Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator

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 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 726000 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 severity 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 FEV1 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 -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. 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. We analyzed the coprimary end points by using a CochranMantelHaenszel 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 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 dete