One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium

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Abstract

Background

Airway medications have not been shown to reduce the loss of lung function in patients with COPD. We explored whether tiotropium 18 μg once daily could slow the rate of decline of lung function over a 1-year period.

Methods

We performed a post-hoc analysis of data from 921 ambulatory COPD patients participating in two, 1-year, double-blind, tiotropium vs. placebo-controlled trials. Serial spirometry was obtained at baseline (before first dose of study drug), on day 8, at 6 weeks, and at 3, 6, 9 and 12 months after start of the study.

Results

Baseline demographics and lung function were comparable. Baseline FEV1 was 1.01±0.41 (SD) L (39±14% predicted). Mean decline in trough FEV1 (i.e. FEV1 23–24 h after prior use of medication) between days 8 and 344 was 58 ml/year in the placebo group and 12 ml/year in the tiotropium group (p=0.005 vs. placebo); and between days 50 and 344 was 59 ml/year in the placebo group and 19 ml/year in the tiotropium group (p=0.036 vs. placebo).

Conclusions

Based on a retrospective analysis of 1-year, placebo-controlled clinical trials, tiotropium was associated with a reduced rate of loss of FEV1. Longer-term trials specifically designed to study this effect are required to confirm this observation.

Introduction

Chronic obstructive pulmonary disease (COPD) affects approximately 16 million people in the United States where it is the fourth leading cause of death [1], [2]. Airflow obstruction in COPD is generally progressive over a period of years and is only partially reversible [3], [4], [5]. Among people who have never smoked, the rate of decline in FEV1 ranges from 17 to 52 ml per year [3], [5], [6], [7], [8], [9]. Among smokers, the rate of decline increases to 34–79 ml/year [5], [6], [7], [8]. In the Lung Health Study, a large cohort of patients with mild to moderate COPD, the average rate of decline in FEV1 in continuing smokers was 62 ml/year [3]. Both cross-sectional and longitudinal studies suggest that the rate of decline in lung function after smoking cessation is similar to that in people who have never smoked [3], [6], [7], [8], [9].

The reversibility of airflow obstruction in COPD is variable and controversial. Tashkin et al. [10] reported that in smokers with mild to moderate airflow limitation over 30% had a decrease of 20% or more in FEV1 after inhalation of ≤5 mg/ml methacholine. Recent studies have suggested that the percentage of COPD patients with reversible airway obstruction exceeds 50% [11], [12]. Although airway responsiveness in COPD is variable, there are no studies that have shown that bronchodilators can alter the accelerated rate of decline in lung function over time. The Lung Health study failed to show that inhaled ipratropium can reduce this rate of decline [3]. The only intervention today that has been shown to be effective is smoking cessation [3].

Tiotropium is a new, once-daily, anticholinergic bronchodilator with a long duration of action attributed to slow dissociation from airway M3 muscarinic receptors [13], [14], [15]. Two large, long-term, 1-year, placebo-controlled studies conducted in the United States, have shown that once daily inhalation with tiotropium 18 μg significantly improves airflow and forced vital capacity over 24 h in patients with COPD. Furthermore, these benefits were consistently maintained over the year [16]. Since these two trials used an identical protocol, data were pooled to analyze if chronic dosing with tiotropium 18 μg once daily could slow the rate of decline of lung function over the 1-year period of these studies.

Section snippets

Study subjects

A retrospective analysis of two identical, 1-year, randomized, double-blind, placebo-controlled, parallel-group studies of inhaled tiotropium 18 μg once daily in patients with COPD was performed [16]. Fifty clinical centers participated in these trials. These studies were approved by each center's institutional review board. All patients provided written informed consent prior to participation.

The study groups consisted of outpatients of either gender who were more than 40 years of age and had a

Results

Of 921 patients enrolled, 550 were randomized to tiotropium and 371 to placebo. There were no differences in the patients' demographic characteristics between studies. The study population had a mean age of 65 years, were predominantly male, smoked an average of 61 pack-years, and had a mean FEV1 of 1.04 L (Table 1). The groups were similar in all the baseline characteristics.

The acute and chronic bronchodilator improvements with tiotropium have been previously described [16]. There was minimal

Discussion

Recently published 1-year studies of tiotropium 18 μg once-daily in COPD have demonstrated that tiotropium provides 24-h bronchodilation, improvements in dyspnea, decreases in exacerbations, and improvements in health-related quality of life [16], [22]. The present post-hoc analysis of two 1-year, placebo-controlled trials suggests that patients continuously using tiotropium have a significant reduction in the rate of decline of their trough (i.e. morning pre-dose) FEV1 over time as compared

Acknowledgements

Financial support for this study was provided by Boehringer Ingelheim Pharmaceuticals, Inc.

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