| Chronic obstructive pulmonary disease(COPD)is an inflammatory disease characterized by the progressive deterioration of pulmonary function and increasing airway obstruction,as the third leading cause of morbidity and mortality worldwide and result in a social burden that is both substantial and increasing.Epidemiological studies show that in China,92.7% of patients with mild and moderate COPD in GOLD stage I~II have never received any treatment.Patients with COPD in GOLD I~II have developed airway lesions in the early stage,and their pulmonary function FEV1 has decreased more rapidly than those of in GOLD stage III~ IV.Therefore,we should pay more attention to the progress of mild and moderate COPD and carry out targeted treatment as soon as possible.However,there is very little literature reported on treatment intervention in the early stage of COPD.As a long-acting anticholinergic drug,tiotropium acts on the cholinergic receptors of the airway smooth muscle,which relax the airway smooth muscle and reduce mucus secretion.Studies have shown that tiotropium can improve the airflow limitation of patients with severe COPD,reduce the difficulty of laboring breathing and improve the endurance of the patients,and improve the quality of survival of patients with COPD.Some small studies and subgroup analysis showed that tiotropium improved lung function in patients with mild to moderate COPD,but there was still no strong evidence.State key laboratory of respiratory diseases,therefore,took the lead to organized a multi-center clinical trials for the treatment of Early-Stage COPD using tiotropium in order to evaluate the role of tiotropium in patients with COPD of GOLD stage I~II.This dissertation reports the research results of our research group in Guangdong province,and the changes of curative effect within three years after tiotropium withdrawn.SectionⅠ Efficacy Observation of two years regular treatment with tiotropium Bromide in Early stage COPD patients in Guangdong.Objective: To evaluate the effect of regular treatment with tiotropium bromide on lung function,acute exacerbation and quality of life in patients with chronic obstructive pulmonary disease of GOLD stage I~II.Methods: This study is part of the national multi-center clinical trial(Tie-COPD),and all studies follow Tie-COPD protocol,i.e a randomized,double-blind,placebo-controlled parallel control method was adopted.Patients with GOLD stage I or II COPD were identified from Guangdong area,and were randomized into two parallel groups to receive either tiotropium(at a dose of 18 μg once daily)or matching placebo for two years.Efficacy mesures were spirometry and COPD exacerbations,symptom scores,quality of life,dyspnea scores,the use of rescue medications and treatment safety.Results:1.A total of 619 patients with GOLD stage I or II COPD were identified from community screening from 13 medical centers in Guangdong area.Of the 619 patients,578(290 patients in placebo group and 289 in treatment group)completed 2 years of follow-up.2.Lung function changes: Analysis of individuals in full analysis set(FAS)shown that: Tiotropium treatment resulted in a significantly higher FEV1 and FVC before and after bronchodilator use than placebo throughout the trial.The mean differences between two parallel groups in FEV1 was 124 to 177 ml before bronchodilator use and 77 to 140 ml after bronchodilator use;P<0.0001 for all comparisons,results of Per Protocol Set(PPS)analysis were synergistic with FAS(ranges of mean differences,126 to 182 ml before bronchodilator use and 91 to 156 ml after bronchodilator use;P<0.0001 for all comparisons).The mean differences between two parallel groups in FVC was 99 to 166 ml before bronchodilator use and 52 to 118 ml after bronchodilator use;P<0.05 for all comparisons,results of Per Protocol Set(PPS)analysis were synergistic with FAS(ranges of mean differences,106 to 187 ml before bronchodilator use and 76 to 129 ml after bronchodilator use;P<0.05 for all comparisons).3.Annual decline in the FEV1: Analysis of individuals in full analysis set(FAS)shown that: Tiotropium treatment resulted in a significantly reduction in the annual decline of FEV1 before and after bronchodilator use than placebo(before bronchodilator use: 33±6 ml per year vs.53±6 ml per year,difference,21 ml per year [95% CI,3 to 39],P = 0.0229;after bronchodilator use: 27±6 ml per year vs.53±6 ml per year,difference,26 ml per year [95% CI,8 to 43],P = 0.0036).Results of Per Protocol Set(PPS)analysis were synergistic with FAS(before bronchodilator use: 34±7 ml per year vs.56±7 ml per year,difference,22 ml per year [95% CI,2 to 41],P = 0.0288;after bronchodilator use: 31±7 ml per year vs.54±7 ml per year,difference,24 ml per year [95% CI,5 to 42],P = 0.0144).Similar result was observed for the between-group differences in the percent of the predicted FEV1 value and in the analyses after adjustment for smoking status,the percent of the predicted FEV1 value at baseline,age,sex,hospitalization,GOLD stage,and body-mass index(the weight in kilograms divided by the square of the height in meters).4.Acute Exacerbations of COPD: The time to the first acute exacerbation of COPD was longer with tiotropium than with placebo(P<0.0289),results of PPS analysis were synergistic with FAS analysis.The 25th-percentile value for the time to the first acute exacerbation of COPD was 452 days(95% CI,325 to 649)in tiotropium group and 265 days(95% CI,177 to 331)in placebo group,similar results were observed in PPS analysis.The hazard ratio for the first acute exacerbation of COPD in the tiotropium group,as compared with the placebo group,was 0.7(95% CI,0.5 to 1.0;P=0.0289),similar result was observed in PPS analysis,with the hazard ratio of 0.6(95% CI,0.4 to 0.8;P=0.0011).The frequency of total acute exacerbations of COPD was lower with tiotropium than with placebo(0.28 events per patient-year vs.0.51 events per patient-year,P=0.0003),results of PPS analysis were synergistic with FAS analysis.The frequency of mile to moderate acute exacerbations of COPD was also lower with tiotropium than with placebo(0.23 events per patient-year vs.0.41 events per patient-year,P=0.0006),similar result was also observed in PPS analysis.The duration time of acute exacerbations of COPD was lower with tiotropium than with placebo(3.3 days vs.6.9 days,P=0.0027)in PPS analysis,but only numeric difference was observed in FAS analysis(3.5 days vs.5.7 days,P=0.0588).No differences were observed in COPD hospitalizations and in hospitalization costs due to COPD exacerbations between tiotropium group and placebo group(P>0.05).5.The used of Rescue medicine: A total of 75 patients(27.7%)in the tiotropium group and 87(32.0%)in the placebo group had a history of using rescue medicine(Atrovent).The tiotropium group had a better performance than placebo group in the usage rescue medicine,with a decreased puff number of using Atrovent(115.3 spraies vs.219.9 spraies,P=0.0020)and lower usage day(56.7 days vs.98.4 days,P=0.0122),similar results were also observed in PPS analysis.6.Tiotropium significantly improved the mean CAT scores at month 9,15,18 and 21 compared with placebo(P<0.05),PPS analysis shown similar improvement at month 6,9,15,18,21 and 24(P<0.05)(Table 1-22).When compared to basline,mean CAT scores were improved with tiotropium versus control at month 24(-1.4 units vs.-0.3 units;P=0.0446),only numeric difference was observed in PPS analysis(-1.2 units vs.-0.1units;P=0.0589)(Table 1-23).Tiotropium significantly improved the m MRC scores at month 6,9,15,18,21 and 24 compared with placebo(P<0.05),PPS analysis shown similar improvement at month 1 and month 6 to 24(P<0.05)(Table 1-26).7.Tiotropium significantly improved the mean CCQ scores at month 9 and month 15 to 24 compared with placebo(P<0.05),PPS analysis shown similar improvement 6,9 and month 15 to 24 compared with placebo(P<0.05)(Table 1-27).When compared to basline,mean CCQ scores were improved with tiotropium versus control at month 24(-0.2 units vs.-0.0 units;P=0.0262),similar result was also observed in PPS analysis(-0.1 units vs.0.0 units;P=0.0393)(Table 1-28).8.Analysis of individuals in Safety Analysis Set(SS)shown that: No significant between-group differences were observed in the incidence of adverse events,serious adverse events,and death except for mild adverse events,such as oropharyngeal discomfort,mostly dry mouth.42 patients(13.6%)in the tiotropium group complained of dry mouth,as compared with 11(3.5%)in the placebo group(P<0.0001)(Table 1-36).Conclusion: Tiotropium improved FEV1 and postponed the annual decline in the FEV1 both before and after bronchodilator use in early stage COPD patients.Maintenance treatment with tiotropium provided significant symptom reduction,reduced acute exacerbation rate,better quality of life and satisfactory safety.SectionⅡ Follow-up results analysis of patients with Early-Stage Chronic Obstructive Pulmonary Disease after two years regular treatment with tiotropium Bromide.Objective: To observe the dynamic changes of patients with Early-Stage Chronic Obstructive Pulmonary Disease in spirometry,COPD exacerbations,symptom scores,quality of life,dyspnea scores and exercise capacity after two years regular treatment of tiotropium withdrawn.Methods: Patients who had completed Tie-COPD study(mainly from Guangdong area)were randomly selected and divided into two groups according to baseline treatment protocols.Follow-ups were adopted in the first month,the first year,the second year and the third year after the tiotropium withdrawn.Lung function test and routine physical examination was conducted for each visit,and demographic data,medication situation,acute exacerbations,smoking status,symptom score and life quality score were collected.Efficacy mesures were spirometry and COPD exacerbations,symptom scores,quality of life,dyspnea scores and exercise capacity.Results:1.A total of 353 patients(180 patients in past placebo group and 173 in past treatment group)with GOLD stage I or II COPD were randomly selected from Tie-COPD in Guangdong area.Of the 262 patients(126 patients in past placebo group and 136 in past treatment group)completed 3 years of follow-up after study withdrawn.2.Patients showed a decrease in FEV1 after discontinuation of tiotropium,but in the first month after the drug withdrawn,the FEV1 before and after bronchodilator use of the treatment group were still significantly higher than that in placebo group.On the first month of tiotropium withdrawn,The FEV1 in the treatment group and the placebo group were: before bronchodilator use: 1.87±0.02 L vs.1.76±0.02 L,difference,0.11 L [95% CI,0.16 to 0.05],P = 0.0002;after bronchodilator use: 1.97±0.02 L vs.1.88±0.02 L,difference,0.08 L [95% CI,0.14 to 0.03],P = 0.0023.On 1 year of tiotropium withdrawn,there was no significant difference between the two groups in FEV1,both before and after bronchodilator use.In the first year of withdrawal,The FEV1 in the treatment group and the placebo group were: before bronchodilator use: 1.78±0.04 L vs.1.71±0.04 L,P = 0.1242;after bronchodilator use: 1.85±0.04 L vs.1.81±0.04 L,P = 0.3090.In the second year of tiotropium withdrawn,The FEV1 in the treatment group and the placebo group were: before bronchodilator use: 1.74±0.03 L vs.1.70±0.03 L,P = 0.2297;after bronchodilator use: 1.85±0.03 L vs.1.84±0.03 L,P = 0.7944.In the third year of tiotropium withdrawn,The FEV1 in the treatment group and the placebo group were: before bronchodilator use: 1.74±0.03 L vs.1.70±0.03 L,P = 0.2297;after bronchodilator use: 1.85±0.03 L vs.1.84±0.03 L,P = 0.7944.3.Patients showed a decrease in FVC after discontinuation of tiotropium,but in the first month after the drug withdrawn,the FVC before bronchodilator use of the treatment group were still significantly higher than that in placebo group,whereas the FVC after bronchodilator use shown no difference between two groups.On the first month of tiotropium withdrawn,The FVC in the treatment group and the placebo group were: before bronchodilator use: 3.08±0.03 L vs.2.98±0.03 L,difference,0.10 L [95% CI,0.19 to 0.01],P = 0.0295;after bronchodilator use: 3.15±0.03 L vs.3.09±0.03 L,P = 0.1359.On 1 year of tiotropium withdrawn,there was no significant difference between the two groups in FVC,both before and after bronchodilator use.In the first year of tiotropium withdrawn,The FVC in the treatment group and the placebo group were: before bronchodilator use: 2.99±0.06 L vs.2.93±0.06 L,P = 0.4127;after bronchodilator use: 3.06±0.05 L vs.3.03±0.05 L,P = 0.6581.In the second year of tiotropium withdrawn,The FVC in the treatment group and the placebo group were: before bronchodilator use: 2.93±0.05 L vs.2.91±0.05 L,P = 6650;after bronchodilator use: 3.07±0.05 L vs.3.10±0.05 L,P = 0.6654.In the third year of tiotropium withdrawn,The FVC in the treatment group and the placebo group were: before bronchodilator use: 3.01±0.07 L vs.2.89±0.07 L,P = 0.2145;after bronchodilator use: 3.10±0.06 L vs.3.00±0.06 L,P = 0.2332.4.Annual decline in the FEV1: After tiotropium withdrawn,tiotropium treatment group shows no difference in the annual decline of FEV1 before and after bronchodilator use than placebo group(before bronchodilator use: 21±20 ml per year vs.31±21 ml per year,difference,10 ml per year [95% CI,-47 to 67],P = 0.7269;after bronchodilator use: 48±15 ml per year vs.68±16 ml per year,difference,20 ml per year [95% CI,-24 to 64],P = 0.3703).5.Acute Exacerbations of COPD: After tiotropium withdrawn,tiotropium treatment group shows no difference in frequency of acute exacerbations of COPD than placebo group.The frequency of total acute exacerbations of COPD in the treatment group and the placebo group were 0.1098 events per patient-year vs.0.1590 events per patient-year,P=0.1368.The frequency of mild to moderate acute exacerbations of COPD were 0.0841 events per patient-year vs.0.0980 events per patient-year,P=0.5246.The frequency of severe acute exacerbations of COPD in the treatment group and the placebo group were 0.0240 events per patient-year vs.0.0370 events per patient-year,P=0.3240.6.On 1 year of tiotropium withdrawn,the mean CAT scores and mean CCQ scores were significantly lower in the tiotropium treatment group compared with placebo(mean CAT scores: 7.82±0.84 units vs.10.14±0.79 units;P=0.0166;mean CCQ scores: 9.63±0.88 units vs.11.67±0.84 units;P=0.0342).No difference was observed in the mean CAT scores and mean CCQ scores between the two groups on the second and the third year after tiotropium withdrawn.No difference was observed in m MRC scores between the two groups during the whole withdrawn period.Conclusion: The lung function of the patient who had received regular treatment with tiotropium for two years began to decline after tiotropium withdrawn,and the lung function of the treatment group was close to the placebo after tiotropium withdrawn for one year. |
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