对于哮喘控制较差的患者，噻托溴铵能改善肺功能、延缓哮喘发作
2013/02/28
摘要
问题：对于皮质激素吸入治疗（ICS）和长效β-受体激动剂（LABA）治疗的哮喘患者，噻托溴铵是否能改善哮喘控制？
方法：设计两项随机安慰剂对照临床试验（PrimoTinA-asthma1 [试验1]和PrimoTinA-asthma2 [试验2]）。盲法： (患者, 医生, {数据收集者, 转归评价者,} 和赞助商)。 随访期为48周。
临床试验注册号：gov NCT00772538 和NCT00776984。
机构：15个国家的临床医学中心。患者：哮喘病史≥ 5年、尽管给予每日ICS和LABA治疗，但仍存在气流受限、过去1年全身糖皮质激素治疗≥ 1 次哮喘发作的18～75岁的成人（试验1：n=459，平均年龄为53岁，63%的女性；试验2：n=453，平均年龄为53岁，58%的女性）患者入选。哮喘诊断时患者< 40岁；哮喘控制问卷调查7（ACQ7）评分≥ 1.5 ；患者为非吸烟者或吸烟史10年但过去1年不吸烟。排除标准包括慢性阻塞性肺疾病（COPD）、严重的共患病和正在使用抗胆碱能支气管扩张剂。
干预：每天早上，采用Respimat软雾吸入器吸入2揿2.5 µg的噻托溴铵（试验1：n = 237；试验2：n = 219）或安慰剂（试验1：n = 222；试验2：n = 234）。患者维持试验之前的ICS和LABA治疗哮喘。沙丁胺醇作为急救用药。
转归：检测FEV1峰值（维持治疗和噻托溴铵给药3 h内）和24周时的FEV1谷值、至出现首次哮喘发作的时间（需要开始全身糖皮质激素治疗或至少全身糖皮质激素剂量加倍，治疗持续3天）次要转归包括24周时的ACQ7和哮喘生活质量问卷调查（AQLQ）及副作用。
患者随访：试验1中90%的患者和试验2中89%的患者完成随访。
ACQ7和AQLQ评分上未见显著差异。在两项试验中，8%的噻托溴铵组和9%的安慰剂组出现严重的副作用。
结论：对于皮质激素吸入和长效β-受体激动剂治疗后哮喘仍控制较差的成人，噻托溴铵能改善肺功能，延长首次出现严重哮喘发作的时间。
Tiotropium improved lung function and delayed exacerbations in poorly controlled asthma.
Greenstone M.
Abstract
QUESTION：In adults with poorly controlled asthma who are receiving inhaled corticosteroids (ICSs) and long-acting β-agonists (LABAs), does tiotropium improve control?
METHODS：design 2 randomized placebo-controlled trials (PrimoTinA-asthma 1 [Trial 1] and PrimoTinA-asthma 2 [Trial 2]).
CLINICALTRIALS：gov NCT00772538 and NCT00776984.
ALLOCATION：{Concealed}.*† BLINDING Blinded† (patients, clinicians, {data collectors, outcome assessors,}* and sponsor). FOLLOW-UP PERIOD 48 weeks. SETTING Clinical centers in 15 countries. PATIENTS Adults 18 to 75 years of age (Trial 1: n = 459, mean age 53 y, 63% women; Trial 2: n = 453, mean age 53 y, 58% women) who had a ≥ 5 year history of asthma; persistent airflow limitation despite daily ICSs and LABAs; ≥ 1 exacerbation treated with systemic glucocorticoids in the past year; asthma diagnosed at < 40 years of age; score ≥ 1.5 on Asthma Control Questionnaire 7 (ACQ7); and were life-long nonsmokers or had a smoking history of < 10 years with no smoking in the past year. Exclusion criteria included chronic obstructive pulmonary disease (COPD), serious comorbid illness, and current use of anticholinergic bronchodilators.
INTERVENTION：2 puffs of 2.5 µg tiotropium (Trial 1: n = 237; Trial 2: n = 219) or placebo (Trial 1: n = 222; Trial 2: n = 234) with a soft-mist inhaler (Respimat) each morning. Patients maintained their pretrial maintenance asthma therapy of ICSs and LABAs. Salbutamol was provided as a rescue medication.
OUTCOMES： Peak FEV1 response (within 3 h of receipt of maintenance and study drugs) and trough FEV1 at 24 weeks, and time to first severe asthma exacerbation (requiring initiation or at least doubling of systemic glucocorticoids for ≥ 3 d) at 48 weeks. Secondary outcomes included the ACQ7 and Asthma Quality of Life Questionnaire (AQLQ) at 24 weeks, and adverse events.
PATIENT FOLLOW-UP：90% (Trial 1) and 89% (Trial 2). MAIN RESULTS The main results are in the Table. Clinically important differences in the ACQ-7 and AQLQ were not achieved. Across both trials, 8% of the tiotropium group and 9% of the placebo group had serious adverse events.
CONCLUSION：In adults with asthma that was poorly controlled on inhaled corticosteroids and long-acting β-agonists, tiotropium improved lung function and time to first severe exacerbation.Tiotropium vs placebo for poorly controlled asthma‡OutcomesMean difference between tiotropium and placebo in change from baseline (95% CI)Trial 1Trial 2Peak FEV1 at 24 wk (mL)86 (20 to 152)154 (91 to 217)Trough FEV1 at 24 wk (mL)88 (27 to 149)111 (53 to 169)Severe exacerbationsHazard ratio (CI)TiotropiumPlaceboTime to first event (d)2822260.79 (0.62 to 1.00)‡CI defined in Glossary.
AnnInternMed.2012Dec18;157(12):JC6-3.doi:10.7326/0003-4819-157-12-201212180-02003.
问题：对于皮质激素吸入治疗（ICS）和长效β-受体激动剂（LABA）治疗的哮喘患者，噻托溴铵是否能改善哮喘控制？
方法：设计两项随机安慰剂对照临床试验（PrimoTinA-asthma1 [试验1]和PrimoTinA-asthma2 [试验2]）。盲法： (患者, 医生, {数据收集者, 转归评价者,} 和赞助商)。 随访期为48周。
临床试验注册号：gov NCT00772538 和NCT00776984。
机构：15个国家的临床医学中心。患者：哮喘病史≥ 5年、尽管给予每日ICS和LABA治疗，但仍存在气流受限、过去1年全身糖皮质激素治疗≥ 1 次哮喘发作的18～75岁的成人（试验1：n=459，平均年龄为53岁，63%的女性；试验2：n=453，平均年龄为53岁，58%的女性）患者入选。哮喘诊断时患者< 40岁；哮喘控制问卷调查7（ACQ7）评分≥ 1.5 ；患者为非吸烟者或吸烟史10年但过去1年不吸烟。排除标准包括慢性阻塞性肺疾病（COPD）、严重的共患病和正在使用抗胆碱能支气管扩张剂。
干预：每天早上，采用Respimat软雾吸入器吸入2揿2.5 µg的噻托溴铵（试验1：n = 237；试验2：n = 219）或安慰剂（试验1：n = 222；试验2：n = 234）。患者维持试验之前的ICS和LABA治疗哮喘。沙丁胺醇作为急救用药。
转归：检测FEV1峰值（维持治疗和噻托溴铵给药3 h内）和24周时的FEV1谷值、至出现首次哮喘发作的时间（需要开始全身糖皮质激素治疗或至少全身糖皮质激素剂量加倍，治疗持续3天）次要转归包括24周时的ACQ7和哮喘生活质量问卷调查（AQLQ）及副作用。
患者随访：试验1中90%的患者和试验2中89%的患者完成随访。
ACQ7和AQLQ评分上未见显著差异。在两项试验中，8%的噻托溴铵组和9%的安慰剂组出现严重的副作用。
结论：对于皮质激素吸入和长效β-受体激动剂治疗后哮喘仍控制较差的成人，噻托溴铵能改善肺功能，延长首次出现严重哮喘发作的时间。
（苏楠 审校）
AnnInternMed.2012Dec18;157(12):JC6-3.doi:10.7326/0003-4819-157-12-201212180-02003.
AnnInternMed.2012Dec18;157(12):JC6-3.doi:10.7326/0003-4819-157-12-201212180-02003.
Tiotropium improved lung function and delayed exacerbations in poorly controlled asthma.
Greenstone M.
Abstract
QUESTION：In adults with poorly controlled asthma who are receiving inhaled corticosteroids (ICSs) and long-acting β-agonists (LABAs), does tiotropium improve control?
METHODS：design 2 randomized placebo-controlled trials (PrimoTinA-asthma 1 [Trial 1] and PrimoTinA-asthma 2 [Trial 2]).
CLINICALTRIALS：gov NCT00772538 and NCT00776984.
ALLOCATION：{Concealed}.*† BLINDING Blinded† (patients, clinicians, {data collectors, outcome assessors,}* and sponsor). FOLLOW-UP PERIOD 48 weeks. SETTING Clinical centers in 15 countries. PATIENTS Adults 18 to 75 years of age (Trial 1: n = 459, mean age 53 y, 63% women; Trial 2: n = 453, mean age 53 y, 58% women) who had a ≥ 5 year history of asthma; persistent airflow limitation despite daily ICSs and LABAs; ≥ 1 exacerbation treated with systemic glucocorticoids in the past year; asthma diagnosed at < 40 years of age; score ≥ 1.5 on Asthma Control Questionnaire 7 (ACQ7); and were life-long nonsmokers or had a smoking history of < 10 years with no smoking in the past year. Exclusion criteria included chronic obstructive pulmonary disease (COPD), serious comorbid illness, and current use of anticholinergic bronchodilators.
INTERVENTION：2 puffs of 2.5 µg tiotropium (Trial 1: n = 237; Trial 2: n = 219) or placebo (Trial 1: n = 222; Trial 2: n = 234) with a soft-mist inhaler (Respimat) each morning. Patients maintained their pretrial maintenance asthma therapy of ICSs and LABAs. Salbutamol was provided as a rescue medication.
OUTCOMES： Peak FEV1 response (within 3 h of receipt of maintenance and study drugs) and trough FEV1 at 24 weeks, and time to first severe asthma exacerbation (requiring initiation or at least doubling of systemic glucocorticoids for ≥ 3 d) at 48 weeks. Secondary outcomes included the ACQ7 and Asthma Quality of Life Questionnaire (AQLQ) at 24 weeks, and adverse events.
PATIENT FOLLOW-UP：90% (Trial 1) and 89% (Trial 2). MAIN RESULTS The main results are in the Table. Clinically important differences in the ACQ-7 and AQLQ were not achieved. Across both trials, 8% of the tiotropium group and 9% of the placebo group had serious adverse events.
CONCLUSION：In adults with asthma that was poorly controlled on inhaled corticosteroids and long-acting β-agonists, tiotropium improved lung function and time to first severe exacerbation.Tiotropium vs placebo for poorly controlled asthma‡OutcomesMean difference between tiotropium and placebo in change from baseline (95% CI)Trial 1Trial 2Peak FEV1 at 24 wk (mL)86 (20 to 152)154 (91 to 217)Trough FEV1 at 24 wk (mL)88 (27 to 149)111 (53 to 169)Severe exacerbationsHazard ratio (CI)TiotropiumPlaceboTime to first event (d)2822260.79 (0.62 to 1.00)‡CI defined in Glossary.
AnnInternMed.2012Dec18;157(12):JC6-3.doi:10.7326/0003-4819-157-12-201212180-02003.
