A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Double blind, placebo controlled study. Eighteen UK hospitals. 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. Ten clinical centers in the United States and Canada. A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. Rate of change and cumulative change in FEV1 over a 5-year period. Participants in the two smoking intervention groups showed significantly smaller declines in FEV1 than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. An aggressive smoking intervention program significantly reduces the age-related decline in FEV1 in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1.

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.