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Original Research: COPD |

Cardiovascular Safety of Tiotropium in Patients With COPD FREE TO VIEW

Bartolome Celli, MD, FCCP; Marc Decramer, MD; Inge Leimer, PhD; Ulrich Vogel, MD; Steven Kesten, MD; Donald P. Tashkin, MD, FCCP
Author and Funding Information

From the Carita-St. Elizabeth’s Medical Center (Dr Celli), Boston, MA; University of Leuven (Dr Decramer), Leuven, Belgium; Boehringer Ingelheim (Drs Leimer, Vogel, and Kesten), Ingelheim, Germany; and David Geffen School of Medicine at UCLA (Dr Tashkin), Los Angeles, CA.

Correspondence to:Bartolome Celli, MD, FCCP, Pulmonary Critical Care Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115; e-mail: bcelli@cchcs.org


For editorial comments see page 1

Funding/support: This study was funded by Boehringer Ingelheim and Pfizer.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(1):20-30. doi:10.1378/chest.09-0011
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Background:  The clinical trial safety database for tiotropium has been augmented with a 4-year trial in patients with COPD, which provides an opportunity to better evaluate the cardiovascular (CV) profile of tiotropium.

Methods:  Trials with the following criteria were considered: ≥ 4 weeks, randomized, double-blind, parallel-group, placebo-controlled. Inclusion/exclusion criteria were similar, including spirometry-confirmed COPD, ≥ 10 pack-year smoking, and age ≥ 40 years. Adverse events were collected throughout each trial using standardized case report forms. Incidence rates (IRs) were determined from the total number of patients with an event divided by total time at risk. Rate ratios (RRs) and 95% CI for tiotropium/placebo were calculated. IRs were determined for all-cause mortality and selected CV events, including a composite CV end point encompassing CV deaths, nonfatal myocardial infarction (MI), nonfatal stroke, and the terms sudden death, sudden cardiac death, and cardiac death.

Results:  There were 19,545 patients randomized: 10,846 (tiotropium) and 8,699 (placebo) from 30 trials. Mean FEV1 = 1.15 ± 0.46 L (41 ± 14% predicted), 76% men, mean age = 65 ± 9 years. Cumulative exposure to study drug was 13,146 (tiotropium) and 11,095 (placebo) patient-years. For all-cause mortality, the IR was 3.44 (tiotropium) and 4.10 (placebo) per 100 patient-years (RR [95% CI] = 0.88 [0.77-0.999]). IR for the CV end point was 2.15 (tiotropium) and 2.67 (placebo) per 100 patient-years (RR [95% CI] = 0.83 (0.71-0.98]). The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 (tiotropium) and 1.24 (placebo) per 100 patient-years (RR [95% CI] = 0.77 [0.60-0.98]). For total MI, cardiac failure, and stroke the RRs (95% CI) were 0.78 (0.59-1.02), 0.82 (0.69-0.98), and 1.03 (0.79-1.35), respectively.

Conclusion:  Tiotropium was associated with a reduction in the risk of all-cause mortality, CV mortality, and CV events.

Figures in this Article

The systematic review of approved and marketed medications for the treatment of chronic diseases has highlighted that additional post-approval evaluations of drugs can assist in the understanding of both expected and unexpected adverse events. Clinical trials designed for approval generally have insufficient sample sizes to detect with certainty the relationship of the drug under study to rare or even infrequent events. Although post-approval clinical trials are often primarily designed for efficacy end points, safety data remain a critical part of data collection. The detail of safety reporting in publications of clinical trials of approved products can vary. However, it is common that only a brief summary of the safety information appears in published reports primarily because of word count limitations; journal and reviewer interest; and the secondary, or sometimes exploratory, nature of the safety analyses.

The safety profile of inhaled anticholinergics has been studied for many years. The short-acting ipratropium bromide has been available to patients for more than 20 years. Tiotropium, available since 2002, is a long-acting anticholinergic that has consistently shown improvements in airflow, hyperinflation, exercise tolerance, exacerbations of COPD, and health-related quality of life with once-daily dosing.17 Several reports have retrospectively examined safety data using different approaches with somewhat conflicting results regarding a possible association between inhaled anticholinergics, including tiotropium, and adverse cardiovascular (CV) consequences.814

A report of a pooled analysis of 19 tiotropium clinical trials of up to 1 year in duration described data on selected safety end points covering those expected from the pharmacology of the drug as well as additional end points of interest.10 Contrary to the report by Singh et al,11 which suggested an increased risk for CV mortality (relative risk = 1.8), the report from the 19 trials noted a decreased risk for fatal CV events in patients randomized to the anticholinergic (rate ratio [RR] = 0.57).10,11 The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial was a 4-year, randomized, placebo-controlled COPD clinical trial of tiotropium with the primary end points of the rate of decline of prebronchodilator and postbronchodilator FEV1. Secondary end points included FVC, exacerbations, health-related quality of life, and mortality. All adverse events were collected during the trial. The UPLIFT trial was recently published and demonstrated that tiotropium provides sustained improvements in lung function without altering its rate of decline as well as improved health-related quality of life, exacerbations, and survival.7 Furthermore, in the UPLIFT trial the risk for fatal CV events was reduced (RR = 0.8), which, as reported by Pedone and Incalzi,15 also included a category of patients in whom the cause of death was deemed to be unknown.

The present report extends the findings described by Tashkin et al7 and Kesten et al10 by combining the UPLIFT trial with all other tiotropium double-blind, parallel-group, placebo-controlled trials of at least 4 weeks’ duration in patients with COPD to better evaluate safety outcomes. The primary objective of this analysis was to explore different collections of adverse events to examine whether there were specific events that might show either a decreased or an increased risk with tiotropium. Attention was focused on selected CV events, including a composite CV end point and mortality.

Study Population

The pooled safety database consisted of 30 completed clinical trials as of September 2008 in the tiotropium (Boehringer Ingelheim GmbH; Ingelheim, Germany) project database. For inclusion, all trials used a placebo-controlled, double-blind, and parallel-group study design. Trials were restricted to COPD and of at least 4 weeks’ duration. In order to be comprehensive, studies with the dry powder (capsules delivered via the HandiHaler) and soft mist (Respimat) formulations have been included.

The Boehringer Ingelheim study numbers of the 30 trials of tiotropium were as follows: 205.114/117,2 205.115/128,2 205.123,16 205.124,17 205.130,3 205.131,4 205.137,3 205.214,18 205.215,19 205.218,20 205.223,5 205.230,21 205.235,7 205.247,22 205.251,23 205.252,23 205.254, 205.255, 205.256,24 205.257,25 205.259,26 205.266,6 205.269, 205.270,27 205.276,28 205.281,29 205.282,30 205.284,31 205.294,32 205.301.33 The individual trial duration and the number of cases per trial for the end points CV events, fatal CV events, and deaths are listed in Table 1.

Table Graphic Jump Location
Table 1 —Trial Duration, Number of Participants, and Number of Cases per End Point According to Trial Included in the Pooled Analysis

CV = cardiovascular.

The protocol inclusion and exclusion criteria for all trials were similar. Men and women who were at least 40 years of age, had a diagnosis of COPD, ≥ 10 pack-years of smoking, and spirometric confirmation of airflow limitation including an FEV1 ≤ 70% of FVC were eligible for participation. Exclusion criteria included a diagnosis of asthma, symptomatic prostatic hypertrophy or bladder neck obstruction, and narrow-angle glaucoma, although more recent protocols have moved the latter two disorders to a caution statement. Patients with significant disease other than COPD that could preclude participation or significantly confound the study results were excluded. Hospitalization for heart failure in the previous 3 years, cardiac arrhythmia requiring drug therapy, or myocardial infarction within the previous year were excluded from earlier protocols; however, other than those specific criteria, patients with ischemic heart disease or heart failure were not specifically excluded. More recent trials changed the exclusion criteria as follows: hospitalization for heart failure in the previous year, myocardial infarction within the previous 6 months, life-threatening cardiac arrhythmia, or arrhythmia requiring a change in medication within the last year. All protocols were approved by ethics committees and written informed consent was obtained from all patients.

All trials permitted concomitant use of short-acting β-agonists, theophyllines, and inhaled corticosteroids. The more recent trials, including the 4-year trial involving approximately 6,000 patients (UPLIFT), also permitted use of long-acting β-agonists as prescribed.

Study Variables

All studies included spirometry that conformed to American Thoracic Society standards.34 Different studies involved a variety of evaluations, including exercise testing, questionnaire-based assessments of dyspnea and health-related quality of life, and collection of exacerbation data. All trials collected information on COPD exacerbations on adverse event case report forms. Several trials additionally collected information on COPD-specific case report forms. Adverse events were collected at all study visits in all trials.

Adverse Event Reporting

All adverse events occurring during the conduct of the trial were reported by the investigational sites to Boehringer Ingelheim. An adverse event was defined as any untoward medical occurrence occurring during the trial that did not necessarily have a causal relationship with the treatment. A serious adverse event was defined as any adverse event that resulted in death, was immediately life-threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, or was deemed serious for any other reason representing a significant hazard, which is comparable to the aforementioned criteria. In one trial (205.266) nonserious adverse events were, a priori, not to be recorded unless the investigator decided that another nonserious event was a contributing factor to the serious event reported.6 Analyses are presented separately for selected adverse events, serious adverse events, and fatal adverse events.

Categorization of Adverse Events

Events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 11.0. The dictionary provides individual terms, referred to as preferred terms, and combines terms into organ classes, referred to as system organ classes (SOC). As several preferred terms in the dictionary can be considered clinically similar, they have been combined to capture clinical end points of interest under the cardiac and vascular SOCs more comprehensively, and to improve the precision of rate estimates (Appendix).

Based on the analysis of Singh et al,11 we created a composite end point of major CV events. The composite end point represents fatal events in the SOC cardiac disorders and SOC vascular disorders combined with myocardial infarction (fatal and nonfatal), stroke (fatal and nonfatal), and the preferred terms sudden death, sudden cardiac death, and cardiac death. The latter three preferred terms are not coded to the cardiac or vascular SOCs as the primary SOC by the MedDRA dictionary and appear under a different SOC. For fatal CV events, nonfatal myocardial infarction and nonfatal stroke were removed.

Statistical Methods

Total exposure time to study drug includes all days from the first dose to the last dose of study drug. Exposure time at risk was determined from first intake of drug until 30 days post treatment (tiotropium, placebo) or until the onset of the specific adverse event analyzed, whichever came first. For each event, an incidence rate (IR) was calculated from the number of patients with an event divided by the cumulative exposure time at risk within a treatment group and expressed as patient-years. To measure the strength of the effect, incidence RRs tiotropium vs placebo were calculated based on a Cochran-Mantel-Haenszel test stratified by study. To indicate the stability or precision of the effect estimate, the width of the 95% CIs was used.35 An RR < 1 indicates a decreased risk with tiotropium and an RR > 1 indicates a decreased risk with placebo. A P value < 0.05 is indicated when the width of the CI excludes the value 1. Potential heterogeneity among trials for adverse events, serious adverse events, and fatal adverse events was explored prior to combining trials using the Zelen test.36

Study Population

There were 19,545 patients randomized with 8,699 receiving placebo and 10,846 receiving tiotropium. Cumulative exposure to study drug (patient-years) was 13,146 for tiotropium and 11,095 for placebo. Baseline demographics (Table 2) were balanced between treatment groups. The mean age of the population was 65 ± 9 years and 76% were men. Mean baseline FEV1 was 1.15 ± 0.46 L (41 ± 14% predicted), FVC was 2.49 ± 0.82 L (70 ± 19% predicted), and FEV1/FVC was 0.47 ± 0.12. Thirty-four percent of patients were active smokers at randomization. There were a total of 5,019 prematurely discontinued patients with a higher discontinuation rate in the placebo-treated patients (22% vs 31%). Zelen test for adverse events, serious adverse events, and fatal adverse events did not indicate heterogeneity among trials (P values = .71, 1.00, 1.00, respectively).

Table Graphic Jump Location
Table 2 —Baseline Characteristics of Patients in the Placebo and Tiotropium Groups From the 30 Clinical Trials

GOLD = Global Obstructive Lung Disease initiative.

a 

Mean (SD).

Adverse Events

A majority of patients overall (65%) experienced an adverse event during the trial, with an 11% lower risk in the tiotropium group (Table 3). Overall, there were 1,655 patients with at least one cardiac event (Table 4) and 1,349 with at least one vascular event (Table 5). The RR (95% CI) for any cardiac event (tiotropium/placebo) was 0.91 (0.83-1.01) and for any vascular event was 0.97 (0.87-1.09). Tiotropium was not associated with a significantly increased risk for a cardiac or vascular adverse event, including the most common events in the categories of hypertension, ischemic heart disease, and cardiac failure. Cardiac failure occurred at a decreased rate with tiotropium relative to placebo (RR [95% CI] = 0.82 [0.69-0.98]). For myocardial infarction and stroke, the RRs (95% CI) were 0.78 (0.59-1.02) and 1.03 (0.79-1.35), respectively.

Table Graphic Jump Location
Table 3 —Summary of Adverse Events in 30 Pooled Clinical Trials

IR = incidence rate (per 100 patient-years of time at risk); RR = rate ratio (tiotropium/placebo).

a 

P < .05.

Table Graphic Jump Location
Table 4 —IRs, RRs, and 95% CIs for Cardiac Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. MedDRA = Medical Dictionary for Regulatory Activities; SOC = system organ classes. See Table 3 for expansion of other abbreviations.

a 

P < .05.

Table Graphic Jump Location
Table 5 —IRs, RRs, and 95% CIs for Vascular Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Serious Adverse Events

Serious adverse events were experienced by 24% of patients. The risk of a serious adverse event was significantly lower in the tiotropium group (Table 3). There were 950 patients with at least one serious cardiac event (Table 6) and 288 with at least one serious vascular event (Table 7). The RR (95% CI) for any serious cardiac event (tiotropium/placebo) was 0.83 (0.73-0.94) and 1.15 (0.91-1.45) for any serious vascular event. Tiotropium was not associated with a significantly increased risk for either a cardiac or vascular serious adverse event, including the most common events in the categories of ischemic heart disease and cardiac failure. Serious events for cardiac failure showed a trend toward a reduced risk (RR [95% CI] = 0.83 [0.67-1.03]). For serious myocardial infarction and stroke, the RRs (95% CI) were 0.77 (0.59-1.02) and 1.09 (0.81-1.48), respectively.

Table Graphic Jump Location
Table 6 —IRs, RRs, and 95% CIs for Cardiac Serious Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

a 

= P < .05.

Table Graphic Jump Location
Table 7 —IRs, RRs, and 95% CIs for Vascular Serious Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Fatal Events

There were 953 fatal cases, representing 5% of the population. The risk of experiencing a fatal adverse event was significantly lower in the tiotropium group (12% reduction) (Table 3). There were 198 patients with a fatal cardiac event (Table 8) and 25 with a fatal vascular event (Table 9). The RR (95% CI) for a fatal cardiac event (tiotropium/placebo) was 0.77 (0.58-1.03) and for a fatal vascular event was 0.44 (0.19-1.02). Tiotropium showed a trend toward a reduced risk for a cardiac or vascular fatal adverse event. For myocardial infarction and stroke, the RRs (95% CI) were 0.74 (0.41- 1.34) and 1.02 (0.49-2.12), respectively. There was a decrease in serious lower respiratory events, with an RR (95% CI) of 0.84 (0.77-0.90).

Table Graphic Jump Location
Table 8 —IRs, RRs, and 95% CIs for Fatal Cardiac Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Table Graphic Jump Location
Table 9 —IRs, RRs, and 95% CIs for Fatal Vascular Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

CV Composite End Point

The incidence rates and RRs for the composite CV end point are displayed in Figure 1. There was a 17% reduction in the risk of a major CV event in the tiotropium group relative to the placebo group and a 23% reduction for fatal CV events, with both values being statistically significant.

Figure Jump LinkFigure 1. Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis. Kaplan-Meier curves show the cumulative incidence estimate of the probability of major CV events (A) and of fatal CV events (B) based on the onset of an event. The numbers of patients at risk are listed for each time point, with the study period truncated at 48 months. All patients who received at least one dose of a study drug were included in the analysis. Incidence rate ratios with 95% CI are based on a stratified analysis, whereas all data were pooled for the Kaplan-Meier curves. CV = cardiovascular.Grahic Jump Location

The tiotropium clinical trial program described in this report represents a substantial database of 19,545 patients studied in randomized, double-blind, parallel-group, placebo-controlled trials for up to 4 years. The data set demonstrates reductions in overall adverse events, serious adverse events, and all-cause mortality. Similarly, reductions were observed for CV end points, including a composite CV-mortality end point. In addition, relative to the control group, the clinical trials have demonstrated sustained improvements in lung function, reduction in exacerbations, and improvements in health-related quality of life.17 In the recently published 4-year UPLIFT trial, patients receiving tiotropium had a decreased risk of mortality and reduced cardiac and respiratory morbidity while receiving the study drug during the 4-year treatment period compared with patients in the control group.7

COPD is an important cause of morbidity and death and is also an independent risk factor for CV morbidity and mortality.3748 Other than tobacco smoking, potential explanations for this association include the negative consequences of dynamic hyperinflation on cardiac physiology, exercise limitation, and deconditioning. It is also likely that exacerbations, hypoxemia, and respiratory failure may have deleterious cardiac consequences. Smoking cessation for patients who continue to smoke, supplemental oxygen in hypoxemic patients, noninvasive ventilation for acute-on-chronic respiratory failure, and lung reduction surgery for patients with inhomogeneous upper lobe emphysema and poor exercise tolerance indicate that it is possible to improve survival and morbidity in groups of patients with COPD.4448 Other than smoking cessation in patients who smoke, the majority of patients with COPD do not qualify for these other modes of therapy. However, most if not all patients with symptomatic COPD are candidates for pharmacological therapy, and it is of paramount importance that such treatments be demonstrated to have a favorable risk-benefit profile.

This analysis of the large tiotropium database indicates a reduced risk for mortality from CV events. The mechanism by which tiotropium may reduce these events and improve survival cannot be precisely determined in the pooled clinical trial database but an association with respiratory events must be considered given the significant reductions in exacerbations and hospitalizations observed. There were also reductions in the overall risk for serious and fatal lower respiratory events. Of special importance is the reduction in the number of episodes of respiratory failure, events that have been associated with an increased risk of death.49,50 This benefit was initially observed in the original pooled safety analysis of tiotropium in which the RR (tiotropium/placebo) of reports of respiratory failure was 0.59 (95% CI, 0.26-1.34), and the risk ratio for serious COPD exacerbations was 0.68 (95% CI, 0.54-0.85).10 Subsequently, these findings were confirmed in the UPLIFT trial with a 33% reduction in the risk for reports of respiratory failure and a 14% reduction in the risk for exacerbations leading to hospitalizations.7 Further insight as to possible mechanisms can be gained by the analysis of the differences in serious adverse events. In the pooled analysis of 30 trials, tiotropium treatment also resulted in significant reductions in serious adverse events under the cardiac and respiratory organ systems.

The results here presented contrast with previous retrospective analyses. An association between ipratropium and CV mortality was noted in an earlier report from the Lung Health Study.8 However, a reanalysis of the same data by Lanes et al9 showed that the increased risk of CV morbidity and mortality in that study was concentrated among patients who were randomized to the ipratropium group but who did not take ipratropium. In a 2-year study in patients with severe and very severe COPD with a history of exacerbations, tiotropium was demonstrated to provide equivalent effects on exacerbations and a significantly lower rate of pneumonia but a higher number of fatal events compared with the combination of salmeterol and fluticasone.51 These results are confounded by the run-in with 2 weeks of prednisolone and salmeterol, which was suddenly withdrawn at randomization (destabilization of patients) and the biases introduced with withdrawal of inhaled steroids used by 51% of patients at baseline.52

Retrospective analyses have recently been published regarding CV events and inhaled anticholinergics. In the first, Lee et al12 examined the association between various respiratory medications and risk for death in patients newly diagnosed with COPD based on a retrospective nested case-control study using various databases. The authors concluded that ipratropium was associated with increased CV deaths, whereas inhaled corticosteroids were associated with reduced risk. By its design, this study contrasted groups that likely entailed important differences in their baseline risk. The authors were limited by the data available to them, which did not include information on smoking or lung function. The analyses reported indicated that the inability to control for these factors produced effect estimates that exaggerated actual risks and could fully explain the association between ipratropium and mortality, noting that all-cause mortality risk ratio was 1.02 for ipratropium when accounting for severity as an unmeasured confounder. In the second analysis, Singh et al11 selected randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on CV events. The primary outcome was a composite of CV death, myocardial infarction, or stroke similar to the one we evaluated in this report using a much larger database. The secondary outcome was all-cause mortality. Although the report describes ipratropium and tiotropium trials both combined and separately, no differences in any CV effects would be expected between the two compounds based on their pharmacology. Singh et al11 concluded that inhaled anticholinergics significantly increased the risk of the composite CV end point, myocardial infarction and CV death, without a statistically significant increase in the risk of stroke. There are numerous limitations to the analysis. The authors incorrectly assumed that the integration of placebo-controlled trials with active controlled ­trials is valid. The analysis did not take into account differential discontinuation (ie, in most of the trials, more patients in the placebo group prematurely discontinued the study than did patients taking active medication and were therefore followed for briefer periods of time during which adverse events were reported) and differences in exposure. This likely contributes to the differences between the two studies. Most of the evidence in the analysis was provided by a single study, the Lung Health Study, and did not consider the report by Lanes et al.52 Finally, reporting of adverse events from data available in peer-reviewed publications is almost always incomplete and does not contain all patient-level data and therefore cannot correct for differences in exposure.

The results here reported are consistent with other published data supporting a beneficial effect on safety outcomes with tiotropium. One retrospective metaanalysis of randomized trials found that inhaled anticholinergic but not β2-agonist medications offered reduced respiratory mortality; however, this analysis also lacked adjustment for exposure and accounting for differential discontinuations.53 An epidemiologic study noted reduced respiratory and overall mortality with tiotropium and no excess in cardiac mortality.54 A recent longitudinal population-based cohort study indicated a reduced risk of mortality with tiotropium relative to salmeterol (hazard ratio 0.80; 95% CI, 0.70-0.93) in patients with COPD during the 6 months following discharge from hospital because of COPD.13 Finally, we have previously reported a reduced, albeit imprecise, risk of CV mortality (0.57; 95% CI, 0.26-1.26) and all-cause mortality (RR, 0.76; 95% CI, 0.50-1.16) in a smaller database (19 trials) that is consistent with the much larger database in the current report.10

There are recognized limitations to pooling of clinical trial data, some of which may apply to this report. There are differences in populations, study design, duration of trials, collection of data, and the ability to adjust for differences in exposure. In addition, it is recognized that the data are dependent on the physician diagnostic reporting and that this may be difficult when elderly patients with COPD become acutely ill. However, the present analysis is based on complete patient-level data in clinical trials that have a similar study design, similar inclusion and exclusion criteria, study population in one disease area (COPD), and a virtually identical manner of collecting adverse event information. Discrepancies in adverse event data are reconciled prior to locking the database and unblinding. We have consistently noted that a higher proportion of patients prematurely discontinue trials in the control group compared with the tiotropium group. These discontinued patients in general have more severe disease, and differentially larger, nonrandom discontinuation of the patients from the placebo group would lead to a bias against tiotropium rather than in favor of tiotropium. This effect has been documented in a previous retrospective analysis of a 6-month trial.55

In summary, increased risk for CV morbidity and mortality is a consequence of COPD. The present report presents a robust and extensive analysis of more than 19,000 patients participating in placebo-controlled tiotropium clinical trials and incorporation of all patient-level data during treatment in a defined set of 30 randomized, double-blind, placebo-controlled trials. The results indicate that tiotropium reduces the risk for CV events, CV mortality, and all-cause mortality.

Pooled Terms and the Associated Preferred Terms in Parenthesis Used in the Analyses

  • Aneurysm (aneurysm, aneurysm arteriovenous, aneurysm ruptured, aortic aneurysm, aortic aneurysm rupture, aortic aneurysm syphilitic, aortic dissection, aortic dissection rupture, aortic intramural hematoma, artery dissection, cardiac aneurysm, carotid aneurysm rupture, cerebral aneurysm ruptured syphilitic, Charcot-Bouchard microaneurysms, coronary artery aneurysm, coronary artery dissection, dissecting coronary artery aneurysm, femoral artery aneurysm, femoral artery dissection, hemorrhage coronary artery, hepatic artery aneurysm, infective aneurysm, intracranial aneurysm, mycotic aneurysm, peripheral artery aneurysm, peripheral artery dissection, pulmonary artery aneurysm, renal aneurysm, renal artery dissection, retinal aneurysm, ruptured cerebral aneurysm, splenic artery aneurysm, subclavian artery aneurysm, venous aneurysm)

  • Atrial fibrillation/flutter (atrial fibrillation, atrial flutter)

  • Cardiac arrest (AV dissociation, cardiac arrest, cardiac death, cardiac massage, cardiogenic shock, cardiorespiratory arrest, electromechanical dissociation, resuscitation)

  • Cardiac failure (acute left ventricular failure, acute pulmonary edema, acute right ventricular failure, cardiac cirrhosis, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiac failure high output, cardiogenic shock, cardiopulmonary failure, cardiorenal syndrome, chronic left ventricular failure, chronic right ventricular failure, congestive cardiomyopathy, cor pulmonale, cor pulmonale acute, cor pulmonale chronic, left ventricular failure, low cardiac output syndrome, pulmonary congestion, pulmonary edema, right ventricular failure, ventricular failure)

  • Hypertension (accelerated hypertension, blood pressure ambulatory increased, blood pressure diastolic increased, blood pressure inadequately controlled, blood pressure increased, blood pressure orthostatic increased, blood pressure systolic increased, diastolic hypertension, essential hypertension, hypertension, hypertensive angiopathy, hypertensive cardiomegaly, hypertensive cardiomyopathy, hypertensive crisis, hypertensive emergency, hypertensive encephalopathy, hypertensive heart disease, hypertensive nephropathy, labile hypertension, Liddle syndrome, malignant hypertension, malignant hypertensive heart disease, malignant renal hypertension, mean arterial pressure increased, neurogenic hypertension, paradoxical pressor response, procedural hypertension, renal hypertension, renovascular hypertension, secondary hypertension, systolic hypertension)

  • Ischemic heart disease (acute coronary syndrome, acute myocardial infarction, angina pectoris, angina unstable, arteriospasm coronary, coronary artery disease, coronary artery dissection, coronary artery insufficiency, coronary artery occlusion, coronary artery reocclusion, coronary artery stenosis, coronary artery thrombosis, electrocardiogram signs of myocardial ischemia, electrocardiogram Q wave abnormal, electrocardiogram Q waves, electrocardiogram ST segment depression, electrocardiogram ST segment elevation, electrocardiogram T wave inversion, ischemic cardiomyopathy, myocardial infarction, myocardial ischemia, myocardial reperfusion injury, myocardial rupture, papillary muscle infarction, papillary muscle rupture, postinfarction angina, Prinzmetal angina, silent myocardial infarction, subendocardial ischemia, ventricular rupture)

  • Myocardial infarction (acute myocardial infarction, electrocardiogram Q wave abnormal, electrocardiogram Q waves, electrocardiogram ST segment elevation, myocardial infarction, myocardial rupture, papillary muscle infarction, papillary muscle rupture, silent myocardial infarction, troponin I increased, troponin increased, troponin T increased, ventricle rupture)

  • Palpitations (extrasystoles, palpitations, supraventricular extrasystoles, ventricular extrasystoles)

  • Stroke (amaurosis fugax, basal ganglia hemorrhage, basilar artery occlusion, basilar artery thrombosis, brain stem hemorrhage, brain stem infarction, brain stem ischemia, brain stem thrombosis, carotid aneurysm rupture, carotid arterial embolus, carotid artery occlusion, carotid artery thrombosis, cerebellar artery occlusion, cerebellar artery thrombosis, cerebellar embolism, cerebellar hematoma, cerebellar hemorrhage, cerebellar infarction, cerebral arteriovenous malformation hemorrhagic, cerebral artery embolism, cerebral artery occlusion, cerebral artery thrombosis, cerebral hematoma, cerebral hemorrhage, cerebral hemorrhage fetal, cerebral hemorrhage neonatal, cerebral infarction, cerebral infarction fetal, cerebral ischemia, cerebral thrombosis, cerebrovascular accident, embolic cerebral infarction, embolic stroke, hemorrhage intracranial, hemorrhagic cerebral infarction, hemorrhagic stroke, hemorrhagic transformation stroke, intracranial hematoma, intracranial tumor hemorrhage, intraoperative cerebral artery occlusion, intraventricular hemorrhage, intraventricular hemorrhage neonatal, ischemic cerebral infarction, ischemic stroke, lacunar infarction, lateral medullary syndrome, pituitary hemorrhage, pituitary infarction, postprocedural stroke, precerebral artery occlusion, putamen hemorrhage, reversible ischemic neurologic deficit, ruptured cerebral aneurysm, stroke in evolution, subarachnoid hemorrhage, subarachnoid hemorrhage neonatal, subdural hemorrhage neonatal, thalamic infarction, thalamus hemorrhage, thrombotic cerebral infarction, thrombotic stroke, transient ischemic attack, vertebral artery occlusion, vertebral artery thrombosis)

  • Supraventricular tachycardia (atrial tachycardia, postural orthostatic tachycardia syndrome, sinus tachycardia, supraventricular tachycardia, tachycardia paroxysmal)

  • Tachycardia (heart rate increased, sinus tachycardia, tachycardia)

  • Ventricular tachycardia/fibrillation (ventricular tachycardia, ventricular fibrillation)

Author contributions:Dr Celli: contributed to the planning and data analysis and was the primary writer of the manuscript.

Dr Decramer: contributed to the planning, data analysis, and writing of the manuscript.

Dr Leimer: contributed to the collection and analysis of the data as a member of the Boehringer Ingelheim staff.

Dr Vogel: contributed to the collection and analysis of the data as a member of the Boehringer Ingelheim staff.

Dr Kesten: contributed to the access to the data, its analysis and interpretation, and generation of the manuscript.

Dr Tashkin: contributed to the planning, data analysis, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to the CHEST the following conflicts of interest: Drs Celli, Tashkin, and Decramer have the following relationships with Boehringer Ingelheim and Pfizer: consultant, member of speakers’ bureau, and recipient of research grants. Drs Kesten, Leimer, and Vogel are employees of Boehringer Ingelheim.

Other contributions: We thank Dr Dacheng Liu and Dr Shailendra Menjoge for statistical support.

CV

cardiovascular

IR

incidence rate

MedDRA

Medical Dictionary for Regulatory Activities

RR

rate ratio

SOC

system organ classes

UPLIFT

Understanding Potential Long-term Impacts on Function with Tiotropium

Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;646–7:457-464. [CrossRef] [PubMed]
 
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;192:217-224. [CrossRef] [PubMed]
 
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;585:399-404. [CrossRef] [PubMed]
 
O’Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;236:832-840. [CrossRef] [PubMed]
 
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;1283:1168-1178. [CrossRef] [PubMed]
 
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;1435:317-326. [PubMed]
 
Tashkin DP, Celli B, Senn S, et al. UPLIFT investigators. A four year trial of tiotropium in patients with chronic obstructive pulmonary disease. N Engl J Med. 2008;35915:1543-1554. [CrossRef] [PubMed]
 
Anthonisen NR, Connett JE, Enright PL, Manfreda J. Lung Health Study Research Group Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;1663:333-339. [CrossRef] [PubMed]
 
Lanes S, Golish W, Mikl J. Ipratropium and Lung Health Study [letter]. Am J Respir Crit Care Med. 2003;1677:801. [PubMed]
 
Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;1306:1695-1703. [CrossRef] [PubMed]
 
Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;30012:1439-1450. [CrossRef] [PubMed]
 
Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008;1496:380-390. [PubMed]
 
Gershon A, Wang L, To T, Luo J, Upshur REG. Survival with tiotropium compared to long-acting beta-2-agonists in chronic obstructive pulmonary disease. COPD. 2008;54:229-234. [CrossRef] [PubMed]
 
Macie C, Wooldrage K, Manfreda J, Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators. Int J Chron Obstruct Pulmon Dis. 2008;31:1-7. [PubMed]
 
Pedone C, Incalzi RA. Tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2009;3602:185. [CrossRef] [PubMed]
 
Calverley PM, Lee A, Towse L, van Noord J, Witek TJ, Kelsen S. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax. 2003;5810:855-860. [CrossRef] [PubMed]
 
McNicholas WT, Calverley PMA, Lee A, et al. Tiotropium Sleep Study in COPD Investigators. Effects of long-acting anticholinergic therapy (tiotropium) on oxygen saturation and sleep quality in adults with severe COPD. Eur Respir J. 2004;236:825-831. [CrossRef] [PubMed]
 
Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J. 2006;273:547-555. [CrossRef] [PubMed]
 
Verkindre C, Bart F, Aguilaniu B, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration. 2006;734:420-427. [CrossRef] [PubMed]
 
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest. 2003;1245:1743-1748. [CrossRef] [PubMed]
 
Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005;1273:809-817. [CrossRef] [PubMed]
 
Ambrosino N, Foglio F, Balzano G, Paggiaro PL, Lessi P, Kesten S. Tiotropium and exercise training in COPD patients: effects on dyspnoea and exercise tolerance. Int J Chron Obstruct Pulmon Dis. 2008;34:771-780. [PubMed]
 
Voshaar T, Lapidus R, Maleki-Yazdi R, et al. A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. Respir Med. 2008;1021:32-41. [CrossRef] [PubMed]
 
Tonnel AB, Perez T, Grosbois JM, Venrkindre C, Bravo ML. Brun M on behalf of the TIPHON study group. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis. 2008;32:301-310. [PubMed]
 
Beeh KM, Beier J, Buhl R, Stark-Lorenzen P, Gerken F, Metzdorf N. ATEM-Studiengruppe Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities. [in German]. Pneumologie. 2006;606:341-346. [CrossRef] [PubMed]
 
Chan CKN, Maltais F, Sigouin S, Haddon JM, Ford G. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J. 2008;148:465-472
 
Powrie DJ, Wilkinson TMA, Donaldson GC, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in chronic obstructive pulmonary disease. Eur Respir J. 2007;303:472-478. [CrossRef] [PubMed]
 
Freeman D, Lee A, Price D. Efficacy and safety of tiotropium in COPD patients in primary care – the Spiriva usual care (SPRUCE) study. Respir Res. 2007;81:45. [CrossRef] [PubMed]
 
Johansson G, Lindberg A, Romberg K, Nordström L, Gerken F, Roquet A. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Prim Care Respir J. 2008;173:169-175. [CrossRef] [PubMed]
 
Moita J, Bárbara C, Cardoso J, et al. Tiotropium improves FEV1in patients with COPD irrespective of smoking status. Pulm Pharmacol Ther. 2008;211:146-151. [CrossRef] [PubMed]
 
Covelli H, Bhattacharya S, Cassino C, Conoscenti C, Kesten S. Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. Pharmacotherapy. 2005;2512:1708-1718. [CrossRef] [PubMed]
 
Criner GJ, Sharafkhaneh A, Player R, et al. Efficacy of tiotropium inhalation powder in African-American patients with chronic obstructive pulmonary disease. COPD. 2008;51:35-41. [CrossRef] [PubMed]
 
Magnussen H, Bugnas B, van Noord J, Schmidt P, Gerken F, Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med. 2008;1021:50-56. [CrossRef] [PubMed]
 
American Thoracic Society Standardization of Spirometry, 1994 update. Am J Respir Crit Care Med. 1995;1523:1107-1136. [PubMed]
 
Rothman KJ, Greenland S.Rothman KJ, Greenland S. Measures of Disease Frequency. Modern Epidemiology. 1998;2nd ed. Philadelphia, PA Lippincott–Raven Publishers:29-46
 
Reis IM, Hirji KF, Afifi AA. Exact and asymptotic tests for homogeneity in several 2 × 2 tables. Stat Med. 1999;188:893-906. [CrossRef] [PubMed]
 
Mannino DM, Buist AS, Petty TL, Enright PL, Redd SC. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax. 2003;585:388-393. [CrossRef] [PubMed]
 
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003;10711:1514-1519. [CrossRef] [PubMed]
 
Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data From the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med. 2003;16312:1475-1480. [CrossRef] [PubMed]
 
Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax. 2008;637:599-605. [CrossRef] [PubMed]
 
Anthonisen NR. Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials. Am Rev Respir Dis. 1989;1403 Pt 2:S95-S99. [CrossRef] [PubMed]
 
Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax. 1990;458:579-585. [CrossRef] [PubMed]
 
Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol. 2006;161:63-70. [CrossRef] [PubMed]
 
Report of the Medical Research Council Working Party Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet. 1981;18222:681-686. [PubMed]
 
Nocturnal Oxygen Therapy Trial Group Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;933:391-398. [PubMed]
 
Fishman A, Martinez F, Naunheim K, et al. National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;34821:2059-2073. [CrossRef] [PubMed]
 
Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation—a consensus conference report. Chest. 1999;1162:521-534. [CrossRef] [PubMed]
 
Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. Lung Health Study Research Group The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005;1424:233-239. [PubMed]
 
Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;1544 pt 1:959-967. [PubMed]
 
Gillespie DJ, Marsh HM, Divertie MB, Meadows JA III. Clinical outcome of respiratory failure in patients requiring prolonged (greater than 24 hours) mechanical ventilation. Chest. 1986;903:364-369. [CrossRef] [PubMed]
 
Wedzicha JA, Calverley PMA, Seemungal TA, Hagan G, Ansari Z, Stockley RA. INSPIRE Investigators The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;1771:19-26. [CrossRef] [PubMed]
 
Lanes SF, Jara M. The INSPIRE study: influence of prior use and discontinuation of inhaled corticosteroids. Am J Respir Crit Care Med. 2008;1785:543-544 author reply 544.. [PubMed]
 
Salpeter SR. Bronchodilators in COPD: impact of B-agonists and anticholinergics on severe exacerbations and mortality. Int J Chron Obstruct Pulmon Dis. 2007;21:11-18. [PubMed]
 
de Luise C, Lanes SF, Jacobsen J, Pedersen L, Sørensen HT. Cardiovascular and respiratory hospitalizations and mortality among users of tiotropium in Denmark. Eur J Epidemiol. 2007;224:267-272. [CrossRef] [PubMed]
 
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;305:898-906. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis. Kaplan-Meier curves show the cumulative incidence estimate of the probability of major CV events (A) and of fatal CV events (B) based on the onset of an event. The numbers of patients at risk are listed for each time point, with the study period truncated at 48 months. All patients who received at least one dose of a study drug were included in the analysis. Incidence rate ratios with 95% CI are based on a stratified analysis, whereas all data were pooled for the Kaplan-Meier curves. CV = cardiovascular.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Trial Duration, Number of Participants, and Number of Cases per End Point According to Trial Included in the Pooled Analysis

CV = cardiovascular.

Table Graphic Jump Location
Table 2 —Baseline Characteristics of Patients in the Placebo and Tiotropium Groups From the 30 Clinical Trials

GOLD = Global Obstructive Lung Disease initiative.

a 

Mean (SD).

Table Graphic Jump Location
Table 3 —Summary of Adverse Events in 30 Pooled Clinical Trials

IR = incidence rate (per 100 patient-years of time at risk); RR = rate ratio (tiotropium/placebo).

a 

P < .05.

Table Graphic Jump Location
Table 4 —IRs, RRs, and 95% CIs for Cardiac Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. MedDRA = Medical Dictionary for Regulatory Activities; SOC = system organ classes. See Table 3 for expansion of other abbreviations.

a 

P < .05.

Table Graphic Jump Location
Table 5 —IRs, RRs, and 95% CIs for Vascular Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Table Graphic Jump Location
Table 6 —IRs, RRs, and 95% CIs for Cardiac Serious Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

a 

= P < .05.

Table Graphic Jump Location
Table 7 —IRs, RRs, and 95% CIs for Vascular Serious Adverse Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Table Graphic Jump Location
Table 8 —IRs, RRs, and 95% CIs for Fatal Cardiac Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

Table Graphic Jump Location
Table 9 —IRs, RRs, and 95% CIs for Fatal Vascular Events in the Pooled Analysis of 30 Trials

Terms used are composed of multiple MedDRA preferred terms. See Tables 3 and 4 for expansion of abbreviations.

References

Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;646–7:457-464. [CrossRef] [PubMed]
 
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;192:217-224. [CrossRef] [PubMed]
 
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;585:399-404. [CrossRef] [PubMed]
 
O’Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;236:832-840. [CrossRef] [PubMed]
 
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;1283:1168-1178. [CrossRef] [PubMed]
 
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;1435:317-326. [PubMed]
 
Tashkin DP, Celli B, Senn S, et al. UPLIFT investigators. A four year trial of tiotropium in patients with chronic obstructive pulmonary disease. N Engl J Med. 2008;35915:1543-1554. [CrossRef] [PubMed]
 
Anthonisen NR, Connett JE, Enright PL, Manfreda J. Lung Health Study Research Group Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;1663:333-339. [CrossRef] [PubMed]
 
Lanes S, Golish W, Mikl J. Ipratropium and Lung Health Study [letter]. Am J Respir Crit Care Med. 2003;1677:801. [PubMed]
 
Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;1306:1695-1703. [CrossRef] [PubMed]
 
Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;30012:1439-1450. [CrossRef] [PubMed]
 
Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008;1496:380-390. [PubMed]
 
Gershon A, Wang L, To T, Luo J, Upshur REG. Survival with tiotropium compared to long-acting beta-2-agonists in chronic obstructive pulmonary disease. COPD. 2008;54:229-234. [CrossRef] [PubMed]
 
Macie C, Wooldrage K, Manfreda J, Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators. Int J Chron Obstruct Pulmon Dis. 2008;31:1-7. [PubMed]
 
Pedone C, Incalzi RA. Tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2009;3602:185. [CrossRef] [PubMed]
 
Calverley PM, Lee A, Towse L, van Noord J, Witek TJ, Kelsen S. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax. 2003;5810:855-860. [CrossRef] [PubMed]
 
McNicholas WT, Calverley PMA, Lee A, et al. Tiotropium Sleep Study in COPD Investigators. Effects of long-acting anticholinergic therapy (tiotropium) on oxygen saturation and sleep quality in adults with severe COPD. Eur Respir J. 2004;236:825-831. [CrossRef] [PubMed]
 
Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J. 2006;273:547-555. [CrossRef] [PubMed]
 
Verkindre C, Bart F, Aguilaniu B, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration. 2006;734:420-427. [CrossRef] [PubMed]
 
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest. 2003;1245:1743-1748. [CrossRef] [PubMed]
 
Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005;1273:809-817. [CrossRef] [PubMed]
 
Ambrosino N, Foglio F, Balzano G, Paggiaro PL, Lessi P, Kesten S. Tiotropium and exercise training in COPD patients: effects on dyspnoea and exercise tolerance. Int J Chron Obstruct Pulmon Dis. 2008;34:771-780. [PubMed]
 
Voshaar T, Lapidus R, Maleki-Yazdi R, et al. A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. Respir Med. 2008;1021:32-41. [CrossRef] [PubMed]
 
Tonnel AB, Perez T, Grosbois JM, Venrkindre C, Bravo ML. Brun M on behalf of the TIPHON study group. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis. 2008;32:301-310. [PubMed]
 
Beeh KM, Beier J, Buhl R, Stark-Lorenzen P, Gerken F, Metzdorf N. ATEM-Studiengruppe Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities. [in German]. Pneumologie. 2006;606:341-346. [CrossRef] [PubMed]
 
Chan CKN, Maltais F, Sigouin S, Haddon JM, Ford G. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J. 2008;148:465-472
 
Powrie DJ, Wilkinson TMA, Donaldson GC, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in chronic obstructive pulmonary disease. Eur Respir J. 2007;303:472-478. [CrossRef] [PubMed]
 
Freeman D, Lee A, Price D. Efficacy and safety of tiotropium in COPD patients in primary care – the Spiriva usual care (SPRUCE) study. Respir Res. 2007;81:45. [CrossRef] [PubMed]
 
Johansson G, Lindberg A, Romberg K, Nordström L, Gerken F, Roquet A. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Prim Care Respir J. 2008;173:169-175. [CrossRef] [PubMed]
 
Moita J, Bárbara C, Cardoso J, et al. Tiotropium improves FEV1in patients with COPD irrespective of smoking status. Pulm Pharmacol Ther. 2008;211:146-151. [CrossRef] [PubMed]
 
Covelli H, Bhattacharya S, Cassino C, Conoscenti C, Kesten S. Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. Pharmacotherapy. 2005;2512:1708-1718. [CrossRef] [PubMed]
 
Criner GJ, Sharafkhaneh A, Player R, et al. Efficacy of tiotropium inhalation powder in African-American patients with chronic obstructive pulmonary disease. COPD. 2008;51:35-41. [CrossRef] [PubMed]
 
Magnussen H, Bugnas B, van Noord J, Schmidt P, Gerken F, Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med. 2008;1021:50-56. [CrossRef] [PubMed]
 
American Thoracic Society Standardization of Spirometry, 1994 update. Am J Respir Crit Care Med. 1995;1523:1107-1136. [PubMed]
 
Rothman KJ, Greenland S.Rothman KJ, Greenland S. Measures of Disease Frequency. Modern Epidemiology. 1998;2nd ed. Philadelphia, PA Lippincott–Raven Publishers:29-46
 
Reis IM, Hirji KF, Afifi AA. Exact and asymptotic tests for homogeneity in several 2 × 2 tables. Stat Med. 1999;188:893-906. [CrossRef] [PubMed]
 
Mannino DM, Buist AS, Petty TL, Enright PL, Redd SC. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax. 2003;585:388-393. [CrossRef] [PubMed]
 
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003;10711:1514-1519. [CrossRef] [PubMed]
 
Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data From the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med. 2003;16312:1475-1480. [CrossRef] [PubMed]
 
Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax. 2008;637:599-605. [CrossRef] [PubMed]
 
Anthonisen NR. Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials. Am Rev Respir Dis. 1989;1403 Pt 2:S95-S99. [CrossRef] [PubMed]
 
Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax. 1990;458:579-585. [CrossRef] [PubMed]
 
Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol. 2006;161:63-70. [CrossRef] [PubMed]
 
Report of the Medical Research Council Working Party Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet. 1981;18222:681-686. [PubMed]
 
Nocturnal Oxygen Therapy Trial Group Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;933:391-398. [PubMed]
 
Fishman A, Martinez F, Naunheim K, et al. National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;34821:2059-2073. [CrossRef] [PubMed]
 
Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation—a consensus conference report. Chest. 1999;1162:521-534. [CrossRef] [PubMed]
 
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