean+/-SD), n=921) were enrolled in two identical
randomized double-blind placebo-controlled 1-yr studies.
Patients inhaled tiotropium 18 microg or placebo (mean
screening forced expiratory volume in one second (FEV1)
1.01 versus 0.99 L, 39.1 and 38.1% of the predicted
value) once daily as a dry powder. The primary spirometric
outcome was trough FEV1 (i.e. FEV1 prior to dosing).
Changes in dyspnoea were measured using the Transition
Dyspnea Index, and health status with the disease-specific
St. George's Respiratory Questionnaire and the generic
Short Form 36. Medication use and adverse events were
recorded. Tiotropium provided significantly superior
bronchodilation relative to placebo for trough FEV1
response (approximately 12% over baseline) (p<0.01)
and mean response during the 3 h following dosing
(approximately 22% over baseline) (p<0.001) over
the 12-month period. Tiotropium recipients showed
less dyspnoea (p<0.001), superior health status
scores, and fewer COPD exacerbations and hospitalizations
(p<0.05). Adverse events were comparable with placebo,
except for dry mouth incidence (tiotropium 16.0% versus
placebo 2.7%, p<0.05). Tiotropium is an effective,
once-daily bronchodilator that reduces dyspnoea and
chronic obstructive pulmonary disease exacerbation
frequency and improves health status. This suggests
that tiotropium will make an important contribution
to chronic obstructive pulmonary disease therapy.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 11866001 [PubMed - indexed for MEDLINE]
 |
|
-
-
Inhaled short-acting
beta2-agonists versus ipratropium for acute exacerbations
of chronic obstructive pulmonary disease.
McCrory DC, Brown CD.
- Pulmonary and Critical Care Medicine, Duke University
Medical Center, Box 3221, 350 Bell Building, Durham,
North Carolina, 27710, USA.
BACKGROUND: Inhaled short acting beta2 adrenergic
agonists and ipratropium bromide are both used in
the treatment of acute exacerbations of chronic obstructive
pulmonary disease. OBJECTIVES: In patients with acute
exacerbations of COPD to: 1. To assess the efficacy
of short-acting beta-2 agonists against placebo; 2.
Compare the efficacy of short-acting beta-2 agonists
and ipratropium. SEARCH STRATEGY: A comprehensive
search of the literature was carried out of EMBASE,
MEDLINE, CINAHL and the Cochrane COPD trials register
was carried out using the terms: bronchodilator* OR
albuterol OR metaproterenol OR terbutaline OR isoetharine
OR pirbuterol OR salbutamol OR beta-2 agonist. SELECTION
CRITERIA: All trials that appeared to be relevant
were assessed by two reviewers who independently selected
trials for inclusion. Differences were resolved by
consensus. DATA COLLECTION AND ANALYSIS: All trials
that appeared to be relevant were assessed by two
reviewers who independently selected trials for inclusion.
Differences were resolved by consensus. References
listed in each included trial were searched for additional
trial reports. Trials were combined using Review Manager
using a fixed effects model. The size of the treatment
effects were tested for heterogeneity. MAIN RESULTS:
We identified no placebo-controlled comparisons of
beta-2 agonists. Three studies permitted comparison
of ipratropium to an inhaled beta-2 agonist. These
studies included a total of 103 patients. The beta2-agonists
used were: fenoterol and metaproterenol. One study
was a parallel group trial of regular therapy for
seven days. The other two were cross over studies
of single dose treatments, with efficacy measured
90 min post dose. There was no washout period between
treatments. Both treatments produced an improvement
in forced expiratory volume (FEV1) after 90 min in
the range 150-250 ml. The was no difference between
treatments, mean difference in FEV1 10 ml; 95% CI
-220, 230 ml. In one small crossover study (n=10)
there was a significant improvement in arterial PaO2
after 30 minutes with ipratropium (+5.8 mm Hg +/-
3.0 (SEM)) compared to metaproterenol (-6.2 +/- 1.2
mm Hg), but this was not significant at 90 min. There
were no data concerning respiratory symptoms. The
crossover studies showed no evidence of an additive
effect of the two treatments, although they were not
designed specifically to test this. REVIEWER'S CONCLUSIONS:
There are few controlled trial data concerning the
use of inhaled beta2-agonist agents in acute exacerbations
of COPD and none that have compared these agents directly
with placebo. None of the studies used the more modern
beta2-agonists used most widely in this setting (salbutamol
and terbutaline). Beta2-agonists and ipratropium both
produce small improvements in FEV1, but beta2-agonists
may worsen PaO2 for a period. We could not draw conclusions
concerning possible additive effects.
Publication Types:
PMID: 11406052 [PubMed - indexed for MEDLINE]
-
-
| Am
J Manag Care 2002 Oct;8(10):902-11 |
|
-
Delivery of ipratropium and albuterol
combination therapy for chronic obstructive pulmonary
disease: effectiveness of a two-in-one inhaler versus
separate inhalers.
Chrischilles E, Gilden D, Kubisiak J, Rubenstein
L, Shah H.
University of Iowa, Iowa City, USA. echrischilles@uiowa.edu
OBJECTIVE: To determine whether a combined formulation
consisting of ipratropium and an inhaled beta2 agonist
(2-in-1 therapy) leads to lower respiratory-related
healthcare use and charges and improved compliance
compared with treatment with separate ipratropium
and beta2-agonist inhalers (separate inhaler therapy).
STUDY DESIGN: Retrospective inception cohort study.
PATIENTS AND METHODS: Healthcare use, charges, and
treatment compliance were examined for adults age
38 years or older who initiated ipratropium therapy
on or after July 1997, based on health claims data
for United Healthcare enrollees from 5 health plans
from July 1997 through December 1998. A total of 428
patients received 2-in-1 therapy, and 658 patients
received separate inhaler therapy. To adjust for disease
severity and other confounders, the following were
determined for the preinitiation period: age; sex;
use of oral steroids, antibiotics, or albuterol; respiratory-related
healthcare use; and respiratory diagnoses. Compliance
was defined as not interrupting or discontinuing therapy
during the follow-up period. RESULTS: After adjusting
for baseline covariates, 2-in-1 therapy users had
a significantly lower risk of emergency department
use or hospitalization (relative risk = 0.58, 95%
confidence interval [CI] = 0.36, 0.94), lower mean
monthly healthcare charges (P= .015), shorter hospital
stays (2.05 vs 4.61 days, P = .040), and greater likelihood
of compliance (odds ratio = 1.77, 95% CI = 1.46, 2.14).
CONCLUSION: A single inhaler containing both ipratropium
and albuterol can increase compliance and decrease
respiratory morbidity and charges over and above the
effects achieved with separate inhalers for these
2 agents.
PMID: 12395958 [PubMed - indexed for MEDLINE]
-
| Respir
Med 2002 Aug;96(8):559-66 |
|
-
Effects of formoterol (Oxis Turbuhaler)
and ipratropium on exercise capacity in patients with
COPD.
Liesker JJ, Van De Velde V, Meysman M, Vincken
W, Wollmer P, Hansson L, Kerstjens HA, Qvint U, Pauwels
RA.
Department of Pulmonary Diseases, University Hospital
Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Although long-acting inhaled beta 2-agonists improve
various outcome measures in COPD, no double-blind
study has yet shown a significant effect of these
drugs on exercise capacity. In a randomized, double-blind,
placebo-controlled, crossover study, patients received
formoterol (4, 5, 9, or 18 micrograms b.i.d. via Turbuhaler),
ipratropium bromide (80 micrograms t.i.d. via pMDI
with spacer), or placebo for 1 week. Main endpoint
was time to exhaustion (TTE) in an incremental cycle
ergometer test. Secondary endpoints were Borg dyspnoea
score during exercise, lung function, and adverse
events. Thirty-four patients with COPD were included,
mean age 64.8 years, FEV1 55.6% predicted, reversibility
6.1% predicted. All doses of formoterol, and ipratropium
significantly improved TTE, FEV1, FEF25-75%, FRC,
IVC, RV and sGAW compared with placebo. A negative
dose-response relationship was observed with formoterol.
Ipratropium increased time to exhaustion more compared
with formoterol, 18 micrograms, but not with formoterol,
4.5 and 9 micrograms. No changes in Borg score were
found. There was no difference in the adverse event
profile between treatments. In conclusion, 1 week
of treatment with formoterol and ipratropium significantly
improved exercise capacity and lung function compared
with placebo. However, a negative dose-response relation
for formoterol was unexpected and needs further investigation.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12195835 [PubMed - indexed for MEDLINE]
-
| Chest
2002 Jul;122(1):47-55 |
|
-
A 6-month, placebo-controlled study
comparing lung function and health status changes
in COPD patients treated with tiotropium or salmeterol.
Donohue JF, van Noord JA, Bateman ED, Langley SJ,
Lee A, Witek TJ Jr, Kesten S, Towse L.
Division of Pulmonary Medicine, University of North
Carolina, Chapel Hill, NC 27599-7020, USA. jdonohue@med.unc.edu
BACKGROUND: Tiotropium, a once-daily anticholinergic,
and salmeterol represent two inhaled, long-acting
bronchodilators from different pharmacologic classes.
A trial was designed to examine the efficacy and safety
of both compounds with multiple outcome measures,
including lung function, dyspnea, and health-related
quality of life (HRQoL) in patients with COPD. METHODS:
A 6-month, randomized, placebo-controlled, double-blind,
double-dummy, parallel-group study of tiotropium,
18 microg once daily via dry-powder inhaler, compared
with salmeterol, 50 microg bid via metered-dose inhaler,
was conducted in patients with COPD. Efficacy was
assessed by 12-h monitoring of spirometry, transition
dyspnea index (TDI), and the St. George's Respiratory
Questionnaire (SGRQ). RESULTS: A total of 623 patients
participated (tiotropium, n= 209; salmeterol, n =
213; and placebo, n = 201). The groups were similar
in age (mean, 65 years), gender (75% men), and baseline
FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted,
40 +/- 12% [+/- SD]). Compared with placebo treatment,
the mean predose morning FEV(1) following 6 months
of therapy increased significantly more for the tiotropium
group (0.14 L) than the salmeterol group (0.09 L;
p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium
was statistically superior to salmeterol (difference,
0.08 L; p < 0.001). Tiotropium improved TDI focal
score by 1.02 U compared with placebo (p = 0.01),
whereas there was no significant change in TDI focal
score with salmeterol (0.24 U). Tiotropium was superior
to salmeterol in improving TDI focal score (p <
0.05). At 6 months, the mean improvement in SGRQ total
score vs baseline was tiotropium, - 5.14 U (p <
0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs
placebo); and placebo, - 2.43 U. A statistically higher
proportion of patients receiving tiotropium achieved
at least a 4-U change in SGRQ score compared to patients
receiving placebo. Both active drugs reduced the need
for rescue albuterol (p < 0.0001). CONCLUSIONS:
Tiotropium once daily produces superior bronchodilation,
improvements in dyspnea, and proportion of patients
achieving meaningful changes in HRQoL compared to
twice-daily salmeterol in patients with COPD.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 12114338 [PubMed - indexed for MEDLINE]
-
| Am
J Manag Care 2002 Oct;8(10):902-11 |
|
-
Delivery of ipratropium and albuterol
combination therapy for chronic obstructive pulmonary
disease: effectiveness of a two-in-one inhaler versus
separate inhalers.
Chrischilles E, Gilden D, Kubisiak J, Rubenstein
L, Shah H.
University of Iowa, Iowa City, USA. echrischilles@uiowa.edu
OBJECTIVE: To determine whether a combined formulation
consisting of ipratropium and an inhaled beta2 agonist
(2-in-1 therapy) leads to lower respiratory-related
healthcare use and charges and improved compliance
compared with treatment with separate ipratropium
and beta2-agonist inhalers (separate inhaler therapy).
STUDY DESIGN: Retrospective inception cohort study.
PATIENTS AND METHODS: Healthcare use, charges, and
treatment compliance were examined for adults age
38 years or older who initiated ipratropium therapy
on or after July 1997, based on health claims data
for United Healthcare enrollees from 5 health plans
from July 1997 through December 1998. A total of 428
patients received 2-in-1 therapy, and 658 patients
received separate inhaler therapy. To adjust for disease
severity and other confounders, the following were
determined for the preinitiation period: age; sex;
use of oral steroids, antibiotics, or albuterol; respiratory-related
healthcare use; and respiratory diagnoses. Compliance
was defined as not interrupting or discontinuing therapy
during the follow-up period. RESULTS: After adjusting
for baseline covariates, 2-in-1 therapy users had
a significantly lower risk of emergency department
use or hospitalization (relative risk = 0.58, 95%
confidence interval [CI] = 0.36, 0.94), lower mean
monthly healthcare charges (P= .015), shorter hospital
stays (2.05 vs 4.61 days, P = .040), and greater likelihood
of compliance (odds ratio = 1.77, 95% CI = 1.46, 2.14).
CONCLUSION: A single inhaler containing both ipratropium
and albuterol can increase compliance and decrease
respiratory morbidity and charges over and above the
effects achieved with separate inhalers for these
2 agents.
PMID: 12395958 [PubMed - indexed for MEDLINE]
-
| Respir
Med 2002 Aug;96(8):559-66 |
|
-
Effects of formoterol (Oxis Turbuhaler)
and ipratropium on exercise capacity in patients with
COPD.
Liesker JJ, Van De Velde V, Meysman M, Vincken
W, Wollmer P, Hansson L, Kerstjens HA, Qvint U, Pauwels
RA.
Department of Pulmonary Diseases, University Hospital
Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Although long-acting inhaled beta 2-agonists improve
various outcome measures in COPD, no double-blind
study has yet shown a significant effect of these
drugs on exercise capacity. In a randomized, double-blind,
placebo-controlled, crossover study, patients received
formoterol (4, 5, 9, or 18 micrograms b.i.d. via Turbuhaler),
ipratropium bromide (80 micrograms t.i.d. via pMDI
with spacer), or placebo for 1 week. Main endpoint
was time to exhaustion (TTE) in an incremental cycle
ergometer test. Secondary endpoints were Borg dyspnoea
score during exercise, lung function, and adverse
events. Thirty-four patients with COPD were included,
mean age 64.8 years, FEV1 55.6% predicted, reversibility
6.1% predicted. All doses of formoterol, and ipratropium
significantly improved TTE, FEV1, FEF25-75%, FRC,
IVC, RV and sGAW compared with placebo. A negative
dose-response relationship was observed with formoterol.
Ipratropium increased time to exhaustion more compared
with formoterol, 18 micrograms, but not with formoterol,
4.5 and 9 micrograms. No changes in Borg score were
found. There was no difference in the adverse event
profile between treatments. In conclusion, 1 week
of treatment with formoterol and ipratropium significantly
improved exercise capacity and lung function compared
with placebo. However, a negative dose-response relation
for formoterol was unexpected and needs further investigation.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12195835 [PubMed - indexed for MEDLINE]
-
| Chest
2002 Jul;122(1):47-55 |
|
-
A 6-month, placebo-controlled study
comparing lung function and health status changes
in COPD patients treated with tiotropium or salmeterol.
Donohue JF, van Noord JA, Bateman ED, Langley SJ,
Lee A, Witek TJ Jr, Kesten S, Towse L.
Division of Pulmonary Medicine, University of North
Carolina, Chapel Hill, NC 27599-7020, USA. jdonohue@med.unc.edu
BACKGROUND: Tiotropium, a once-daily anticholinergic,
and salmeterol represent two inhaled, long-acting
bronchodilators from different pharmacologic classes.
A trial was designed to examine the efficacy and safety
of both compounds with multiple outcome measures,
including lung function, dyspnea, and health-related
quality of life (HRQoL) in patients with COPD. METHODS:
A 6-month, randomized, placebo-controlled, double-blind,
double-dummy, parallel-group study of tiotropium,
18 microg once daily via dry-powder inhaler, compared
with salmeterol, 50 microg bid via metered-dose inhaler,
was conducted in patients with COPD. Efficacy was
assessed by 12-h monitoring of spirometry, transition
dyspnea index (TDI), and the St. George's Respiratory
Questionnaire (SGRQ). RESULTS: A total of 623 patients
participated (tiotropium, n= 209; salmeterol, n =
213; and placebo, n = 201). The groups were similar
in age (mean, 65 years), gender (75% men), and baseline
FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted,
40 +/- 12% [+/- SD]). Compared with placebo treatment,
the mean predose morning FEV(1) following 6 months
of therapy increased significantly more for the tiotropium
group (0.14 L) than the salmeterol group (0.09 L;
p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium
was statistically superior to salmeterol (difference,
0.08 L; p < 0.001). Tiotropium improved TDI focal
score by 1.02 U compared with placebo (p = 0.01),
whereas there was no significant change in TDI focal
score with salmeterol (0.24 U). Tiotropium was superior
to salmeterol in improving TDI focal score (p <
0.05). At 6 months, the mean improvement in SGRQ total
score vs baseline was tiotropium, - 5.14 U (p <
0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs
placebo); and placebo, - 2.43 U. A statistically higher
proportion of patients receiving tiotropium achieved
at least a 4-U change in SGRQ score compared to patients
receiving placebo. Both active drugs reduced the need
for rescue albuterol (p < 0.0001). CONCLUSIONS:
Tiotropium once daily produces superior bronchodilation,
improvements in dyspnea, and proportion of patients
achieving meaningful changes in HRQoL compared to
twice-daily salmeterol in patients with COPD.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 12114338 [PubMed - indexed for MEDLINE]
 |
|
-
-
The spirometric efficacy of once-daily
dosing with tiotropium in stable COPD: a 13-week multicenter
trial. The US Tiotropium Study Group.
Casaburi R, Briggs DD Jr, Donohue JF, Serby CW,
Menjoge SS, Witek TJ Jr.
Harbor-UCLA Research and Education Institute (Dr.
Casaburi), Torrance, CA 90509, USA. casaburi@ucla.edu
STUDY OBJECTIVE: To compare the bronchodilator efficacy
and safety of tiotropium and placebo. DESIGN: A 3-month,
randomized, double-blind, placebo-controlled, multicenter
trial. SETTING: Outpatient. PATIENTS: Four hundred
seventy patients with stable COPD (mean FEV(1) = 38.6%
predicted). INTERVENTIONS: Tiotropium 18 microg (N
= 279) or placebo (N = 191) given once daily via a
lactose-based dry-powder inhaler device. Measurements
and results: Spirometry was evaluated on days 1, 8,
50, and 92. Data were expressed as the mean trough
(ie, before morning dose; 23 to 24 h after previous
dose) and average response observed in the 3 h after
the dose was received. Tiotropium produced significant
improvement in trough FEV(1) and FVC, averaging 12%
greater than baseline on day 8; these improvements
were maintained on days 50 and 92. The average postdose
FEV(1) was 16% greater than baseline on day 1 and
20% greater than baseline on day 92; FVC was 17% greater
than baseline on day 1 and 19% greater than baseline
on day 92. Tiotropium was significantly more effective
than placebo in both trough and average FEV(1) and
FVC response (p < 0.001). These spirometric effects
were corroborated by significant improvements in daily
morning and evening peak expiratory flow rate, as
well as a reduction in "as-needed" albuterol use.
Symptoms of wheezing and shortness of breath were
significantly less in patients receiving tiotropium,
and the physician global assessment noted overall
improvements with those treated with tiotropium relative
to placebo. The most common reported adverse event
after tiotropium was dry mouth (9.3% vs 1.6% relative
to placebo; p < 0.05). CONCLUSIONS: These data
demonstrate that tiotropium is a safe and effective
once-daily anticholinergic bronchodilator and should
prove useful as first-line maintenance therapy in
COPD.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 11083677 [PubMed - indexed for MEDLINE]
-
-
Long-acting bronchodilation with
once-daily dosing of tiotropium (Spiriva) in stable
chronic obstructive pulmonary disease.
Littner MR, Ilowite JS, Tashkin DP, Friedman M,
Serby CW, Menjoge SS, Witek TJ Jr.
Sepulveda Ambulatory Care and Nursing Home, Veterans
Administration Greater Los Angeles Healthcare System,
Sepulveda, CA, USA.
Tiotropium (Spiriva; Ba679BR) is a new-generation,
long-acting anticholinergic bronchodilator that has
muscarinic M(1) and M(3) receptor subtype selectivity.
A multicenter, randomized, double-blind, parallel
group, placebo-controlled study was conducted to evaluate
the dose-response characteristics of tiotropium inhalation
powder given once daily to stable patients with chronic
obstructive pulmonary disease (COPD). Patients (mean
FEV(1) = 1.08 L [42% predicted]) were randomized to
receive 0, 4.5, 9, 18, or 36 microg tiotropium once
daily at noon for 4 wk, with spirometry done before
and hourly for 6 h after dosing. Patients measured
and recorded their peak expiratory flow rates (PEFRs)
three times each day. Significant dose-related improvement
in FEV(1) and significant improvement in FVC occurred
within 1 h after the first dose of tiotropium as compared
with placebo. Over the 29 d of the study, all doses
of tiotropium produced significant increases over
placebo in trough (i.e., as measured spirometrically
at 20 to 24 h after the previous dose and just before
the next dose of tiotropium), peak, and 6-h postdose
average FEV(1) and FVC, and in PEFR, without a significant
difference among the different doses investigated.
PEFR gradually returned to pretreatment baseline levels
over a 3-wk evaluation period following the discontinuation
of tiotropium. The overall safety profile for the
tiotropium doses was similar to that for placebo.
In summary, tiotropium was shown to be safe and effective
in doses ranging from 4.5 to 36 microg delivered once
daily. The improvements in spirometry with once-daily
dosing confirm the long duration of action of tiotropium
reported in single-dose studies, and its sustained
improvement of spirometric measures over the 1 mo
of testing in the study points to utility of tiotropium
as a maintenance bronchodilator for patients with
COPD. On the basis of the comparable bronchodilator
response at doses from 9 to 36 microg, and advantages
suggested by the safety profile at doses below 36
microg in this study, a dose of 18 microg once daily
was selected for use in long-term studies of the safety
and efficacy of tiotropium.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 10764302 [PubMed - indexed for MEDLINE]
-
Comment in:
- ACP Journal Club 2000 Nov-Dec;133(3):101
A randomised controlled comparison
of tiotropium nd ipratropium in the treatment of chronic
obstructive pulmonary disease. The Dutch Tiotropium
Study Group.
van Noord JA, Bantje TA, Eland ME, Korducki L,
Cornelissen PJ.
Department of Respiratory Diseases, Atrium Medisch
Centrum, Heerlen, The Netherlands.
BACKGROUND: A study was undertaken
to evaluate and compare the efficacy and safety of
tiotropium and ipratropium during long term treatment
in patients with stable chronic obstructive pulmonary
disease (COPD). METHODS: 288 patients of mean (SD)
age 65 (8) years and forced expiratory volume in one
second (FEV(1)) 41 (12)% predicted participated in
a 14 centre, double blind, double dummy, parallel
group study and were randomised after a run in period
of two weeks to receive either tiotropium 18 microg
once daily from a dry powder inhaler (HandiHaler;
two thirds of patients) or ipratropium 40 microg four
times daily from a metered dose inhaler (one third
of patients) for a period of 13 weeks. Outcome measures
were lung function, daily records of peak expiratory
flow (PEF), and the use of concomitant salbutamol.
FEV(1) and forced vital capacity (FVC) were measured
one hour before and immediately before inhalation
(mean value of the two measurements on test day 1
was the baseline value while on all other test days
it was known as the trough FEV(1) and FVC), and 0.5,
1, 2, 3, 4, 5, and 6 hours after inhalation of the
study drug on days 1, 8, 50, and 92. RESULTS: During
treatment tiotropium achieved a significantly greater
improvement than ipratropium (p<0.05) in trough,
average, and peak FEV(1) levels and in trough and
average FVC levels. The trough FEV(1) response on
days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11
to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium
and between 0.01 l (95% CI -0.03 to 0.05) and 0.03
l (95% CI 0.01 to 0. 07) for ipratropium. The trough
FVC response on days 8, 50, and 92 ranged between
0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31
to 0.47) for tiotropium and between 0.08 l (95% CI
0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for
ipratropium. On all test days tiotropium produced
a greater improvement in FEV(1) than ipratropium starting
three hours after inhalation (p<0.05). During treatment
weekly mean morning and evening peak expiratory flow
(PEF) was consistently better in the tiotropium group
than in the ipratropium group, the difference in morning
PEF being significant up through week 10 and in evening
PEF up through week 7 of treatment (p<0.05). The
use of concomitant salbutamol was also lower in the
tiotropium group (p<0.05). The only drug related
adverse event was dry mouth (tiotropium 14.7%, ipratropium
10.3% of patients). CONCLUSIONS: Tiotropium in a dose
of 18 microg inhaled once daily using the HandiHaler
was significantly more effective than 40 microg ipratropium
four times daily in improving trough, average, and
peak lung function over the 13 week period. The safety
profile of tiotropium was similar to ipratropium.
These data support the use of tiotropium as first
line treatment for the long term maintenance treatment
of patients with airflow obstruction due to COPD.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 10722768 [PubMed - indexed for MEDLINE]
-
-
The effects of oxitropium bromide
on exercise performance in patients with stable chronic
obstructive pulmonary disease. A comparison of three
different exercise tests.
Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda
A, Izumi T.
Department of Respiratory Medicine, Graduate School
of Medicine, Kyoto University, Kyoto, Japan.
The purpose of the present study was to compare the
characteristics of three different exercise tests
in evaluating the effects of oxitropium bromide on
exercise performance. Thirty-eight males with stable
chronic obstructive pulmonary disease (COPD) (FEV(1)
= 40.8 +/- 16.5% predicted; mean +/- SD) completed
randomized, double-blind, placebo-controlled, crossover
studies for each exercise test. The exercise tests
were performed 60 min after the inhalation of either
oxitropium bromide 400 microg or placebo. The patients
performed 6-min walking tests (6MWT) on Days 1 and
2, progressive cycle ergometry (PCE) on Days 3 and
4, and cycle endurance tests at 80% of the maximal
workload of PCE on Days 5 and 6. Spirometry was conducted
before and at 45 and 90 min after the inhalation.
Oxitropium bromide significantly increased FEV(1)
as compared with placebo. Oxitropium bromide increased
the endurance time significantly, by 19% (p < 0.001),
and caused a small but significant increase in the
6-min walking distance by 1% (p < 0.05), but induced
no significant increase in maximal oxygen consumption
(V O(2)max) in PCE. The responses in these three exercise
tests were different, and we conclude that the endurance
test was the most sensitive in detecting the effects
of inhaled anticholinergic agents on exercise performance
in patients with stable COPD. An endurance procedure
may be performed to detect clinical changes in evaluating
the effects of oxitropium bromide on exercise performance.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 10852763 [PubMed - indexed for MEDLINE]
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