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Background
Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β2-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β2-agonist salmeterol in preventing exacerbations of COPD.
Methods
In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.
Results
A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.
Conclusions
These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations.
Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381. Dr. Vogelmeier reports receiving consulting fees and travel support from Boehringer Ingelheim, payment for board membership from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, Novartis, and Nycomed, fees for expert testimony and grant support from Talecris Biotherapeutics, and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck, Novartis, Nycomed, and Talecris Biotherapeutics; Dr. Hederer, being formerly employed by Boehringer Ingelheim; Drs. Glaab and Schmidt, being currently employed by Boehringer Ingelheim; Dr. Rutten-van Mölken, receiving grant support from Boehringer Ingelheim and having consulting fees, travel support, and fees for participation in review activities from Boehringer Ingelheim paid to her institution on her behalf; Dr. Beeh, having consulting fees or honoraria, grant support, and payments for development of educational materials from Boehringer Ingelheim and grant support from Almirall, Novartis, Mundipharma, Cytos Biotechnology, GlaxoSmithKline, Pfizer, and Revotar Biopharmaceuticals paid to his institution on his behalf; Dr. Rabe, receiving consulting fees and honoraria and payment for board membership from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck, Novartis, Nycomed, and Pfizer and grant support from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche; and Dr. Fabbri, receiving travel support from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck, Novartis, Nycomed, Pfizer, and Sigma-Tau Pharmaceuticals, and lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck, Novartis, Nycomed, and Pfizer and having grant support from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, Merck, Nycomed, Pfizer, Schering-Plough (now Merck), Sigma-Tau Pharmaceuticals, and Union Chimique Belge paid to his institution on his behalf. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the patients who participated in the trial; Dr. Klaus Fichtner, Vera Drews, and Nicole Bader for administrative trial support; Dr. Steven Kesten, Dr. Fee Rühmkorf, Dr. Harald Kögler, Dr. Susanne Stowasser, Dr. Brigitta Monz, and Dagmar Selim for scientific advice; Dr. Inge Leimer and Achim Müller for statistical advice; Michael Betke-Hornfeck for technical trial support; Christine Meissner and Christina Raabe for data management support; Bernd Damian and Rafal Falkowski for programming support; Dr. Silke Wienecke, Declan Tobin, and Karen Ryan from Parexel for onsite monitoring and site management support; Natalie Barker and Claire Scarborough, from Parexel MedCom, for editorial and technical support in the preparation of the manuscript; and Dr. Franklin Cerasoli, Dr. Idelle Weisman, and Dr. Lalitha Aiyer for review of the manuscript. |
