Aaron Shawn D, Vandemheen Katherine L, Fergusson Dean, Maltais François, Bourbeau Jean, Goldstein Roger, Balter Meyer, O'Donnell Denis, McIvor Andrew, Sharma Sat, Bishop Graham, Anthony John, Cowie Robert, Field Stephen, Hirsch Andrew, Hernandez Paul, Rivington Robert, Road Jeremy, Hoffstein Victor, Hodder Richard, Marciniuk Darcy, McCormack David, Fox George, Cox Gerard, Prins Henry B, Ford Gordon, Bleskie Dominique, Doucette Steve, Mayers Irvin, Chapman Kenneth, Zamel Noe, FitzGerald Mark
The Ottawa Health Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
Ann Intern Med. 2007 Apr 17;146(8):545-55. doi: 10.7326/0003-4819-146-8-200704170-00152. Epub 2007 Feb 19.
Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.
To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.
Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.
27 academic and community medical centers in Canada.
449 patients with moderate or severe COPD.
1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.
The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.
The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.
More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.
Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.
吸入性糖皮质激素、长效β受体激动剂和长效抗胆碱能支气管扩张剂联合用于治疗中度或重度慢性阻塞性肺疾病（COPD）很常见，但尚未得到研究。
确定与单用噻托溴铵相比，噻托溴铵联合沙美特罗或氟替卡松-沙美特罗是否能改善中度至重度COPD成人患者的临床结局。
2003年10月至2006年1月进行的随机、双盲、安慰剂对照试验。
加拿大27个学术和社区医疗中心。
449例中度或重度COPD患者。
接受噻托溴铵加安慰剂、噻托溴铵加沙美特罗或噻托溴铵加氟替卡松-沙美特罗治疗1年。
主要终点是经历COPD加重且需要全身用类固醇或抗生素治疗的患者比例。
噻托溴铵加安慰剂组中经历病情加重的患者比例（62.8%）与噻托溴铵加沙美特罗组（64.8%；差异为-2.0个百分点[95%CI，-12.8至8.8个百分点]）或噻托溴铵加氟替卡松-沙美特罗组（60.0%；差异为2.8个百分点[CI，-8.2至13.8个百分点]）相比无差异。在敏感性分析中，点估计值和95%置信区间向有利于噻托溴铵加沙美特罗和噻托溴铵加氟替卡松-沙美特罗的方向偏移。与噻托溴铵加安慰剂相比，噻托溴铵加氟替卡松-沙美特罗改善了肺功能（P = 0.049）和疾病特异性生活质量（P = 0.01），并减少了因COPD加重导致的住院次数（发病率比，0.53[CI，0.33至0.86]）和全因住院次数（发病率比，0.67[CI，0.45至0.99]）。相比之下，与噻托溴铵加安慰剂相比，噻托溴铵加沙美特罗在肺功能或住院率方面未显示出统计学上的改善。
接受噻托溴铵加安慰剂和噻托溴铵加沙美特罗治疗的患者中，超过40%过早停药，许多患者转而接受开放标签的吸入性类固醇或长效β受体激动剂治疗。
在噻托溴铵治疗中加用氟替卡松-沙美特罗对COPD加重率无统计学影响，但可改善中度至重度COPD患者的肺功能、生活质量和住院率。国际标准随机对照试验注册号：ISRCTN29870041。
