Original Article
A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease
N Engl J Med 2008; 359:1543-1554October 9, 2008
- Abstract
Background
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.
Methods
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 (FEV1) of 70% or less after bronchodilation and a ratio of FEV1 to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV1 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.
Results
Of a total of 5993 patients (mean age, 65±8 years) with a mean FEV1 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 FEV1 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 FEV1 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.
Conclusions
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 FEV1. (ClinicalTrials.gov number, NCT00144339.)
Media in This Article
Figure 1
Enrollment and Outcomes.Figure 2
Probability of Treatment Discontinuation, Mean FEV1 and FVC before and after Bronchodilation, and Scores for Health-Related Quality of Life.Article Activity
- Article
Prospective studies testing effects on the progression of chronic obstructive pulmonary disease (COPD) through the evaluation of the slope of the forced expiratory volume in 1 second (FEV1) have not shown that inhaled short-acting anticholinergic drugs, inhaled corticosteroids, or N-acetylcysteine alter this marker of disease progression.1-7 To date, only smoking cessation has prospectively been shown to alter the rate of decline of FEV1 in patients with COPD.2
Tiotropium is a once-daily, inhaled anticholinergic drug that provides at least 24-hour improvements in airflow and hyperinflation in patients with COPD.8-10 Clinical trials lasting 6 weeks to 12 months have shown improvements in exercise tolerance, health-related quality of life, and rates of dyspnea and exacerbations.8-13 A retrospective analysis of 1-year, placebo-controlled trials indicated that tiotropium had the potential to slow the rate of decline in FEV1.14
Given previous favorable clinical outcomes, we designed this trial to prospectively extend these observations to 4 years.15 In the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, we tested whether tiotropium would reduce the rate of decline in FEV1 in patients with COPD who were permitted therapy other than other inhaled anticholinergic drugs, according to current COPD guidelines. We evaluated the long-term effects of tiotropium therapy on the clinically important outcomes of health-related quality of life, exacerbations, related hospitalizations, and mortality.
Methods
Study Design
Details of the study design were reported previously by Decramer et al.15 and are summarized below. The protocol is provided in Supplementary Appendix 2, available with the full text of this article at www.nejm.org.
The study was a 4-year, randomized, double-blind, placebo-controlled, parallel-group trial involving patients with moderate-to-very-severe COPD.15 The two coprimary end points were the yearly rate of decline in the mean FEV1 before the use of a study drug and short-acting bronchodilators in the morning (prebronchodilator) and after the use of a study drug (postbronchodilator) from day 30 (steady state) until completion of double-blind treatment. Secondary outcome measures included the rate of decline in the mean forced vital capacity (FVC) and slow vital capacity (SVC); health-related quality of life, as measured by the total score on St. George's Respiratory Questionnaire (SGRQ), in which scores range from 0 to 100, with lower scores indicating improvement and a change of 4 units or more considered to be clinically meaningful; exacerbations of COPD (as defined below) and related hospitalizations; and the rate of death from any cause and from lower respiratory conditions. Details regarding secondary end points are provided in Supplementary Appendix 3.
Patients received either 18 μg of tiotropium or a matching placebo once daily, delivered through the HandiHaler inhalation device (Boehringer Ingelheim). All respiratory medications, except other inhaled anticholinergic drugs, were permitted during the trial. Smoking cessation programs were offered to all patients before randomization, and self-reported smoking behavior was recorded at each visit. At the end of the study, all patients were provided with and asked to take 40 μg of ipratropium (two inhaler actuations) four times daily and to return for a final assessment 30 days later.
Patients
Patients were recruited at 490 investigational centers in 37 countries. Criteria for participation included a diagnosis of COPD, an age of 40 years or more, a smoking history of at least 10 pack-years, a postbronchodilator FEV1 of 70% or less of the predicted value, and an FEV1 of 70% or less of the FVC (after supervised administration of 80 μg of ipratropium [four actuations], followed by 400 μg of albuterol [four actuations] 60 minutes later).16 Key exclusion criteria were a history of asthma, a COPD exacerbation or respiratory infection within 4 weeks before screening, a history of pulmonary resection, use of supplemental oxygen for more than 12 hours per day, and the presence of a coexisting illness that could preclude participation in the study or interfere with the study results. The protocol was approved by the ethics committee at each center, and all patients provided written informed consent.
Procedures
After a screening period, eligible patients were randomly assigned in a 1:1 ratio to receive either tiotropium or placebo with the use of centralized randomization in blocks of four, stratified according to site. After randomization, clinic visits occurred at 1 month and 3 months and then every 3 months throughout the 4-year study period.
Spirometry was performed according to American Thoracic Society guidelines17 at randomization, at the 1-month visit, at visits every 6 months throughout the study period, and at a follow-up visit approximately 30 days after the end of the study. Before spirometry testing, respiratory medications were withheld according to the following schedule: study drug, 24 hours; morning dose of inhaled corticosteroids, 12 hours; short-acting beta-agonists, 8 hours; short-acting (twice-daily or four-times-daily) theophyllines and long-acting beta-agonists (including fixed combination with inhaled corticosteroids), 24 hours; and once-daily theophyllines, 48 hours. Prebronchodilator spirometry was performed initially, followed immediately by the blinded administration of a study drug. Immediately thereafter, all patients received 80 μg of ipratropium (four inhaler actuations), followed 60 minutes later by 400 μg of albuterol (four inhaler actuations). Thirty minutes after the administration of albuterol, spirometry was again performed. Sites were provided with identical spirometry equipment and study-specific software. A centralized quality-assurance review of all spirometry data was performed during the study.15
Health-related quality of life was measured with the use of the SGRQ before prebronchodilator spirometry testing at baseline and every 6 months.18 Reports of adverse events were collected at each visit.
Exacerbations were defined as an increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid. Data regarding exacerbations and related hospitalizations were collected on study-specific case-report forms at every visit. An independent data and safety monitoring committee reviewed data throughout the trial (for details, see Supplementary Appendixes 2 and 4).
Study Oversight
The design of the trial, the monitoring of the trial conduct, the approval of the statistical analyses, the review and interpretation of the data, the writing of the manuscript, and the decision to publish the manuscript involved a joint advisory committee composed of four academic researchers (three investigators and a statistician), three researchers employed by Boehringer Ingelheim, and a representative of Pfizer (see Supplementary Appendix 4). The first draft of the manuscript was written by an academic investigator, and the final content of the manuscript was developed collaboratively by all authors. Statistical analyses were performed by employees of Boehringer Ingelheim. All authors had full access to the data and vouch for the accuracy and completeness of the data and the analyses.
Statistical Analysis
The number of patients needed for the study was based on the assumption of a standard deviation of 90 ml in the rate of decline in the mean FEV1 during the 4-year period2 to detect a difference of 15 ml between the tiotropium group and the placebo group, with a power of more than 90% at a significance level of 5% with the use of a two-sided test. The sample size was also based on an assumption that it would not be possible to perform a complete evaluation of 35% of patients because of early discontinuation. The sample size was chosen to be sufficiently large to undertake subgroup analyses of the primary end point in smokers, who were assumed to comprise about 40% of enrolled patients. The other planned subgroup analyses included the variables of age, sex, severity of COPD, region, reversibility, body-mass index, and concomitant use of medication. In addition, we conducted a post hoc subgroup analysis comparing patients in each study group who were or were not receiving inhaled corticosteroids or long-acting beta-agonists at baseline.
The two coprimary end points were analyzed with the use of a normal random-effects model in which the mean FEV1 changed linearly after day 30 for each patient, the intercepts and slopes among patients were assumed to be random with an arbitrary covariance matrix, and the treatment effect was fixed.19 The same model was used for the secondary end points of FVC and SVC (from day 30 until study completion) and the total score on the SGRQ (from 6 months until study completion). All patients who underwent randomization and received a study drug and who had at least three post-randomization data points (at least two for the SGRQ) were included in the analyses. We used likelihood-based methods to handle missing data for the random coefficient regression analysis, and therefore no imputation was deemed necessary. A sensitivity analysis was conducted for the rate of decline in the mean FEV1, with adjustment for baseline FEV1, smoking status, age, sex, and height. Analyses of heterogeneity of subgroups were assessed by testing for interaction between study-group slope and each baseline factor. The yearly rates of decline from baseline to 30 days after the discontinuation of a study drug were analyzed using the Wilcoxon rank-sum test. The mean effects at various visits were compared in the two study groups with the use of repeated-measures analysis of covariance without imputation of missing values. SGRQ data from Turkey were excluded owing to incorrect validation of the questionnaire.
The times to the first exacerbation and associated hospitalization in the two study groups were compared with the use of log-rank tests and were prespecified as the key secondary analyses. Cox regression was used to derive hazard ratios. Kaplan–Meier curves of the probability of no exacerbation and related hospitalization were calculated. The number of events and event days were compared between study groups with the use of Poisson regression with correction for treatment exposure and overdispersion.20
All patients who received a study drug were included in the analysis of safety and discontinuations. Incidence rates were computed as the number of patients with events divided by the time at risk. Time-to-event analyses were performed with the use of the log-rank test; hazard ratios were calculated with the use of Cox regression.
Analyses were performed with the use of SAS software, version 8.2 (SAS Institute). All reported P values are two-sided and were not adjusted for multiple testing. The scientific steering committee (Joint Advisory Committee) added a number of secondary end points and updated the analyses during the course of the trial while its members were unaware of study-group assignments. Details of the statistical analysis plan are provided in Supplementary Appendix 3.
Results
Study Population
Patients were recruited from January 2003 through March 2004; the study ended in February 2008. Of the 8020 patients who were recruited, 5993 underwent randomization (Figure 1Figure 1
Enrollment and Outcomes.). Of these patients, 4383 (73%) completed 2 years, 3891 (65%) completed 3 years, and 3569 (60%) completed at least 45 months. The median duration of treatment was 1436 days in the tiotropium group and 1435 days in the placebo group. A higher proportion of patients did not complete at least 45 months of treatment in the placebo group (44.6%) than in the tiotropium group (36.2%, P<0.001) (Figure 2AFigure 2Probability of Treatment Discontinuation, Mean FEV1 and FVC before and after Bronchodilation, and Scores for Health-Related Quality of Life.). The majority of discontinuations were due to adverse events.Baseline characteristics and concomitant use of respiratory medications were similar in the two study groups (Table 1Table 1
Baseline Characteristics of the Patients.). The mean age was 65±8 years among the patients, of whom 75% were men and 30% were current smokers. The mean prebronchodilator FEV1 was 1.10±0.40 liters (39% of the predicted value), and the mean postbronchodilator FEV1 was 1.32±0.44 liters (48% of the predicted value). The mean increase in FEV1 after maximal bronchodilation was 23±18%.21 Patients whose disease was classified as stage II, III, or IV, according to criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), comprised 46%, 44%, and 9% of patients, respectively.1 The mean baseline prebronchodilator FEV1 was lower in patients who discontinued a study drug than in those who completed the study period (37% vs. 41% of the predicted value, P<0.001). More than 90% of patients were receiving respiratory medications at baseline.During the study period, 26% of patients changed their smoking behavior. On at least one clinic visit, 74% of patients reported having received inhaled corticosteroids, 72% long-acting beta-agonists, and 46% a fixed combination of the two.
Rate of Decline in Lung Function
The rate of decline in the mean postbronchodilator FEV1 was greater in patients who prematurely discontinued a study drug (55±4 ml per year in the tiotropium group and 57±4 ml per year in the placebo group), as compared with those who completed the study period (38±1 ml per year in the tiotropium group and 40±1 ml per year in the placebo group).
There were no significant differences between study groups in the rate of decline in the mean values for FEV1 and FVC either before or after bronchodilation from day 30 to the end of study-drug treatment (Table 2Table 2
Annual Rates of Decline in FEV1 and FVC before and after Bronchodilation and Scores on Health-Related Quality of Life.; for SVC measures, see Supplementary Appendix 5). In the tiotropium group, the mean values for FEV1 and FVC before and after bronchodilation showed significant improvements that were maintained at all time points after randomization (Figure 2B and 2C). Mean improvements in FEV1 in the tiotropium group, as compared with the placebo group, ranged from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation (P<0.001). Adjustments for baseline FEV1, smoking status, age, sex, and height had similar results.The prespecified subgroup analyses revealed no significant heterogeneity in the effect of tiotropium according to the baseline variables examined (Supplementary Appendix 6). In a post hoc analysis, between-group differences in the rate of decline in postbronchodilator FEV1 were observed in favor of tiotropium, as compared with placebo (40±3 ml in the tiotropium group and 47±3 in the placebo group, P=0.046) in the subgroup of 1554 patients who were not receiving either inhaled corticosteroids or long-acting beta-agonists at baseline.
Among 3421 patients from baseline until 30 days after treatment discontinuation, the median rate of decline in prebronchodilator FEV1 did not differ significantly between the tiotropium group (15 ml per year) and the placebo group (17 ml per year) (P=0.25). However, among 3418 patients who had technically acceptable postbronchodilator spirometry, there was a significant difference in favor of tiotropium in the median rate of decline in postbronchodilator FEV1 (27 ml per year in the tiotropium group, as compared with 32 ml per year in the placebo group; P=0.01).
Health-Related Quality of Life
Significant differences in favor of tiotropium were observed at all time points for the mean absolute change in the SGRQ total score (ranging from 2.3 to 3.3 units, P<0.001), although the differences on average were below what is considered to have clinical significance (Figure 2D). The overall mean between-group difference in the SGRQ total score at any time point was 2.7 (95% confidence interval [CI], 2.0 to 3.3) in favor of tiotropium (P<0.001). A higher proportion of patients in the tiotropium group than in the placebo group had an improvement of 4 units or more in the SGRQ total scores from baseline at 1 year (49% vs. 41%), 2 years (48% vs. 39%), 3 years (46% vs. 37%), and 4 years (45% vs. 36%) (P<0.001 for all comparisons). There were no significant between-group differences in the rate of decline in SGRQ scores from 6 months to the end of the study (Table 2).
Exacerbations
Tiotropium was associated with a significant delay in the time to the first exacerbation, with a median of 16.7 months (95% CI, 14.9 to 17.9) in the tiotropium group and 12.5 months (95% CI, 11.5 to 13.8) in the placebo group. Tiotropium was also associated with a significant delay in the time to the first hospitalization for an exacerbation. Since hospitalizations for exacerbations occurred in less than 50% of patients, a median time to the first event cannot be calculated. In the tiotropium group, the associated hazard ratios were 0.86 (95% CI, 0.81 to 0.91) and 0.86 (95% CI, 0.78 to 0.95), respectively. Tiotropium was also associated with a reduction in the mean number of exacerbations of 14% (P<0.001) (Figure 3AFigure 3
Kaplan–Meier Estimates of the Probability of COPD Exacerbation and Death from Any Cause. and Supplementary Appendix 7). The mean numbers of exacerbations leading to hospitalizations were infrequent and did not differ significantly between the two study groups (Table 3Table 3
Exacerbations of COPD and Related Hospitalizations.).Mortality
Data regarding vital status were systematically requested for patients who prematurely discontinued study participation on a recorded date determined as 4 years from the first day of administration of a study drug. Data regarding deaths extending beyond 4 years (up to and beyond 1470 days) were not systematically collected but were occasionally received. Every effort was made to ensure that vital-status data were full and complete up to 4 years, as described. Vital-status information (at least 45 months of follow-up, including patients who discontinued treatment) was known for 98% of patients in the tiotropium group and 97% in the placebo group. During a period of 4 years plus 30 days (1470 days) included in the intention-to-treat analysis, 941 patients died: 14.9% in the tiotropium group and 16.5% in the placebo group (hazard ratio, 0.89; 95% CI, 0.79 to 1.02) (Figure 3B). For the 4-year, protocol-defined study period up to day 1440, among patients for whom vital-status information was available, 921 patients died: 14.4% in the tiotropium group and 16.3% in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 0.99).
Adverse Events
Safety was monitored through the collection of reports of adverse events, serious adverse events, and fatal events while patients were receiving a study drug (including the last day of a study drug plus 30 days). Adverse events were reported by 92.6% of the tiotropium group and 92.3% of the placebo group. The proportions of serious adverse events were 51.6% in the tiotropium group and 50.2% in the placebo group. Fatal events occurred in 381 patients (12.8%) in the tiotropium group and 411 (13.7%) in the placebo group (hazard ratio, 0.84; 95% CI, 0.73 to 0.97).
In the tiotropium group, as compared with the placebo group, the most common adverse events were due to lower respiratory causes, including COPD exacerbations (64.8% and 66.1%, respectively; relative risk, 0.84; 95% CI, 0.79 to 0.89), pneumonia (14.5% and 13.9%; relative risk, 0.96; 95% CI, 0.84 to 1.10), and dyspnea (12.2% and 14.7%; relative risk, 0.75; 95% CI, 0.65 to 0.86). Respiratory failure developed in 88 patients in the tiotropium group and in 120 in the placebo group (relative risk, 0.67; 95% CI, 0.51 to 0.89). Myocardial infarction developed in 67 patients in the tiotropium group and 85 in the placebo group (relative risk, 0.73; 95% CI, 0.53 to 1.00), and stroke developed in 82 in the tiotropium group and 80 in the placebo group (relative risk, 0.95; 95% CI, 0.70 to 1.29). Adverse events consistent with the known safety profile of tiotropium, such as dry mouth and constipation, were observed.22,23
Serious adverse events reported by more than 1% of patients in either study group were either cardiac or respiratory in nature (Table 4Table 4
Incidence Rate of Serious Adverse Events per 100 Patient-Years.). The incidence of such serious adverse events was lower in the tiotropium group than in the placebo group, including a reduced risk of congestive heart failure, COPD exacerbation, dyspnea, or respiratory failure. Serious adverse events according to organ system and adverse events that were reported by more than 3% of patients in either of the study groups are provided in Supplementary Appendix 8.Discussion
In our study, we showed that in the presence of freely prescribed respiratory medications (i.e., inhaled long-acting beta-agonists, inhaled corticosteroids, and theophyllines) other than another inhaled anticholinergic agent, tiotropium (at a dose of 18 μg once daily) did not alter the rate of decline in the mean FEV1 in patients with COPD. However, lung function was significantly better than in the placebo group throughout the trial, and there were improvements in health-related quality of life and the rate of exacerbations.
As compared with results of previous long-term, prospective studies, the yearly rate of decline in FEV1 that we observed was numerically lower than the rates of decline reported previously.2-6 Prospective interventional studies that were designed to examine the decline in FEV1 — such as the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP), the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) trial, the Lung Health Study II, and the Bronchitis Randomized on NAC [N-acetylcysteine] Cost–Utility Study (BRONCUS) — showed a decline in postbronchodilator rates ranging from 44 to 57 ml per year in the active-treatment groups and 47 to 69 ml per year in the placebo groups.3-6 In our study, the decline in lung function averaged 30 ml per year before bronchodilation and 41 ml per year after bronchodilation in the two study groups, a change that is less than that in any of the previous studies. The values for the decline in FEV1 are also smaller than those observed in the post hoc analysis of lung function in the Towards a Revolution in COPD Health (TORCH) trial (ClinicalTrials.gov number, NCT00268216).24
There are several potential explanations for the discrepancies in the rate of decline in our study, as compared with those in previous studies. First, our study design allowed for prescription of all respiratory therapies at the discretion of physicians, with the exception of another inhaled anticholinergic agent. It is therefore possible that the medical care that patients received during our study, including both short-acting and long-acting inhaled respiratory medications and aggressive treatment of exacerbations, differed from that in earlier trials and, as a whole, contributed to the generally lower rates of decline. However, such factors have not been definitively shown. Second, in our study, a higher proportion of patients with sustained abstinence from smoking tobacco may have resulted in a lower mean rate of decline. In our study, self-reports of smoking behavior indicated that only 30% of patients were current smokers at baseline, as compared with 38 to 90% in other studies.3-6 Third, other factors, such as differences in study design, selection of patients, and regional factors, could also account for discrepancies. In interpreting the results of our study, one should consider that the rates of decline in our study are similar to those reported for healthy nonsmokers and sustained quitters with mild-to-moderate COPD.2
Similar, low rates of decline in lung function were seen in the two study groups. A possible explanation for this finding is that tiotropium does not influence the decline in lung function over time. There are other potential explanations. Current management of COPD could affect the decline in lung function so that a ceiling effect occurs and further improvements are not seen in the absence of an intervention that repairs or regenerates lung tissue. This possibility is supported by the high rate of prescriptions for concomitant respiratory medications in our study and by the differences between tiotropium and placebo in the rate of decline in postbronchodilator FEV1 in patients who did not use inhaled corticosteroids or long-acting beta-agonists. Another potential reason is the higher rate of discontinuation in the placebo group. Data from our study and other trials suggest that patients who discontinue treatment have a more rapid decline in lung function than those who do not discontinue treatment.25 Since patients who discontinued treatment had, on average, significantly more severe airflow obstruction at baseline, those in the placebo group who completed the trial probably represent “healthy survivors.” The possibility of a healthy-survivor effect may not be adequately addressed with the prespecified analysis presented here.25,26
Tiotropium improved measures of airflow obstruction and vital capacity that were performed 24 hours after daily study-drug administration during the 4-year study period. Tiotropium also improved lung function, as compared with placebo, beyond the improvement resulting from serial administration of maximal doses of salbutamol and ipratropium. These improvements in lung function were accompanied by improvements in some of the clinical outcomes measured. Scores regarding health-related quality of life improved relative to placebo during the entire 4-year study period. In the tiotropium group, there were significant delays in the onset of exacerbations and associated hospitalizations. These outcomes appeared in the presence of substantial use of concomitant COPD therapies.
The results of our study are consistent with the published pooled safety analysis23 and indicate a reduction in cardiac adverse events associated with tiotropium. The reduced risk of respiratory failure was also observed in the previous pooled safety analysis of tiotropium, in which the relative risk of respiratory failure in the tiotropium group, as compared with the placebo group, was 0.59 (95% CI, 0.26 to 1.34).23 However, our study had significantly more power to detect such differential event reporting because of a larger and longer exposure to tiotropium.
Our data show that among patients with COPD who were receiving other classes of respiratory medications during the study period, the addition of 18 μg of tiotropium once daily for up to 4 years did not result in changes in the rate of decline in lung function. However, there were important lung-function benefits associated with tiotropium that were maintained during the 4 years, as well as positive effects on health-related quality of life and a reduced risk of exacerbations and exacerbation-related hospitalizations consistent with a relevant effect on the clinical course of COPD. Finally, tiotropium reduced respiratory morbidity (including a decreased risk of respiratory failure) and reduced cardiac morbidity.
Supported by Boehringer Ingelheim and Pfizer.
Dr. Tashkin reports receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Dey Laboratories, and Schering, lecture fees from AstraZeneca, Boehringer Ingelheim, and Dey Laboratories, and grant support from Almirall, AstraZeneca, Boehringer Ingelheim, Dey Laboratories, GlaxoSmithKline, Ivax, MediciNova, Nabi Biopharmaceuticals, Novartis, Pfizer, and Sepracor; Dr. Celli, receiving consulting fees from Almirall, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline, lecture fees from Almirall, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline, and grant support from Boehringer Ingelheim, Forrest, and GlaxoSmithKline; Dr. Senn, receiving consulting fees from Bayer, Boehringer Ingelheim, Chiesi, Eisai, GlaxoSmithKline, INOT, Novartis, Pfizer, Servier, and Takeda, lecture fees from Amgen, Alcon, and Unilever, and grant support from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis, having an equity interest in Novartis, and serving as an expert witness for GlaxoSmithKline; Ms. Burkhart, Dr. Kesten, and Dr. Menjoge, being employees of Boehringer Ingelheim; and Dr. Decramer, receiving consulting fees from Boehringer Ingelheim, Pfizer, GlaxoSmithKline, and Nycomed, lecture fees from Boehringer Ingelheim and Pfizer, and grant support from AstraZeneca. No other potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0805800) was published at www.nejm.org on October 5, 2008.
We thank the UPLIFT trial team and clinical monitors; Dr. Dacheng Liu and Dr. Inge Leimer of Boehringer Ingelheim for their statistical support; Terry Keyser (funded by Boehringer Ingelheim) for editorial and technical support in the preparation of this manuscript; and Dr. Romain Pauwels, who contributed to the design of the study and was a key member of the UPLIFT Joint Advisory Committee before his death in 2005.
Source Information
From the David Geffen School of Medicine at the University of California, Los Angeles (D.P.T.); Caritas St. Elizabeth's Medical Center, Boston (B.C.); Glasgow University, Glasgow, Scotland (S.S.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.B., S.K., S.M.); and the University of Leuven, Leuven, Belgium (M.D.).
Address reprint requests to Dr. Tashkin at the David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, or at dtashkin@mednet.ucla.edu.
Investigators in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial are listed in Supplementary Appendix 1, available with the full text of this article at www.nejm.org.
- References
References
1
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, April 2001 (revised 2007). (Accessed September 16, 2008, at http://www.goldcopd.org.)
2
Anthonisen NR ,Connett JE ,Kiley JP , et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA 1994;272:1497-1505
CrossRef | Web of Science | Medline3
The Lung Health Study Research Group
Full Text | Web of Science | Medline4
Pauwels RA ,Lofdahl CG ,Laitinen LA , et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340:1948-1953
Full Text | Web of Science | Medline5
Burge PS ,Calverley PM ,Jones PW ,Spencer S ,Anderson JA ,Maslen TK . Randomised, double blind placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-1303
CrossRef | Web of Science | Medline6
Decramer M . Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005;365:1552-1560[Erratum, Lancet 2005;366:984.]
CrossRef | Web of Science | Medline7
Soriano JB ,Sin DD ,Zhang X , et al. A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo. Chest 2007;131:682-689
CrossRef | Web of Science | Medline8
Casaburi R ,Mahler DA ,Jones PW , et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19:217-224
CrossRef | Web of Science | Medline9
O'Donnell DE ,Fluge T ,Gerken F , et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23:832-840
CrossRef | Web of Science | Medline10
Maltais F ,Hamilton A ,Marciniuk D , et al. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest 2005;128:1168-1178
CrossRef | Web of Science | Medline11
Vincken W ,van Noord JA ,Greefhorst APM , et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002;19:209-216
CrossRef | Web of Science | Medline12
Brusasco V ,Hodder R ,Miravitlles M ,Korducki L ,Towse L ,Kesten S . Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399-404[Erratum, Thorax 2005;60:105.]
CrossRef | Web of Science | Medline13
Niewoehner DE ,Rice K ,Cote C , et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. Ann Intern Med 2005;143:317-326
Web of Science | Medline14
Anzueto A ,Tashkin D ,Menjoge S ,Kesten S . One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther 2005;18:75-81
CrossRef | Web of Science | Medline15
Decramer M ,Celli B ,Tashkin DP , et al. Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial. COPD 2004;1:303-312
CrossRef | Medline16
Quanjer PH . Standardised lung function testing: report of the European Community for Coal and Steel. Bull Eur Physiopathol Respir 1983;19:Suppl:7-28
Medline17
American Thoracic Society
Web of Science | Medline18
Jones PW ,Quirk FH ,Baveystock CM ,Littlejohns P . A self-complete measure of health status for chronic airflow limitation: the St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321-1327
Web of Science | Medline19
Laird NM ,Ware JH . Random-effects models for longitudinal data. Biometrics 1982;38:963-974
CrossRef | Web of Science | Medline20
Suissa S . Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:842-846
CrossRef | Web of Science | Medline21
Tashkin DP ,Celli B ,Decramer M , et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J 2008;31:742-750
CrossRef | Web of Science | Medline22
Spiriva HandiHaler. Ingelheim, Germany: Boehringer Ingelheim Pharma GmbH, 2008 (package insert).
23
Kesten S ,Jara M ,Wentworth C ,Lanes S . Pooled clinical trial analysis of the safety of tiotropium. Chest 2006;130:1695-1703
CrossRef | Web of Science | Medline24
Celli BR ,Thomas NE ,Anderson JA , et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008;178:332-338
CrossRef | Web of Science | Medline25
Calverley PM ,Spencer S ,Willits L ,Burge PS ,Jones PW . Withdrawal from treatment as an outcome in the ISOLDE study of COPD. Chest 2003;124:1350-1356
CrossRef | Web of Science | Medline26
Kesten S ,Plautz M ,Piquette CA ,Habib MP ,Niewoehner DE . Premature discontinuation of patients: a potential bias in COPD clinical trials. Eur Respir J 2007;30:898-906
CrossRef | Web of Science | Medline
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CrossRef10
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CrossRef21
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CrossRef22
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CrossRef24
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CrossRef26
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CrossRef27
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CrossRef28
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CrossRef29
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CrossRef31
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CrossRef32
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CrossRef33
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CrossRef35
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CrossRef36
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CrossRef37
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CrossRef39
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CrossRef40
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CrossRef42
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CrossRef43
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CrossRef44
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CrossRef45
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CrossRef50
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CrossRef51
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CrossRef52
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CrossRef53
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CrossRef54
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CrossRef55
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CrossRef56
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CrossRef57
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CrossRef59
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CrossRef60
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CrossRef61
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Full Text62
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CrossRef63
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CrossRef64
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CrossRef65
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CrossRef66
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CrossRef67
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CrossRef68
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CrossRef69
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CrossRef70
O. Freynet, G. Jebrak, P.-R. Burgel. (2011) Bronchopneumopathie chronique obstructive. Revue des Maladies Respiratoires Actualités 3:6, 45-63
CrossRef71
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CrossRef72
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CrossRef73
Sabina A Antoniu. (2011) Long-term effects of inhaled bronchodilators in stable chronic obstructive pulmonary disease. Therapy 8:4, 431-441
CrossRef74
(2011) Tiotropium versus Salmeterol in COPD. New England Journal of Medicine 364:26, 2552-2554
Full Text75
Omar S. Usmani, Peter J. Barnes. (2011) Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. Annals of Medicine1-11
CrossRef76
Peter J Barnes. (2011) Triple inhalers for obstructive airways disease: will they be useful?. Expert Review of Respiratory Medicine 5:3, 297-300
CrossRef77
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CrossRef78
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CrossRef79
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CrossRef80
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CrossRef81
Matthew C Miles, James F Donohue, Jill A Ohar. (2011) Combination therapy for COPD: emerging evidence from recent clinical trials. Clinical Investigation 1:6, 879-890
CrossRef82
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CrossRef83
Stephen Senn. (2011) U is for Unease: Reasons for Mistrusting Overlap Measures for Reporting Clinical Trials. Statistics in Biopharmaceutical Research 3:2, 302-309
CrossRef84
Chris Garvey. (2011) Best Practices in Chronic Obstructive Pulmonary Disease. The Nurse Practitioner 36:5, 16-22
CrossRef85
Nathaniel M. Hawkins, Mark C. Petrie, Michael R. MacDonald, Pardeep S. Jhund, Leonardo M. Fabbri, John Wikstrand, John J.V. McMurray. (2011) Heart Failure and Chronic Obstructive Pulmonary Disease. Journal of the American College of Cardiology 57:21, 2127-2138
CrossRef86
Alison C. Cave, Martin M. Hurst. (2011) The use of long acting β2-agonists, alone or in combination with inhaled corticosteroids, in Chronic Obstructive Pulmonary Disease (COPD). Pharmacology & Therapeutics 130:2, 114-143
CrossRef87
Arthur F. Gelb, Christine Fraser, Noe Zamel. (2011) Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD. Respiratory Medicine 105:5, 755-760
CrossRef88
Jean Bourbeau. (2011) Preventing hospitalizations for COPD exacerbation: Early pulmonary rehabilitation?. Respirology 16:4, 579-580
CrossRef89
Bart C Moulton, Allison D Fryer. (2011) Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD. British Journal of Pharmacology 163:1, 44-52
CrossRef90
Heinrich Worth, Kian Fan Chung, James M. Felser, Huilin Hu, Peter Rueegg. (2011) Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol, tiotropium and placebo in COPD. Respiratory Medicine 105:4, 571-579
CrossRef91
Luis Seijo Maceiras. (2011) Luces y sombras del tratamiento endoscópico del enfisema. Archivos de Bronconeumología 47:4, 167-168
CrossRef92
Gerald W. Smetana, Jane S. Sillman. (2011) Update in New Medications for Primary Care. Journal of General Internal Medicine 26:4, 427-432
CrossRef93
Vogelmeier, Claus, Hederer, Bettina, Glaab, Thomas, Schmidt, Hendrik, Rutten-van Mölken, Maureen P.M.H., Beeh, Kai M., Rabe, Klaus F., Fabbri, Leonardo M., . (2011) Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD. New England Journal of Medicine 364:12, 1093-1103
Full Text94
Carlo Nozzoli, Giovanni Mathieu, Gianfranco Gensini. (2011) BPCO e scompenso cardiaco. Italian Journal of Medicine 5:1, 22-37
CrossRef95
Domenico Panuccio. (2011) BPCO e cardiopatia ischemica. Italian Journal of Medicine 5:1, 46-54
CrossRef96
Lorenzo Corbetta, Fabrizio Luppi, Raffaele A. Incalzi. (2011) Linee guida sulla BPCO non associata a comorbilità croniche. Italian Journal of Medicine 5:1, 14-21
CrossRef97
Raffaele Antonelli Incalzi, Massimo Giusti. (2011) BPCO nell’anziano. Italian Journal of Medicine 5:1, 142-150
CrossRef98
Jun-Xia Jiang, Rui Cao, Wan-Ding Deng, Fang Jin, Xin-Wei Dong, Yu Zhu, Xiao-Ping Chen, Yi-Cheng Xie, Meng-Jing Bao, Fen-Fen Li, Qiang-Min Xie. (2011) Characterization of bencycloquidium bromide, a novel muscarinic M3 receptor antagonist in guinea pig airways. European Journal of Pharmacology 655:1-3, 74-82
CrossRef99
Xuedong An, Anthony Lin Zhang, Angela Weihong Yang, Lin Lin, Darong Wu, Xinfeng Guo, Johannah Linda Shergis, Francis Chung Kong Thien, Christopher J. Worsnop, Charlie Changli Xue. (2011) Oral ginseng formulae for stable chronic obstructive pulmonary disease: A systematic review. Respiratory Medicine 105:2, 165-176
CrossRef100
Thomas Glaab, Christian Taube. (2011) Effects of inhaled corticosteroids in stable chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics 24:1, 15-22
CrossRef101
Jessica Nadigel, David Préfontaine, Carolyn J Baglole, François Maltais, Jean Bourbeau, David H Eidelman, Qutayba Hamid. (2011) Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8+ T cells in chronic obstructive pulmonary disease. Respiratory Research 12:1, 149
CrossRef102
Jørgen Vestbo, Julie Anne Anderson, Peter Mark Anthony Calverley, Bartolomé Celli, Gary Thomas Ferguson, Christine Jenkins, Julie Carol Yates, Paul Wyatt Jones. (2011) Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study. The Clinical Respiratory Journal 5:1, 44-49
CrossRef103
Gwyneth A. Davies, Mike Pynn. 2011. Drugs that act on the respiratory tract. , 353-376.
CrossRef104
Luis Seijo Maceiras. (2011) Pros and Cons of Endoscopic Treatment of Emphysema. Archivos de Bronconeumología (English Edition) 47:4, 167-168
CrossRef105
Marie Westwood, Jean Bourbeau, Paul W Jones, Annamaria Cerulli, Gorana Capkun-Niggli, Gill Worthy. (2011) Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review. Respiratory Research 12:1, 40
CrossRef106
Steven Kesten, Bartolome Celli, Marc Decramer, Dacheng Liu, Donald Tashkin. (2011) Adverse health consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial. Respiratory Research 12:1, 129
CrossRef107
P.W. Jones, G. Brusselle, R.W. Dal Negro, M. Ferrer, P. Kardos, M.L. Levy, T. Perez, J.J. Soler-Cataluña, T. van der Molen, L. Adamek, N. Banik. (2011) Health-related quality of life in patients by COPD severity within primary care in Europe. Respiratory Medicine 105:1, 57-66
CrossRef108
Paul W Jones, Julie A Anderson, Peter MA Calverley, Bartolome R Celli, Gary T Ferguson, Christine Jenkins, Julie C Yates, Jørgen Vestbo, Michael D Spencer, . (2011) Health status in the TORCH study of COPD: treatment efficacy and other determinants of change. Respiratory Research 12:1, 71
CrossRef109
Gabriela Vacca, Winfried J Randerath, Adrian Gillissen. (2011) Inhibition of granulocyte migration by tiotropium bromide. Respiratory Research 12:1, 24
CrossRef110
Rokhsara Rafii, Timothy E. Albertson, Samuel Louie, Andrew L. Chan. (2011) Update on Pharmaceutical and Minimally Invasive Management Strategies for Chronic Obstructive Pulmonary Disease. Pulmonary Medicine 2011, 1-11
CrossRef111
Masaki Ogoda, Ryo Niiya, Tadatsura Koshika, Shizuo Yamada. (2011) Comparative Characterization of Lung Muscarinic Receptor Binding After Intratracheal Administration of Tiotropium, Ipratropium, and Glycopyrrolate. Journal of Pharmacological Sciences 115:3, 374-382
CrossRef112
Mario Cazzola, Andrea Segreti, Germano Bettoncelli, Luigino Calzetta, Claudio Cricelli, Franco Pasqua, Paola Rogliani. (2011) Change in asthma and COPD prescribing by Italian general practitioners between 2006 and 2008. Primary Care Respiratory Journal 20:3, 291
CrossRef113
Jadwiga A Wedzicha. (2011) Winter forecasting of COPD exacerbations. Primary Care Respiratory Journal 20:3, 235
CrossRef114
Wouter D van Dijk, Lisette van den Bemt, Saskia van den Haak-Rongen, Erik Bischoff, Chris van Weel, Johannes CCM in 't Veen, Tjard RJ Schermer. (2011) Multidimensional prognostic indices for use in COPD patient care. A systematic review. Respiratory Research 12:1, 151
CrossRef115
Xuan Zhou, Zuomin Wang, Yiqing Song, Jing Zhang, Chen Wang. (2011) Periodontal health and quality of life in patients with chronic obstructive pulmonary disease. Respiratory Medicine 105:1, 67-73
CrossRef116
Ian M. Adcock, Gaetano Caramori, Peter J. Barnes. (2011) Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights. Respiration 81:4, 265-284
CrossRef117
Yang Deok Lee, Yongseon Cho, Min Soo Han. (2011) Issues on Safety of Long-Acting Muscarinic Antagonist. Tuberculosis and Respiratory Diseases 70:5, 384
CrossRef118
Makoto HOSHINO, Junichi OHTAWA. (2011) Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease. Respirology 16:1, 95-101
CrossRef119
Ahmed M Katsha, Shinya Ohkouchi, Hong Xin, Masahiko Kanehira, Ruowen Sun, Toshihiro Nukiwa, Yasuo Saijo. (2011) Paracrine Factors of Multipotent Stromal Cells Ameliorate Lung Injury in an Elastase-induced Emphysema Model. Molecular Therapy 19:1, 196-203
CrossRef120
D.F. Heigener, K.F. Rabe. (2011) Palliative Care Concepts in Respiratory Disease. Respiration 82:6, 483-491
CrossRef121
Andrea Rossi, Erika Zanardi. (2011) E pluribus plurima: Multidimensional indices and clinical phenotypes in COPD. Respiratory Research 12:1, 152
CrossRef122
Paul W Jones, Stephen I Rennard, Alvar Agusti, Pascal Chanez, Helgo Magnussen, Leonardo Fabbri, James F Donohue, Eric D Bateman, Nicholas J Gross, Rosa Lamarca, Cynthia Caracta, Esther Gil. (2011) Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respiratory Research 12:1, 55
CrossRef123
Mariëlle EAC Broeders, Walter Vincken, Lorenzo Corbetta, . (2011) The ADMIT series – Issues in Inhalation Therapy. 7) Ways to improve pharmacological management of COPD: the importance of inhaler choice and inhalation technique. Primary Care Respiratory Journal 20:3, 338
CrossRef124
Sei Won Lee, Jee-Hong Yoo, Myung Jae Park, Eun Kyung Kim, Ho Il Yoon, Deog Kyeom Kim, Chang Hoon Lee, Yong Bum Park, Joo Hun Park, Yong Il Hwang, Ki-Suck Jung, Kwang Ha Yoo, Hye Yoon Park, Jae Seung Lee, Jin-Won Huh, Yeon Mok Oh, Seong Yong Lim, Ji Ye Jung, Young Sam Kim, Hui Jung Kim, Chin Kook Rhee, Young Kyoon Kim, Jin Woo Kim, Hyoung Kyu Yoon, Sang-Do Lee. (2011) Early Diagnosis and Management of Chronic Obstructive Pulmonary Disease. Tuberculosis and Respiratory Diseases 70:4, 293
CrossRef125
Douglas W Mapel, Michael P Dutro, Jenő P Marton, Kimberly Woodruff, Barry Make. (2011) Identifying and characterizing COPD patients in US managed care. A retrospective, cross-sectional analysis of administrative claims data. BMC Health Services Research 11:1, 43
CrossRef126
Anthony D'Urzo, Gary T Ferguson, Jan A van Noord, Kazuto Hirata, Carmen Martin, Rachael Horton, Yimeng Lu, Donald Banerji, Tim Overend. (2011) Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respiratory Research 12:1, 156
CrossRef127
Kazuhisa Takahashi. (2011) Guideline for diagnosis and treatment for COPD. Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics 48:6, 644-647
CrossRef128
Paul W Jones, James F Donohue, Jerry Nedelman, Steve Pascoe, Gregory Pinault, Cheryl Lassen. (2011) Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respiratory Research 12:1, 161
CrossRef129
Peter MA Calverley. (2011) Taking the long view of COPD care. Primary Care Respiratory Journal 20:2, 109
CrossRef130
Vuokko L Kinnula, Tuula Vasankari, Eva Kontula, Anssi Sovijarvi, Olli Saynajakangas, Anne Pietinalho. (2011) The 10-year COPD Programme in Finland: effects on quality of diagnosis, smoking, prevalence, hospital admissions and mortality. Primary Care Respiratory Journal 20:2, 178
CrossRef131
Kevin Gruffydd-Jones, Chris Loveridge. (2011) The 2010 NICE COPD Guidelines: how do they compare with the GOLD guidelines?. Primary Care Respiratory Journal 20:2, 199
CrossRef132
Paul Enright, Patrick White. (2011) Detecting mild COPD: don’t waste resources. Primary Care Respiratory Journal 20:1, 6
CrossRef133
Mark T Dransfield, William Bailey, Glenn Crater, Amanda Emmett, Dianne M O’Dell, Barbara Yawn. (2011) Disease severity and symptoms among patients receiving monotherapy for COPD. Primary Care Respiratory Journal 20:1, 46
CrossRef134
Rupert Jones, Anders Østrem. (2011) Optimising pharmacological maintenance treatment for chronic obstructive pulmonary disease in primary care. Primary Care Respiratory Journal 20:1, 33
CrossRef135
P.M.A. Calverley, P. Kuna, E. Monsó, M. Costantini, S. Petruzzelli, F. Sergio, G. Varoli, A. Papi, V. Brusasco. (2010) Beclomethasone/formoterol in the management of COPD: A randomised controlled trial. Respiratory Medicine 104:12, 1858-1868
CrossRef136
Nancy Kline Leidy, Teresa K. Wilcox, Paul W. Jones, Lindsey Murray, Randall Winnette, Kellee Howard, Jennifer Petrillo, John Powers, Sanjay Sethi. (2010) Development of the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): A Patient-Reported Outcome (PRO) Measure. Value in Health 13:8, 965-975
CrossRef137
A.H. Morice, B. Celli, S. Kesten, T. Lystig, D. Tashkin, M. Decramer. (2010) COPD in young patients: A pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respiratory Medicine 104:11, 1659-1667
CrossRef138
Jorien Hannink, Anke Lahaije, Erik Bischoff, Hanneke van Helvoort, Richard Dekhuijzen, Tjard Schermer, Yvonne Heijdra. (2010) Dynamic hyperinflation after metronome-paced hyperventilation in COPD– A 2 year follow-up. Respiratory Medicine 104:11, 1700-1705
CrossRef139
Keita Inanaga, Toshihiro Ichiki, Ryohei Miyazaki, Kotaro Takeda, Toru Hashimoto, Hirohide Matsuura, Kenji Sunagawa. (2010) Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice. Atherosclerosis 213:1, 52-58
CrossRef140
L. Van Den Bemt, T. R. J. Schermer. (2010) Multicomponent staging indices for chronic obstructive pulmonary disease in daily patient care: what’s the yield?. International Journal of Clinical Practice 64:11, 1475-1479
CrossRef141
E.D. Bateman, D. Tashkin, N. Siafakas, R. Dahl, L. Towse, D. Massey, D. Pavia, N.S. Zhong. (2010) A one-year trial of tiotropium Respimat® plus usual therapy in COPD patients. Respiratory Medicine 104:10, 1460-1472
CrossRef142
(2010) Meta-analysis and moderation. Nature Reviews Drug Discovery 9:10, 747-747
CrossRef143
Klaus F Rabe. (2010) Roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Review of Respiratory Medicine 4:5, 543-555
CrossRef144
Donald Tashkin, Bartolome Celli, Steven Kesten, Ted Lystig, Marc Decramer. (2010) Effect of tiotropium in men and women with COPD: Results of the 4-year UPLIFT® trial. Respiratory Medicine 104:10, 1495-1504
CrossRef145
Antonio Anzueto. (2010) Primary Care Management of Chronic Obstructive Pulmonary Disease to Reduce Exacerbations and Their Consequences. The American Journal of the Medical Sciences 340:4, 309-318
CrossRef146
Michele, Theresa M., Pinheiro, Simone, Iyasu, Solomon, . (2010) The Safety of Tiotropium — The FDA's Conclusions. New England Journal of Medicine 363:12, 1097-1099
Full Text147
Tashkin, Donald P., . (2010) Frequent Exacerbations of Chronic Obstructive Pulmonary Disease — A Distinct Phenotype?. New England Journal of Medicine 363:12, 1183-1184
Full Text148
Hurst, John R., Vestbo, Jørgen, Anzueto, Antonio, Locantore, Nicholas, Müllerova, Hana, Tal-Singer, Ruth, Miller, Bruce, Lomas, David A., Agusti, Alvar, MacNee, William, Calverley, Peter, Rennard, Stephen, Wouters, Emiel F.M., Wedzicha, Jadwiga A., . (2010) Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease. New England Journal of Medicine 363:12, 1128-1138
Full Text149
Antoine Fremault, Wim Janssens, François Beaucage, Geert Celis, Silvia Pérez-Bogerd, Marc Decramer. (2010) Modification of COPD Presentation During the Last 25 Years. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:5, 345-351
CrossRef150
Cristine E. Berry, Robert A. Wise. (2010) Mortality in COPD: Causes, Risk Factors, and Prevention. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:5, 375-382
CrossRef151
Jose Echave-Sustaeta, Lorena Comeche Casanova, Ricardo García Luján, Javier Sayas Catalan, Agustin Gómez de la Cámara, Angel López Encuentra. (2010) Pronóstico tras una agudización grave de la EPOC tratada con ventilación mecánica no invasiva. Archivos de Bronconeumología 46:8, 405-410
CrossRef152
L. Wollin, M.P. Pieper. (2010) Tiotropium bromide exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD. Pulmonary Pharmacology & Therapeutics 23:4, 345-354
CrossRef153
R. ZuWallack, M.C. De Salvo, T. Kaelin, E.D. Bateman, C.S. Park, R. Abrahams, F. Fakih, P. Sachs, K. Pudi, Y. Zhao, C.C. Wood. (2010) Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat® inhaler versus MDI. Respiratory Medicine 104:8, 1179-1188
CrossRef154
(2010) Outpatient Management of Severe COPD. New England Journal of Medicine 363:5, 493-495
Full Text155
Matthias Grauert, Michael P. Pieper, Paola Casarosa. 2010. Muscarinic Receptor Antagonists in the Treatment of COPD. , 297-318.
CrossRef156
Juan José Soler-Cataluña, Roberto Rodriguez-Roisin. (2010) Frequent Chronic Obstructive Pulmonary Disease Exacerbators: How Much Real, How Much Fictitious?. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:4, 276-284
CrossRef157
Ingrid Solanes Garcia, Pere Casan Clarà. (2010) Causas de muerte y predicción de mortalidad en la EPOC. Archivos de Bronconeumología 46:7, 343-346
CrossRef158
Donald P Tashkin. (2010) Impact of tiotropium on the course of moderate-to-very severe chronic obstructive pulmonary disease: the UPLIFT ® trial. Expert Review of Respiratory Medicine 4:3, 279-289
CrossRef159
Nalaka S. Gooneratne, Nirav P. Patel, Amy Corcoran. (2010) Chronic Obstructive Pulmonary Disease Diagnosis and Management in Older Adults. Journal of the American Geriatrics Society 58:6, 1153-1162
CrossRef160
Emma J Welsh, Christopher J Cates, Phillippa Poole, Emma J Welsh. 2010. Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. .
CrossRef161
Kenneth R. Chapman, Robert A. Stockley, Mahlon M. Wilkes, Roberta J. Navickis. (2010) Letter to the Editor Response. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:3, 235-236
CrossRef162
Cormac McCarthy, Borislav D. Dimitrov. (2010) Augmentation Therapy for Alpha-1 Antitrypsin Deficiency—Not Enough Evidence to Support its Use Yet!. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:3, 234-234
CrossRef163
Paul L. Enright. (2010) COPD patients with higher education are much less likely to adhere to prescribed daily inhaler use. Respiratory Medicine 104:5, 760-761
CrossRef164
Salahaddin Mahmudi-Azer. 2010. Breathing Easier: Respiratory Disease in the Older Adult. , 43-57.
CrossRef165
Niewoehner, Dennis E., . (2010) Outpatient Management of Severe COPD. New England Journal of Medicine 362:15, 1407-1416
Full Text166
Natalie H. Yip, George Yuen, Eliot J. Lazar, Brian K. Regan, Marcia D. Brinson, Brian Taylor, Liziamma George, Stephen R. Karbowitz, Richard Stumacher, Neil W. Schluger, Byron M. Thomashow. (2010) Analysis of Hospitalizations for COPD Exacerbation: Opportunities for Improving Care. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:2, 85-92
CrossRef167
Tomohiro HARUKI, Hiroshige NAKAMURA, Yuji TANIGUCHI, Ken MIWA, Yoshin ADACHI, Shinji FUJIOKA. (2010) ‘Lung age’ predicts post-operative complications and survival in lung cancer patients. Respirology 15:3, 495-500
CrossRef168
Sabina A Antoniu. (2010) Effects of inhaled therapies on health-related quality of life in stable chronic obstructive pulmonary disease. Expert Review of Pharmacoeconomics & Outcomes Research 10:2, 155-162
CrossRef169
Kenji Tsushima, Shusuke Sone, Keisaku Fujimoto, Keishi Kubo, Satoshi Morita, Misa Takegami, Shunichi Fukuhara. (2010) Identification of Occult Parechymal Disease Such as Emphysema or Airway Disease Using Screening Computed Tomography. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:2, 117-125
CrossRef170
Marco Contoli, Simonetta Baraldo, Brunilda Marku, Paolo Casolari, John A. Marwick, Graziella Turato, Micaela Romagnoli, Gaetano Caramori, Marina Saetta, Leonardo M. Fabbri, Alberto Papi. (2010) Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up. Journal of Allergy and Clinical Immunology 125:4, 830-837
CrossRef171
Donald P Tashkin. (2010) Long-acting anticholinergic use in chronic obstructive pulmonary disease: efficacy and safety. Current Opinion in Pulmonary Medicine 16:2, 97-105
CrossRef172
Kai M. Beeh, Jutta Beier. (2010) The short, the long and the “ultra-long”: Why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Advances in Therapy 27:3, 150-159
CrossRef173
Sabina A. Antoniu. (2010) Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease. Biomarkers 15:2, 97-103
CrossRef174
Mark Spears, Euan Cameron, Rekha Chaudhuri, Neil C Thomson. (2010) Challenges of treating asthma in people who smoke. Expert Review of Clinical Immunology 6:2, 257-268
CrossRef175
Sidney S Braman, David W Lee. (2010) Primary care management of chronic obstructive pulmonary disease: an integrated goal-directed approach. Current Opinion in Pulmonary Medicine 16:2, 83-88
CrossRef176
Zhao-hui MA, Jing ZHANG, Ruo-hua CHEN, Xia-hui GE, Chong BAI. (2010) Presence of dentritic cells in bronchi and lung tissues of rats with chronic obstructive pulmonary disease and influence of budesonide and ipratropium bromide. Academic Journal of Second Military Medical University 29:6, 706-709
CrossRef177
R. Wood-Baker, B. Cochrane, M. T. Naughton. (2010) Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatment. Internal Medicine Journal 40:2, 94-101
CrossRef178
M. Ichinose, T. Fujimoto, Y. Fukuchi. (2010) Tiotropium 5μg via Respimat and 18μg via HandiHaler; efficacy and safety in Japanese COPD patients. Respiratory Medicine 104:2, 228-236
CrossRef179
Helen K. REDDEL, John W. UPHAM, Sundeep S. SALVI, Ian A. YANG. (2010) Year-in-review 2009: Asthma, COPD and airway biology. Respirology 15:2, 365-376
CrossRef180
W.D. van Dijk, Y. Heijdra, P.T.J. Scheepers, J.W.M. Lenders, C. van Weel, T.R.J. Schermer. (2010) Interaction in COPD experiment (ICE): A hazardous combination of cigarette smoking and bronchodilation in chronic obstructive pulmonary disease. Medical Hypotheses 74:2, 277-280
CrossRef181
Maria Montes de Oca, Rogelio Perez-Padilla, Carlos Tálamo, Ronald J. Halbert, Dolores Moreno, Maria Victorina Lopez, Adriana Muiño, B. Jardim José Roberto, Gonzalo Valdivia, Julio Pertuzé, B. Menezes Ana Maria. (2010) Acute bronchodilator responsiveness in subjects with and without airflow obstruction in five Latin American cities: The PLATINO study. Pulmonary Pharmacology & Therapeutics 23:1, 29-35
CrossRef182
Craig P Hersh. (2010) Pharmacogenetics of chronic obstructive pulmonary disease: challenges and opportunities. Pharmacogenomics 11:2, 237-247
CrossRef183
Masakazu Ichinose, Kuniaki Seyama, Masaharu Nishimura, Yoshinosuke Fukuchi, Atsushi Nagai, Michiaki Mishima, Keishi Kubo. (2010) Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with COPD. Respiratory Medicine 104:2, 267-274
CrossRef184
David M. Mannino. (2010) Preventing COPD: Evidence of Progress. COPD: Journal of Chronic Obstructive Pulmonary Disease 7:1, 3-4
CrossRef185
John G. Montana, Hazel J. Dyke, J. Craig Fox, Nicholas C. Ray. 2010. Current and Emerging Therapies in Chronic Obstructive Pulmonary Disease. .
CrossRef186
Virginia Moya, David Nieto, José María Marín. (2010) Parámetros de evaluación reportados por el paciente en la EPOC. Archivos de Bronconeumología 46, 15-19
CrossRef187
Makoto Sata. (2010) Cardiovascular Disease and Chronic Obstructive Pulmonary Disease. Circulation Journal 74:2, 254-255
CrossRef188
Aurelio Arnedillo Muñoz. (2010) Impacto de las agudizaciones e ingresos en la EPOC. Archivos de Bronconeumología 46, 8-14
CrossRef189
Dramane I Lainé. (2010) Long-acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease. Expert Review of Clinical Pharmacology 3:1, 43-53
CrossRef190
José Luis Izquierdo Alonso. (2010) EPOC y enfermedad cardiovascular. Archivos de Bronconeumología 46, 18-22
CrossRef191
Pilar de Lucas Ramos, Soledad López Martín, José Miguel Rodríguez González-Moro. (2010) Limitaciones del tratamiento actual: necesidades no cubiertas en el tratamiento de la EPOC. Archivos de Bronconeumología 46, 8-13
CrossRef192
Adolfo Baloira. (2010) Triple terapia en el tratamiento de la EPOC. Archivos de Bronconeumología 46, 25-30
CrossRef193
Toru Oga, Mitsuhiro Tsukino, Takashi Hajiro, Akihiko Ikeda, Hiroshi Koyama, Michiaki Mishima, Kazuo Chin, Koichi Nishimura. (2010) Multidimensional Analyses of Long-Term Clinical Courses of Asthma and Chronic Obstructive Pulmonary Disease. Allergology International 59:3, 257-265
CrossRef194
José Luis López-Campos. (2010) Importancia y variabilidad de los síntomas en la EPOC. Su importancia para el tratamiento. Archivos de Bronconeumología 46, 20-24
CrossRef195
Myriam Calle Rubio, Celia Pinedo Sierra, Juan Luis Rodríguez Hermosa. (2010) Tratamiento farmacológico de la EPOC. ¿Dónde nos encontramos?. Archivos de Bronconeumología 46, 3-7
CrossRef196
Alvar Agustí. (2010) Impacto de las nuevas opciones terapéuticas en la EPOC. Archivos de Bronconeumología 46, 1-2
CrossRef197
Georges Juvelekian, James K. Stoller. 2010. Chronic Obstructive Pulmonary Disease. , 1022-1029.
CrossRef198
Paola Casarosa, Tobias Kiechle, Remko A. Bakker. 2010. Differential Inverse Agonism at the Human Muscarinic M3 Receptor. , 81-101.
CrossRef199
Steven D. Shapiro, John J. Reilly, Stephen I. Rennard. 2010. Chronic Bronchitis and Emphysema. , 919-967.
CrossRef200
Keir E. Lewis, Gwyneth A. Davies. 2010. Drugs that act on the respiratory tract. , 311-331.
CrossRef201
Marianna Siganaki, Anastasios V Koutsopoulos, Eirini Neofytou, Eleni Vlachaki, Maria Psarrou, Nikolaos Soulitzis, Nikolaos Pentilas, Sophia Schiza, Nikolaos M Siafakas, Eleni G Tzortzaki. (2010) Deregulation of apoptosis mediators' p53 and bcl2 in lung tissue of COPD patients. Respiratory Research 11:1, 46
CrossRef202
Agnes Kliber, Larry D Lynd, Don D Sin. (2010) The effects of long-acting bronchodilators on total mortality in patients with stable chronic obstructive pulmonary disease. Respiratory Research 11:1, 56
CrossRef203
E.D. Bateman, S. Rennard, P.J. Barnes, P.V. Dicpinigaitis, R. Gosens, N.J. Gross, J.A. Nadel, M. Pfeifer, K. Racké, K.F. Rabe, B.K. Rubin, T. Welte, I. Wessler. (2009) Alternative mechanisms for tiotropium. Pulmonary Pharmacology & Therapeutics 22:6, 533-542
CrossRef204
Vuokko L Kinnula, Nobuhisa Ishikawa, Ulrich Bergmann, Steffen Ohlmeier. (2009) Proteomic approaches for studying human parenchymal lung diseases. Expert Review of Proteomics 6:6, 619-629
CrossRef205
Dennis E. Niewoehner, Robert Lapidus, Claudia Cote, Amir Sharafkhaneh, Mark Plautz, Philip Johnson, Steven Kesten. (2009) Therapeutic conversion of the combination of ipratropium and albuterol to tiotropium in patients with chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics 22:6, 587-592
CrossRef206
Sally Spencer. (2009) Health status measurement in exacerbations of COPD. Expert Review of Respiratory Medicine 3:6, 573-583
CrossRef207
H. Worth. (2009) Was ist gesichert in der Therapie der COPD?. Der Internist 50:12, 1345-1357
CrossRef208
Michael J. Lewis, Joe Annandale, Keir E. Lewis. (2009) Influence of long-term oxygen therapy on heart rate and QT time-series in hypoxic patients with chronic obstructive pulmonary disease. Clinical Physiology and Functional Imaging 29:6, 431-439
CrossRef209
C. Göggelmann, A. Filusch, F.J. Meyer. (2009) Pulmonale Effekte kardialer Therapie und vice versa. Der Pneumologe 6:6, 399-404
CrossRef210
Anthony Grosso, Ian Douglas, Aroon D. Hingorani, Raymond MacAllister, Richard Hubbard, Liam Smeeth. (2009) Inhaled tiotropium bromide and risk of stroke. British Journal of Clinical Pharmacology 68:5, 731-736
CrossRef211
Ilaria Peretto, Paola Petrillo, Bruno P. Imbimbo. (2009) Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists. Medicinal Research Reviews 29:6, 867-902
CrossRef212
David MG Halpin. (2009) Preventing chronic obstructive pulmonary disease. Expert Review of Respiratory Medicine 3:5, 449-452
CrossRef213
Robert A. Flynn, Deirdre A. Glynn, Marcus P. Kennedy. (2009) Anticholinergic treatment in airways diseases. Advances in Therapy 26:10, 908-919
CrossRef214
Marc Decramer, Bartolome Celli, Steven Kesten, Theodore Lystig, Sunil Mehra, Donald P Tashkin. (2009) Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. The Lancet 374:9696, 1171-1178
CrossRef215
Maher R. Khdour, Joseph C. Kidney, Bronagh M. Smyth, James C. McElnay. (2009) Clinical pharmacy-led disease and medicine management programme for patients with COPD. British Journal of Clinical Pharmacology 68:4, 588-598
CrossRef216
Shelley R. Salpeter. (2009) Do Inhaled Anticholinergics Increase or Decrease the Risk of Major Cardiovascular Events?. Drugs 69:15, 2025-2033
CrossRef217
Gustavo J. Rodrigo, José A. Castro-Rodriguez, Luís J. Nannini, Vicente Plaza Moral, Eduardo A. Schiavi. (2009) Tiotropium and risk for fatal and nonfatal cardiovascular events in patients with chronic obstructive pulmonary disease: Systematic review with meta-analysis. Respiratory Medicine 103:10, 1421-1429
CrossRef218
Lisa Davies, Peter MA Calverley. (2009) UPLIFTing care for chronic obstructive pulmonary disease. The Lancet 374:9696, 1129-1130
CrossRef219
Shoab A. Nazir, Marcia L. Erbland. (2009) Chronic Obstructive Pulmonary Disease. Drugs & Aging 26:10, 813-831
CrossRef220
Marc Roig, Janice J. Eng, Jeremy D. Road, W. Darlene Reid. (2009) Falls in patients with chronic obstructive pulmonary disease: A call for further research. Respiratory Medicine 103:9, 1257-1269
CrossRef221
Z.M. Sund, T. Powell, R. Greenwood, N.A. Jarad. (2009) Remote daily real-time monitoring in patients with COPD – A feasibility study using a novel device. Respiratory Medicine 103:9, 1320-1328
CrossRef222
Todd A Lee, Glen T Schumock, Brian Bartle, A. Simon Pickard. (2009) Mortality Risk in Patients Receiving Drug Regimens with Theophylline for Chronic Obstructive Pulmonary Disease. Pharmacotherapy 29:9, 1039-1053
CrossRef223
Peter MA Calverley, Klaus F Rabe, Udo-Michael Goehring, Søren Kristiansen, Leonardo M Fabbri, Fernando J Martinez. (2009) Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. The Lancet 374:9691, 685-694
CrossRef224
Joan B Soriano, Jan Zielinski, David Price. (2009) Screening for and early detection of chronic obstructive pulmonary disease. The Lancet 374:9691, 721-732
CrossRef225
Paul M O'Byrne, Gail Gauvreau. (2009) Phosphodiesterase-4 inhibition in COPD. The Lancet 374:9691, 665-667
CrossRef226
Don D Sin, Donald Tashkin, Xuekui Zhang, Finn Radner, Ulf Sjöbring, Anders Thorén, Peter MA Calverley, Stephen I Rennard. (2009) Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. The Lancet 374:9691, 712-719
CrossRef227
T. Welte. (2009) Optimising treatment for COPD - new strategies for combination therapy. International Journal of Clinical Practice 63:8, 1136-1149
CrossRef228
Leonardo M Fabbri, Peter MA Calverley, José Luis Izquierdo-Alonso, Daniela S Bundschuh, Manja Brose, Fernando J Martinez, Klaus F Rabe. (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. The Lancet 374:9691, 695-703
CrossRef229
G. Tack. (2009) ATS 2009 Conference Report. Respiratory Medicine: COPD Update 5:3-4, 62-66
CrossRef230
Qibiao WU, Guochun LI, Wun I. LEI, Xiqiao ZHOU. (2009) The efficacy and safety of tiotropium in Chinese patients with stable chronic obstructive pulmonary disease: A meta-analysis. Respirology 14:5, 666-674
CrossRef231
(2009) Tiotropium-Lessons from recent studies. Respirology 14:5, 623-624
CrossRef232
Amy L. Dzierba, Sanja Jelic. (2009) Chronic Obstructive Pulmonary Disease in the Elderly. Drugs & Aging 26:6, 447-456
CrossRef233
Mutsuo Yamaya, Naoya Fujino, Hiroshi Kubo, Hiroyuki Arai. (2009) Effects of pneumococcal vaccination on hospitalization and exacerbations in elderly Japanese chronic obstructive pulmonary disease patients. Geriatrics & Gerontology International 9:2, 206-209
CrossRef234
Mario Cazzola, Pierachille Santus, Alice D'Adda, Silvia Pizzolato, Fabiano Di Marco, Stefano Centanni. (2009) Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD. Pulmonary Pharmacology & Therapeutics 22:3, 177-182
CrossRef235
A James Mamary, Gerard J Criner. (2009) Tiotropium bromide for chronic obstructive pulmonary disease. Expert Review of Respiratory Medicine 3:3, 211-220
CrossRef236
Masaru Kubota, Gakuji Shirai, Tomoyuki Nakamori, Kenichi Kokubo, Noriyuki Masuda, Hirosuke Kobayashi. (2009) Low frequency oscillometry parameters in COPD patients are less variable during inspiration than during expiration. Respiratory Physiology & Neurobiology 166:2, 73-79
CrossRef237
Daiana Stolz, Michael Tamm. (2009) Discriminate use of antibiotics for exacerbation of COPD. Current Opinion in Pulmonary Medicine 15:2, 126-132
CrossRef238
Adrian Gillissen, Thomas Glaab, Roland Buhl. (2009) Klinische Bedeutung der forcierten Einsekundenkapazität (FEV1) bei chronisch-obstruktiver Lungenerkrankung (COPD). Medizinische Klinik 104:2, 119-124
CrossRef239
G. Rohde. (2009) ERS 2008 Conference Report. Respiratory Medicine: COPD Update 5:1, 3-6
CrossRef240
(2009) Tiotropium in Chronic Obstructive Pulmonary Disease. New England Journal of Medicine 360:2, 185-187
Full Text241
Joan B. Soriano Ortiz, Pere Almagro, Jaume Sauleda Roig. (2009) Causas de mortalidad en la EPOC. Archivos de Bronconeumología 45, 8-13
CrossRef242
Marc Miravitlles. (2009) Tratamiento individualizado de la EPOC: una propuesta de cambio. Archivos de Bronconeumología 45, 27-34
CrossRef243
Tomoaki Hoshino, Reiko Toda, Hisamichi Aizawa. (2009) Pharmacological Treatment in Asthma and COPD. Allergology International 58:3, 341-346
CrossRef244
Felipe Villar Álvarez, Germán Peces-Barba Romero. (2009) Marcadores pronósticos en la EPOC. Papel de la comorbilidad. Archivos de Bronconeumología 45, 2-7
CrossRef245
Juan José Soler Cataluña, Miguel Ángel Martínez García. (2009) Comorbilidad cardiovascular en la EPOC. Archivos de Bronconeumología 45, 18-23
CrossRef246
Juan José Soler-Cataluña, Miguel Ángel Martínez García. (2009) Impacto de los estudios de eficacia y mortalidad (TORCH y UPLIFT) en el tratamiento broncodilatador de la EPOC. Archivos de Bronconeumología 45, 14-20
CrossRef247
Carles Sanjuás. (2009) Tolerabilidad y seguridad de los broncodilatadores en la EPOC. Archivos de Bronconeumología 45, 21-26
CrossRef248
Amy P. Abernethy. (2009) Palliative Care Pharmacotherapy Literature Summaries and Analyses. Journal of Pain and Palliative Care Pharmacotherapy 23:2, 174-181
CrossRef249
Reilly, John J., . (2008) COPD and Declining FEV1 — Time to Divide and Conquer?. New England Journal of Medicine 359:15, 1616-1618
Full Text250
Nestor A. Molfino. (2008) New anti-inflammatory therapies for the treatment of COPD. Drug Discovery Today: Therapeutic Strategies 5:2, 93-96
CrossRef
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