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Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease With Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator: A Randomized Trial

Posted on: Wednesday, 7 September 2005, 03:00 CDT

Background: Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications.

Objective: To prospectively evaluate the effectiveness of a long- acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization.

Design: Randomized, double-blind study.

Setting: 26 Veterans Affairs medical centers.

Patients: 1829 patients with moderate to severe COPD (mean baseline FEV^sub 1^, 36% predicted).

Intervention: Once-daily tiotropium (18 g) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators.

Measurements: The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.

Results: Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, -5.7 percentage points [95% CI, -10.4 to -1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, -3.0 percentage points [CI, -5.9 to -0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates.

Limitations: Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months.

Conclusions: Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD.

Ann Intern Med. 2005;143:317-326. www.annals.org

Exacerbations of chronic obstructive pulmonary disease (COPD) can lead to costly and clinically significant consequences. Proven treatments for exacerbations are only modestly effective (1, 2). Recovery from even mild exacerbations may be protracted (3). Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time (4, 5). Patients with severe exacerbations commonly seek care in emergency departments, and many of these patients are hospitalized. In 2000, COPD was responsible for 1.5 million emergency department visits and 726 000 hospitalizations in the United States (6). Economic analyses suggest that hospitalization alone consumes up to 70% of all medical expenses for patients with COPD (7, 8).

Interventions that reduce the frequency or seventy of exacerbations are a highly desirable but poorly met medical need. An expert panel convened by the National Heart, Lung, and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations (9).

Tiotropium is a newly developed, once-daily inhaled anticholinergic bronchodilator. Because of its very slow dissociation from muscarinic M3 receptors, 1 inhaled dose produces sustained bronchodilation for at least 24 hours (10). In controlled clinical trials, compared with placebo or the short-acting anticholinergic bronchodilator ipratropium, tiotropium improved lung function, dyspnea, and health-related quality of life in patients with COPD (11, 12). An analysis of adverse event reports submitted during those studies suggested that tiotropium might also reduce exacerbation and COPD-related hospitalization rates. Therefore, we designed a clinical trial to prospectively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD.

METHODS

Study Design

Our study was a parallel-group, randomized, double-blind, placebo- controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States. The sole intervention was tiotropium given by inhalation once daily. The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period. The protocol is consistent with the principles of Helsinki. The institutional review boards of participating medical centers approved the study. All trial participants provided written informed consent.

Patients

All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants. We enrolled enough participants to ensure a minimum of 1800 randomly assigned patients. Eligibility criteria included an age of 40 years or older, a cigarette smoking history of 10 pack-years or more, a clinical diagnosis of COPD, and an FEV^sub 1^ of 60% predicted or less and 70% or less of the FVC. Exclusion criteria were a clinical diagnosis of asthma, a myocardial infarction within the previous 6 months, a serious cardiac arrhythmia or hospitalization for heart failure within the previous year, known moderate to severe renal impairment, moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction, narrow-angle glaucoma, current radiation or chemotherapy for a malignant condition, or inability to give informed consent. We also excluded patients who took systemic corticosteroids at unstable doses, or in regular daily doses of 20 mg or more of prednisone (or equivalent), or who had not fully recovered from an exacerbation for at least 30 days before the first study visit. We gathered baseline data on respiratory disease and other relevant medical history by questionnaire.

Procedures

We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a centrally generated blocked randomization list. We generated a single randomization and assigned blocks to centers. We provided randomly assigned patients with training and detailed instructions on the use of the dry powder inhalation device (HandiHaler, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany) (13).

Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites. The double-blind remained in place until all patients were clinically complete or until a serious adverse event required unblinding.

Each morning during the trial, patients inhaled 1 capsule of tiotropium (18 g) or 1 identical placebo capsule. Participants otherwise received usual medical care, except that they could not take any open-label anticholinergic bronchodilator. They continued taking all other respiratory medications (including inhaled corticosteroids and long-acting β-agonists), and primary providers were allowed to prescribe additional medications according to medical need. Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions. For purposes of recall, patients kept a daily diary throughout the treatment period, recording information about specific respiratory symptoms, medications taken for exacerbations, clinic visits, and hospitalizations. We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits. We assessed study drug adherence by query and by counting returned capsules. Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits. We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy. However, patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits. All open-label bronchodilators and the study drug were withheld overnight before spirometry. Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations (14, 15).

Objectives

We aimed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations.

Outcome Measures

The coprimary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation. We defined an exacerbation as a complex of respiratory symptoms (increase or new-onset) of more than 1 of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both. The study team at each site requested discharge summaries for all hospitalizations, wherever they occurred. We identified hospitalizations due to COPD exacerbations from events on case report forms that met \the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event resulted in a hospitalization. We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours. Admissions to nursing homes or other extended care facilities were not considered hospitalizations. Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation, the frequencies of exacerbations and of exacerbation-related health care utilization (hospitalizations, hospitalization days, unscheduled clinic visits, antibiotic treatment days, and systemic corticosteroid treatment days), the frequencies of all-cause hospitalizations and hospitalization days, and results of spirometry.

Figure 1. Trial flow chart.

Statistical Analysis

We analyzed the data by using a modified intention-to-treat principle. Therefore, we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event (for the time-to- event end points) or their withdrawal from the trial. For the time- to-event end points, we censored patients without an event at the end of their participation in the trial.

Although we intended to follow all patients for the full 6 months, some patients were lost to follow-up. We handled missing data by using longitudinal data analysis methods (spirometry), analysis of observed data only (number of events), or analysis methods for censored data (time-to-event data). For the percentage of patients with an event, we considered that patients who discontinued the study drug therapy before having an event did not have an event.

Table 1. Baseline Characteristics of the Patients*

We analyzed the coprimary end points by using a Cochran-Mantel- Haenszel test with center as a stratum. We used a stepwise procedure to test the percentage of patients with an exacerbation and, if rejected, to test percentage of patients with a hospitalization due to COPD exacerbation, each at a 2-sided α level of 0.05. Because of the prespecified closed testing procedure, no adjustment for multiplicity was required. We calculated that a sample size of 1800 patients would have 80% power to detect an 18% relative reduction in the percentage of patients with at least 1 exacerbation. We used the Breslow-Day test to assess homogeneity of odds ratios across the centers. We also used this test to evaluate the consistency of the percentage of patients with an exacerbation or hospitalization across subgroups (for example, current cigarette smoker vs. exsmoker). Although the Cochran-Mantel-Haenszel procedure is a test of the odds ratio for the treatments, we used an additional analysis to estimate treatment differences and 95% CIs weighted by center (16). We analyzed the time-to-event data by using a Cox proportional hazards model stratified by center with treatment as the only term. Kaplan-Meier curves show survival functions. We checked the proportional hazards assumption by using plots of log(- log(survival)) versus log of time. These showed parallel lines indicating no violation of the proportional hazards assumption.

We analyzed the numbers of events (for example, exacerbations, exacerbation days, and hospitalization days) by using a stratified Wilcoxon-Mann-Whitney test using observed (nonimputed) data. The data for analysis were the number of events for a patient divided by the patient's exposure, and we used centers as the strata. The amounts of missing data were about 5% for the tiotropium group and 7% for the placebo group.

We analyzed the spirometry data by using a linear mixed-effects model with terms for center, treatment, time, and the treatment-by- time interaction as fixed categorical effects and baseline value as a continuous covariate. We used an unstructured variance-covariance matrix, and time within patient was the repeated measure. This analysis method assumes the data are missing at random (that is, the likelihood of a value being missing may depend on the observed data but not on the unobserved data). If this does not hold, the results may be biased.

We used Proc-StatXact (Cytel Software, Cambridge, Massachusetts) for the Cochran-Mantel-Haenszel, Breslow-Day, and stratified Wilcoxon-Mann-Whitney tests. We used SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina), for the stratified Cox models (PHREG procedure) and the longitudinal analysis (MIXED procedure).

Role of the Funding Sources

Boehringer Ingelheim Pharmaceuticals and Pfizer, Inc., provided financial support for the trial. Boehringer Ingelheim Pharmaceuticals collaborated with Dr. Niewoehner in designing the trial and writing the protocol, and it collected the data and performed the analyses. The authors had full access to the data. Boehringer Ingelheim Pharmaceuticals and the authors participated in the decision to submit the manuscript for publication.

RESULTS

Study Sample

Enrollment began in September 2001, and follow-up concluded in February 2003. Study personnel obtained informed consent and determined eligibility criteria in 2498 potential study participants (Figure 1). We randomly assigned the 1829 patients who met all eligibility criteria: 915 to placebo and 914 to tiotropium.

Differences in baseline characteristics between the 2 treatment groups were small, and none was statistically significant (Table 1). The sex and race compositions (99% men and 91% white) of the study participants are representative of patients who receive medical care at Veterans Affairs facilities. The low baseline FEV^sub 1^ (36% predicted) and the high rate of home oxygen use (29%) denote a study sample in which all patients would have at least moderately severe COPD and most would have severe or very severe COPD (17).

Of the randomly assigned patients, 245 (27%) patients from the placebo group and 149 (16%) patients from the tiotropium group discontinued the study therapy prematurely. Total study drug exposure was 151 892 patient-days in the tiotropium group and 138 710 patient-days in the placebo group. Time to study drug withdrawal was significantly longer in the tiotropium group than in the placebo group (P < 0.001 by log-rank test). The most commonly cited reason for withdrawal was worsening of COPD. However, all patients were asked to keep their regularly scheduled study visits and provide clinical information, even if trial medication therapy was discontinued. Ninety percent of the randomly assigned patients completed all study visits. Discharge summaries were available for review from 94% of all hospitalizations. The amounts of missing data based on patients discontinuing the study for any reason were as follows: spirometry, 14.8% (11.7% tiotropium and 17.8% placebo), and exacerbation and hospitalization end points, 6.1% (5.0% tiotropium and 7.2% placebo).

Table 2. Comparison of Chronic Obstructive Pulmonary Disease Exacerbation and Hospitalization Rates during 6-Month Treatment with Tiotropium or Placebo*

Primary Outcomes

As compared with placebo, tiotropium significantly reduced the percentage of patients who experienced at least 1 COPD exacerbation during the 6-month treatment period (27.9% vs. 32.3%, respectively; P = 0.037) (Table 2). Tiotropium also reduced the percentage of patients who experienced 1 or more hospitalizations due to COPD exacerbation during the same period (7.0% vs. 9.5%, respectively; P = 0.056), but this difference did not reach our prespecified significance level (P = 0.050). The method used to estimate the P value, Cochran-Mantel-Haenszel, differs slightly from the procedure of Bhning and Sarol (16) used to estimate treatment differences and 95% CIs. Hence, the estimated P value is slightly greater than 0.050, while the upper limit on the 95% CI is slightly lower than 0.0. Both tests are consistent and provide a statistically significant result of about 0.050, which is our prespecified significance level. This analysis assumed that the 47 (5.1%) tiotropium patients and 66 (7.2%) placebo patients who withdrew from the study before an event had no event.

Secondary Outcomes

As shown in Kaplan-Meier plots (Figure 2), tiotropium, as compared with placebo, extended the time to first exacerbation (hazard ratio, 0.83 [95% CI, 0.70 to 0.98]; P = 0.028). The time to first hospitalization due to COPD exacerbation was also extended in the tiotropium group (hazard ratio, 0.73 [CI, 0.53 to 1.01]; P = 0.055), although this relationship was of borderline statistical significance.

Table 3 summarizes other secondary end point data. Tiotropium reduced the frequencies of exacerbations (P = 0.031), unscheduled medical visits due to COPD exacerbations (P = 0.019), and hospitalizations due to COPD exacerbations (P = 0.047). It also decreased exacerbation days (P = 0.019) and the duration of antibiotic treatment for COPD exacerbations (P = 0.015). The relative decrease is between 15% and 28% for each event. Hospitalization days and systemic corticosteroid treatment days for COPD did not statistically significantly differ between the 2 groups, nor did all-cause hospitalizations and all-cause hospitalization days.

Subgroup Analyses

We performed subgroup analyses according to each of these prespecified entry variables: age; race; current cigarette smoking; baseline FEV^sub 1^; hospitalization for COPD in the past year; 1 or more courses of systemic corticosteroids for COPD in the past year; 1 or more courses of antibiotics for COPD in the past year; and use at study entry of home oxygen, inhaled corticosteroids, long-acting inhaled β-agonists, and theophylline. As shown in Figure 3, tiotropium fairly uniformly reduced exacerbations for all subsets included in the analyses. A test for nonhomogeneity of odds ra\tios for percentage of patients with an exacerbation performed for each variable indicated no statistically significant interactions with treatment assignment.

Figure 2. Kaplan-Meier estimates of the rate of first treatment failure at 6 months for the first chronic obstructive pulmonary disease exacerbation (top) and for the first hospitalization due to chronic obstructive pulmonary disease exacerbation (bottom), according to treatment assignment.

Spirometry

Compared with placebo, tiotropium increased the FEV^sub 1^ response at 90 minutes after administration of study medication at study days 0, 90, and 180 by mean values of 0.13 L (CI, 0.12 L to 0.14 L), 0.17 L (CI, 0.15 L to 0.19 L), and 0.17 L (CI, 0.15 L to 0.19 L), respectively (P < 0.001 for all comparisons). In addition, the morning trough FEV^sub 1^ before administration of the study drug was higher in tiotropium-treated patients than in placebo patients. The mean values at study days 90 and 180 were 0.10 L (CI, 0.08 L to 0.12 L) and 0.10 L (CI, 0.07 L to 0.12 L), respectively (P < 0.001 for both comparisons).

Serious Adverse Events

Serious adverse events, including deaths, were assigned to a treatment group if they occurred within 30 days of the last dose of study medication. One hundred fifty-six (17%) patients had a serious adverse event in the placebo group compared with 162 (18%) patients in the tiotropium group. The most frequently occurring serious adverse events were lower respiratory system disorders, which were reported in 7.8% of patients in the tiotropium group and 9.9% of patients in the placebo group. Cardiac disorders were the next most frequently occurring events. Congestive heart failure was the most commonly reported serious adverse event of cardiac etiology, reported by 10 patients in each treatment group. Atrial fibrillation occurred in fewer patients in the tiotropium group than in the placebo group (2 patients vs. 9 patients, respectively). There were no appreciable imbalances in ischemic events.

In the placebo group, 19 (2.1%) patients died compared with 22 (2.4%) patients in the tiotropium group. The tiotropium group reported fewer fatal lower respiratory tract events than the placebo group (2 patients vs. 7 patients, respectively). Seven cardiac deaths (including patients found dead with no other information) occurred in each group. The next most common cause of death was cancer (8 patients in the tiotropium group and 5 patients in the placebo group). The other causes of death varied and were few in number.

Table 3. Comparison of Secondary Outcomes during 6 Months of Treatment with Tiotropium or Placebo*

DISCUSSION

Our large multicenter trial confirms that tiotropium statistically significantly reduced the percentage of patients with moderate to severe COPD who experienced at least 1 exacerbation over a 6-month period. The absolute and relative reductions were 4.4% and 14.0%, respectively, which are consistent with previous tiotropium studies in which exacerbation data were acquired through adverse event reporting and were analyzed as a secondary end point (11, 12). Our other study outcomes suggest that tiotropium may reduce rates of hospitalization and some other health care events attributable to COPD exacerbations. These treatment effects were small to modest, and their overall clinical importance must be weighed against other considerations, including cost. We should emphasize that COPD exacerbations are common; morbid; and, particularly in the case of hospitalization, very costly (3, 7, 8).

We compared tiotropium against placebo in this trial, leaving unanswered the question of whether similar treatment differences would have been observed if tiotropium had been compared with the short-acting anticholinergic ipratropium. Tiotropium was compared with either ipratropium, given 4 times daily, or placebo in 2 previous 1-year trials (11, 12). Tiotropium reduced the percentage of patients with at least 1 exacerbation from 46% to 35% when ipratropium was the comparator and from 42% to 36% when placebo was the comparator (P < 0.05 for both comparisons). Similarly, tiotropium reduced the percentage of patients with at least 1 COPD- related hospitalization from 11.7% to 7.3% when ipratropium was the comparator (P = 0.11) and from 9.4% to 5.5% when placebo was the comparator (P < 0.05). These results suggest that it is the duration of the bronchodilation, and not the class of drug, that confers protection against COPD exacerbations.

We chose a definition of exacerbation that excluded milder events because they are medically less important and often go unreported, even in a research setting (3). Our definition of COPD exacerbation is similar to that used in other trials and fulfills the Global Initiative for Chronic Obstructive Lung Disease criteria for being an "important clinical event" (17). Eighty percent of the patients who experienced a first exacerbation as defined by our protocol received care through an unscheduled medical visit or hospitalization.

Figure 3. Odds ratios and 95% CIs for reduction in first chronic obstructive pulmonary disease (COPD) exacerbation with tiotropium, according to selected baseline characteristics.

It is unlikely that we missed many exacerbations because patients kept daily diaries to record symptoms and medical events and we interviewed all participants on a monthly basis. We obtained discharge summaries in all but a few hospitalizations. Patient retention in the trial was very high, and about 90% of patients completed all scheduled study visits.

We designed this trial to reflect community practice as closely as possible. The eligibility criteria ensured a study sample that was broadly representative of patients with moderate to severe COPD. Of note, 29% of our participants reported home oxygen use at entry into the study. All previous multicenter trials of long-acting bronchodilator or inhaled corticosteroid therapy in COPD specifically excluded patients who were using home oxygen or made no mention of its use (18). Home oxygen use defines an important subset of patients with COPD with generally more severe disease and a greater likelihood of a severe exacerbation. In our trial, 37% of the patients with home oxygen had at least 1 exacerbation and 13% had at least 1 COPD-related hospitalization compared with 27% and 6% for the corresponding events in the patients without home oxygen.

Most patients with moderate to severe COPD use several respiratory medications because the usual prescribing pattern is one of addition rather than substitution. Consequently, trials that restrict concomitant respiratory medications may be less relevant to community practice. Patients in our trial were allowed to continue or to initiate any respiratory medication, except for another anticholinergic. Tiotropium proved effective even though 94% of the study sample used any inhaled β-agonist, 38% used a long- acting inhaled β-agonist, 60% used an inhaled corticosteroid, 14% used a methylxanthine, and 11% used a systemic corticosteroid.

Sin and colleagues' recent systematic review (18) concluded that inhaled long-acting β-agonists and inhaled corticosteroids also reduce COPD exacerbation rates. All trials included in the review either found no effect of treatment on hospitalization rates or did not provide such information. In most of these trials, spirometry was the primary outcome and information about exacerbations was collected only secondarily. The few trials specifically designed to show an effect of long-acting β-agonists and inhaled corticosteroids on exacerbation rates, singly or in combination, yielded somewhat mixed results (19-21). The strongest effect was seen with the combination.

Most COPD exacerbations are thought to have an infectious cause, so why a bronchodilator should prevent exacerbations is not intuitively evident. Extended bronchodilation from tiotropium might reduce infection rates by improving clearance of respiratory secretions and other aspects of lung host defenses. More specific effects on cholinergic-mediated mucus secretion and bronchial inflammatory responses are possible (22-24). Alternatively, tiotropium may simply lessen the dyspnea associated with an exacerbation as a result of the sustained increase in expiratory flow rates and the reduction in lung hyperinflation (25). For example, a patient who would otherwise seek emergency care for an exacerbation might, with the addition of tiotropium, self-treat at home with increased doses of short-acting bronchodilators. That patient would not have been identified as having had a COPD exacerbation according to our protocol.

We conclude that tiotropium reduces exacerbations and may reduce health care utilization in patients with moderate to severe COPD who are already receiving most elements of usual care. Caution must be used in generalizing these findings because the trial was restricted to a predominantly male study sample within 1 health care system and with a follow-up period of only 6 months.

Context

Tiotropium, a new once-daily inhaled anticholinergic bronchodilator, has been shown to improve lung function in patients with chronic obstructive pulmonary disease (COPD). Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients.

Contribution

This randomized, parallel-group, double-blind, placebo- controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period.

Cautions

The study period was relatively short, and the beneficial effects were modest.

-The Editors

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Dennis E. Niewoehner, MD; Kathryn Rice, MD; Claudia Cote, MD; Daniel Paulson, MD; J. Allen D. Cooper Jr., MD; Larry Korducki, MS; Cara Cassino, MD; and Steven Kesten, MD

From the Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota; Bay Pines Veterans Affairs Medical Center, Bay Pines, Florida; Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia; Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.

Acknowledgments: The authors recognize the contributions of the trial investigators, co-investigators, and study staff (Appendix, available at www .annals.org); P. Arnold, B. Caldwell, S. Johnson, J. Tallman, and D. Chow; and the Duke Clinical Research Institute (which managed the data); and the Minnesota Veterans Research Institute (which furnished administrative support for all study centers).

Grant Support: By Boehringer Ingelheim and Pfizer, Inc.

Potential Financial Conflicts of Interest: Employment: L. Korducki, C. Cassino, S. Kesten (Boehringer Ingelheim Pharmaceuticals); Consultancies: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals, Chiron Corp., AstraZeneca, Avenus, Sanofi Pasteur), C. Cote (Boehringer Ingelheim Pharmaceuticals); Honoraria: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals), K. Rice (Boehringer Ingelheim Pharmaceuticals), J.A.D. Cooper Jr. (Boehringer Ingelheim Pharmaceuticals); Grants received: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals, Chiron Corp., Sanofi Pasteur), K. Rice (Boehringer Ingelheim Pharmaceuticals), C. Cote (Boehringer Ingelheim Pharmaceuticals), D. Paulson (Boehringer Ingelheim Pharmaceuticals); Grants pending: C. Cote (Boehringer Ingelheim Pharmaceuticals).

Requests for Single Reprints: Dennis E. Niewoehner, MD, Pulmonary Section (111N), Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, MN 55417; e-mail, niewo001@umn.edu.

Current author addresses and author contributions are available at www .annals.org.

Copyright American College of Physicians Sep 6, 2005

Source: Annals of Internal Medicine

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