Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD. METHODS: We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233. FINDINGS: 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated. INTERPRETATION: Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.

Efficiency of neural respiratory drive for the assessment of bronchodilator responsiveness in patients with chronic obstructive pulmonary disease: an exploratory study.

BACKGROUND: Conventional lung function parameters, such as forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC) are often used to assess the therapeutic outcomes of bronchodilators, but they lack sensitivity. A novel indicator, namely efficiency of neural respiratory drive (NRD), may objectively evaluate the physiological changes in patients with chronic obstructive pulmonary disease (COPD). We investigated whether this indicator could be used to more accurately assess the responsiveness to inhaled bronchodilators. METHODS: Thirty-six subjects with moderate-to-severe COPD were randomized into group A (n=18) and group B (n=18). Participants in group A inhaled 400 µg placebo, 400 µg salbutamol and 80 µg ipratropium in sequence whereas those in group B had the salbutamol and ipratropium reversed. At different time points after administration of placebo or bronchodilators, evaluated indices included FEV1, FVC, IC, root mean square (RMS) of diaphragm electromyogram (EMGdi), and efficiency of NRD [herein defined as the ratio of minute ventilation (VE) to RMS, or VE/RMS]. RESULTS: FEV1, FVC, IC, RMS, and VE/RMS significantly improved after inhaled bronchodilators and VE/RMS had the largest improvement among five indices. The detection efficiency of VE/RMS was greater than FEV1, FVC, IC (all P<0.05), but not different from RMS. The accuracy and sensitivity of VE/RMS were significantly higher than FEV1, FVC, IC, and RMS (all P<0.05). CONCLUSIONS: Efficiency of NRD may be a sensitive tool to evaluate the efficacy of inhaled bronchodilators in COPD.