Key Point

Inhaled tiotropium was shown to reduce the risk of COPD exacerbations and associated hospitalizations. The drug also decreased the mean incidence, number, and duration of COPD exacerbations, whether or not the patient was receiving inhaled corticosteroids concomitantly.

SAN DIEGO—Several analyses presented at the annual meeting of the American Thoracic Society confirmed the effectiveness of inhaled tiotropium for COPD. The first analysis, in which investigators pooled nine randomized placebo-controlled trials, found that inhaled tiotropium significantly reduced the risk of COPD exacerbations and the resulting hospitalizations.¹

"Our pooled analysis combined individual patient data from the studies and so was not subject to the biases inherent in meta-analysis," principal investigator David M.G. Halpin, MD, told Pulmonary Reviews. "By combining the data in this way we were also able to look at the robustness of the effect of tiotropium by age, sex, and FEV1," related Dr. Halpin, who is a consultant physician and Honorary Senior Clinical Lecturer at the Royal Devon and Exeter Hospital in the United Kingdom.

In the other two analyses, the MISTRAL study group compared inhaled tiotropium to placebo among 1,010 COPD patients from 177 centers.²,³ In these patients, tiotropium reduced moderate to severe exacerbations requiring treatment with systemic corticosteroids, antibiotics, or inpatient interventions and prevented such exacerbations regardless of concomitant inhaled corticosteroid use.

RESULTS OF A POOLED ANALYSIS

All of the trials in Dr. Halpin’s analysis evaluated a dose of 18 µg of inhaled tiotropium taken daily for at least six months. They defined a COPD exacerbation as an increase in or new onset of two or more of the following over three or more days: cough, sputum production, wheezing, dyspnea, and chest tightness. In addition, the exacerbation had to require systemic corticosteroid or antibiotic therapy or hospitalization.

The patients in the trials all had a diagnosis of stable COPD and were 40 or older. They had a predicted FEV₁ of 65% or less, an FEV₁:FVC ratio of 70% or less, and a smoking history of 10 pack-years or greater.

Compared to placebo, tiotropium was associated with reductions in the adjusted incidence (per 100 patient-years) of COPD exacerbations and exacerbations requiring hospitalization of, respectively, 22.5% and 20.3%. The risk ratios for those outcomes with tiotropium were 0.781 and 0.791, respectively.

In addition, tiotropium significantly delayed the time to first COPD exacerbation and time to first hospitalization for an exacerbation. The study findings were robust regardless of patients’ sex, baseline age, or FEV1, Dr. Halpin pointed out.

EFFECT ON MODERATE TO SEVERE EXACERBATIONS

The MISTRAL study group randomized their COPD patients to receive 18 µg of inhaled tiotropium daily or placebo for one year. The patients were 40 or older and had an FEV1 of 30% to 65% predicted, an FEV1:slow vital capacity ratio of 70% or lower, a smoking history of 10 pack-years or longer, and a history of exacerbations in the past year but not the previous six weeks.

An exacerbation was defined as the presence of at least one "clinical descriptor" for two or more days and the need for a new medication or an increase in current bronchodilator, antibiotic, or inhaled corticosteroid dosage. The clinical descriptors used were a worsening of dyspnea, cough, or sputum production, the appearance of purulent sputum or a new chest film abnormality, and fever (a body temperature above 38°C).

An exacerbation was classified as mild if a patient had one or two clinical descriptors and moderate if three or more descriptors were present. A severe exacerbation was one in which the patient required hospitalization or displayed one of the following: a decline in FEV₁ or peak expiratory flow rate of more than 30% from baseline on two or more consecutive days; a Pao2 decrease of 10 mm Hg or greater from baseline or a Pao2 of 60 mm Hg or lower; or a Paco2 increase of 5 mm Hg or greater from baseline or a Paco2 of 45 mm Hg or higher.

Overall, compared to placebo, inhaled tiotropium decreased the incidence of moderate to severe exacerbations by 20.3%, the mean number of such exacerbations per patient by 36.1%, and the mean duration of the exacerbations by 39.1%. "In addition, tiotropium significantly delayed the time to first moderate-to-severe exacerbation compared with placebo," the MISTRAL investigators related.

In a subgroup analysis, tiotropium reduced the rate of moderate to severe exacerbations by 30.2% among patients also receiving inhaled corticosteroids and by 28.9% among those not taking inhaled steroids. In those two subgroups, tiotropium decreased the mean number of moderate to severe exacerbations per patient by 16.3% and 63.3%, respectively, and the mean duration of moderate to severe exacerbations by 20.1% and 57.5%, respectively; the differences between tiotropium and placebo did not quite achieve significance for these two outcomes, however.

The MISTRAL investigators noted that in patients receiving inhaled steroids, baseline characteristics were less favorable than in the steroid nonusers, as shown by a slightly higher exacerbation rate. The mechanisms by which tiotropium and inhaled corticosteroids reduce COPD exacerbations may be different, the investigators suggested.

—Timothy Begany

Reference
1. Halpin DMG, Menjoge S, Dusser D, et al. Pooled analysis of effect of tiotropium on COPD exacerbations and related hospitalizations. Presented at: annual meeting of the American Thoracic Society; May 19-24, 2006; San Diego, Calif.
2. Dusser D, Viel K, Bravo M-L, Iacono P. Tiotropium reduces moderate-to-severe exacerbations in COPD patients irrespective of concomitant use of inhaled corticosteroids. Presented at: annual meeting of the American Thoracic Society; May 19-24, 2006; San Diego, Calif.
3. Dusser D, Viel K, Rouyrre N, Iacono P. Tiotropium reduces COPD exacerbations requiring treatment with systemic corticosteroids, antibiotics, or hospitalization. Presented at: annual meeting of the American Thoracic Society; May 19-24, 2006; San Diego, Calif.

Return to table of contents