Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease

A Randomized Trial

  1. Shawn D. Aaron, MD;
  2. Katherine L. Vandemheen, BScN;
  3. Dean Fergusson, PhD;
  4. François Maltais, MD;
  5. Jean Bourbeau, MD;
  6. Roger Goldstein, MD;
  7. Meyer Balter, MD;
  8. Denis O'Donnell, MD;
  9. Andrew McIvor, MD;
  10. Sat Sharma, MD;
  11. Graham Bishop, MD;
  12. John Anthony, MD;
  13. Robert Cowie, MD;
  14. Stephen Field, MD;
  15. Andrew Hirsch, MD;
  16. Paul Hernandez, MD;
  17. Robert Rivington, MD;
  18. Jeremy Road, MD;
  19. Victor Hoffstein, MD;
  20. Richard Hodder, MD;
  21. Darcy Marciniuk, MD;
  22. David McCormack, MD;
  23. George Fox, MD;
  24. Gerard Cox, MB;
  25. Henry B. Prins, MD;
  26. Gordon Ford, MD;
  27. Dominique Bleskie, BHScN;
  28. Steve Doucette, MSc;
  29. Irvin Mayers, MD;
  30. Kenneth Chapman, MD;
  31. Noe Zamel, MD;
  32. Mark FitzGerald, MD; and
  33. for the Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium
  1. From The Ottawa Health Research Institute and University of Ottawa, Ottawa, Ontario, Canada; The University of Toronto, Toronto, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada; Queen's University, Kingston, Ontario, Canada; Scarborough Centenary Hospital, Scarborough, Ontario, Canada; University of Western Ontario, London, Ontario, Canada; St. Lawrence Medical Clinic, Morrisburg, Ontario, Canada; University of British Columbia, Vancouver, British Columbia, Canada; Centre de Recherche, Hôpital Laval, Université Laval, Québec, Québec, Canada; McGill University, Montréal, Québec, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; University of Manitoba, Winnipeg, Manitoba, Canada; University of New Brunswick, St. John, New Brunswick, Canada; University of Saskatchewan, Saskatoon, Saskatchewan, Canada; University of Calgary, Calgary, Alberta, Canada; University of Alberta, Edmonton, Alberta, Canada; Memorial University, St. John's, Newfoundland, Canada; and The Woolcock Institute of Medical Research, Sydney, Australia.

    Abstract

    Background: Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting β-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.

    Objective: To determine whether combining tiotropium with salmeterol or fluticasone–salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.

    Design: Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.

    Setting: 27 academic and community medical centers in Canada.

    Patients: 449 patients with moderate or severe COPD.

    Intervention: 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone–salmeterol.

    Measurements: The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.

    Results: 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.

    Limitations: 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 β-agonists.

    Conclusions: 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.

    For more information on treatments for chronic obstructive pulmonary disease click here.

    Article and Author Information

    • Acknowledgments: The authors thank the following people for their assistance. Study investigators: Drs. Elizabeth Powell, Gregory Berg, Thomas Baitz, Matthew Stanbrook, Ted Marras. Study coordinators: Gay Pratt, Shobha Chakravorty, Rommel Mangaser, Elizabeth Sukhdeo, Heidi Haupt, Margot Underwood, Diane Conley, Kathleen Currie, Sarah Goodwin, Linda Hui, Gladys Wolters, Erin Condon Pennell, Bruce Krip, Kim Danovitch, Myra Slutsky, Marie-Josée Breton, Josée Picard, Brigitte Jean, Lenny Scharfstein, Janet Baron, Janet Knechtel, Andrea Dale, Scott Fulton, Ian McBride, Veronica Harris-McAllister, Tracy Bonifacio, Deborah Sciberras, Nicole Marten, Kym Wiebe, Shauna Leeson, Patricia McClean, Pearl Latty, Krisha Berg, Cheryl McIntyre, Wendy Casselman, Wendy Hoogeveen, Goulnar Kasymjanova, Sylvain Gagné, Ginette Ferguson, Bonnie Chubb, Lisa Courneya. Study pharmacists: Anne Marie Dugal, Susan Fetzer. Data managers: Mohammed Jahangir Kabir, Sheryl Domingo. Statistical consultant: Jennifer Clinch. They also thank Boehringer Ingelheim, Inc. (Ridgefield, Connecticut), for supplying placebo inhalers and blinding devices and Trudell Medical, Inc. (London, Ontario, Canada), for supplying Aerochamber Plus spacer devices.

    • Grant Support: By the Canadian Institutes of Health Research (grant MCT-63139; $1 464 139) and the Ontario Thoracic Society ($50 000). Dr. Aaron is supported by a Canadian Institutes of Health Research New Investigator Award. This study was not funded by the pharmaceutical industry.

    • Potential Financial Conflicts of Interest: Consultancies: S.D. Aaron (AstraZeneca, Boehringer Ingelheim), F. Maltais (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline), J. Bourbeau (Boehringer Ingelheim, GlaxoSmithKline, Pfizer), M. Balter (Boehringer Ingelheim, GlaxoSmithKline), S. Sharma (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), G. Bishop (AstraZeneca, GlaxoSmithKline), R. Cowie (ALTANA Pharma, GlaxoSmithKline), S. Field (ALTANA Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck & Co. Inc., Novartis, Pfizer Inc., Wyeth), P. Hernandez (Actelion, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), R. Rivington, J. Road (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline), D. Marciniuk (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), G. Cox (AstraZeneca, Boehringer Ingelheim, Pfizer Inc.), G. Ford (Abbott Canada, ALTANA Pharma Canada Inc., AstraZeneca, Boehringer Ingelheim Canada Ltd., GlaxoSmithKline, Pfizer Canada), K. Chapman (ALTANA Pharma, AstraZeneca, Biovail, Boehringer Ingelheim, Genpharm, GlaxoSmithKline, Hoffmann-La Roche, Merck Frosst Laboratories, Novartis, Pfizer Inc., Roche, Schering-Plough, Telacris), M. FitzGerald (3M, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche); Honoraria: S.D. Aaron (Boehringer Ingelheim), F. Maltais (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline) J. Bourbeau (AstraZeneca, Boehringer Ingelheim, Pfizer, GlaxoSmithKline), M. Balter (GlaxoSmithKline), A. McIvor (ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Frosst Laboratories, Novartis), S. Sharma (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), G. Bishop (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), R. Cowie (ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), S. Field (ALTANA Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck & Co. Inc., Pfizer Inc., Wyeth), A. Hirsch (GlaxoSmithKline), P. Hernandez (Actelion, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), R. Rivington (AstraZeneca, Pfizer Inc.), J. Road (Boehringer Ingelheim), D. Marciniuk (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), G. Cox (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co. Inc., Pfizer Inc.), G. Ford (Abbott Canada, ALTANA Pharma Canada Inc., AstraZeneca, Boehringer Ingelheim Canada Ltd., GlaxoSmithKline, Merck Canada, Pfizer Canada), K. Chapman (3M, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Frosst Laboratories, Novartis, Pfizer Inc., Telacris), M. FitzGerald (3M, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche); Grants received: F. Maltais (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline, Merck), J. Bourbeau (ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer), G. Bishop (AstraZeneca, GlaxoSmithKline), S. Field (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), P. Hernandez (Boehringer Ingelheim), J. Road (Boehringer Ingelheim), D. Marciniuk (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), G. Ford (Alberta Lung Association/AstraZeneca/Boehringer Ingelheim/GlaxoSmithKline, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, Calgary Health Region, Canadian Institutes of Health Research, GlaxoSmithKline, Pfizer Canada, University of British Columbia/GlaxoSmithKline), K. Chapman (3M, ALTANA Pharma, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche, Merck Frosst Laboratories, Novartis, Roche, Telacris, Theratechnologies), M. FitzGerald (3M, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche; Other: F. Maltais (AstraZeneca), P. Hernandez (ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis), G. Cox (AstraZeneca, GlaxoSmithKline).

    • Requests for Single Reprints: Shawn Aaron, MD, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; e-mail, saaron{at}ohri.ca.

    • Current Author Addresses: Dr. Aaron and Ms. Vandemheen: The Ottawa Hospital, Mailbox 211, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.

    • Dr. Fergusson: The Ottawa Hospital, Mailbox 201-CEP Unit, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.

    • Dr. Maltais: Hôpital Laval, 2725 chemin Sainte-Foy, Québec, Québec G1V 4G5, Canada.

    • Dr. Bourbeau: Montreal Chest Institute Foundation, McGill University Health Centre, 3650 rue Saint-Urbain, Montréal, Québec H2X 2P4, Canada.

    • Dr. Goldstein: 82 Buttonwood Avenue, West Park Healthcare Centre, Toronto, Ontario M6M 2J5, Canada.

    • Dr. Balter: 640-600 University Avenue, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

    • Dr. O'Donnell: 102 Stuart Street, Richardson House, Kingston, Ontario K7L 2V6, Canada.

    • Dr. McIvor: 50 Charlton Avenue East, St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada.

    • Dr. Sharma: St. Boniface General Hospital, Bg034-409 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada.

    • Dr. Bishop: 640 Manawagonish Road, St. John, New Brunswick E2M 3W5, Canada.

    • Dr. Anthony: Scarborough Professional Centre, 423-1371 Neilson Road, Scarborough, Ontario M1B 4Z8, Canada.

    • Dr. Cowie: Faculty of Medicine, Health Science Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

    • Dr. Field: Foothills Medical Centre, 1403 29 Street NW, Calgary, Alberta T2N 2T9, Canada.

    • Dr. Hirsch: Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin Côte-Sainte-Catherine, Montréal, Québec H3T 1E2, Canada.

    • Dr. Hernandez: 4458-1796 Summer Street, Halifax, Nova Scotia B3H 3A7 Canada.

    • Dr. Rivington: Canadian Medical Protective Association, PO Box 8225, Station T Crescent, Ottawa, Ontario K1G 3H7, Canada.

    • Dr. Road: Respiratory Medicine, 2775 Heather Street, Vancouver, British Columbia V5Z 3J5, Canada.

    • Dr. Hoffstein: St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.

    • Dr. Hodder: The Ottawa Hospital-Civic Campus, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.

    • Dr. Marciniuk: Royal University Hospital, 103 Hospital Drive, Saskatoon, Saskatchewan S7N 0W8, Canada.

    • Dr. McCormack: London Health Sciences Centre, Victoria Campus, PO Box 5375, Station B, London, Ontario N6A 4G5, Canada.

    • Dr. Fox: Health Sciences Centre, 300 Prince Philip Drive, St. John's, Newfoundland A1B 3V6, Canada.

    • Mr. Cox: St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

    • Dr. Prins: St. Lawrence Medical Clinic, PO Box 772, Morrisburg, Ontario K0C 1X0, Canada.

    • Dr. Ford: Rockyview General Hospital, 4A183-7007 14 Street SW, Calgary, Alberta T2V 1P9, Canada.

    • Ms. Bleskie and Mr. Doucette: The Ottawa Hospital, Mailbox 208, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.

    • Dr. Mayers: University of Alberta Hospital, 2E438-8440 112 Street NW, Edmonton, Alberta T6G 2B7, Canada.

    • Dr. Chapman: University Health Network-Toronto Western Hospital, Room 7-451 West Wing, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.

    • Dr. Zamel: University Health Network-Toronto General, En207-200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada

    • Dr. FitzGerald: Vancouver Coastal Health Research Institute, 703-828 West 10th Avenue, Vancouver, British Columbia V5Z 1M9, Canada.

    • Author Contributions: Conception and design: S.D. Aaron, K.L. Vandemheen, D. Fergusson, F. Maltais, J. Bourbeau, M. Balter, D. O'Donnell, A. McIvor, S. Sharma, P. Hernandez, R. Hodder, K. Chapman, M. FitzGerald.

    • Analysis and interpretation of the data: S.D. Aaron, K.L. Vandemheen, D. Fergusson, F. Maltais, J. Bourbeau, A. McIvor, J. Anthony, P. Hernandez, R. Hodder, D. Marciniuk, D. McCormack, G. Fox, G. Ford, S. Doucette, I. Mayers, M. FitzGerald.

    • Drafting of the article: S.D. Aaron, K.L. Vandemheen, D. Fergusson, F. Maltais, J. Bourbeau, A. McIvor, J. Anthony, D. McCormack, G. Fox, I. Mayers, K. Chapman, M. FitzGerald.

    • Critical revision of the article for important intellectual content: S.D. Aaron, K.L. Vandemheen, D. Fergusson, M. Balter, A. McIvor, S. Sharma, R. Cowie, S. Field, A. Hirsch, P. Hernandez, J. Road, R. Hodder, D. Marciniuk, G. Ford, S. Doucette, K. Chapman, M. FitzGerald.

    • Final approval of the article: S.D. Aaron, K.L. Vandemheen, M. Balter, A. McIvor, S. Sharma, G. Bishop, R. Cowie, S. Field, A. Hirsch, R. Rivington, J. Road, R. Hodder, D. Marciniuk, G. Ford, N. Zamel, M. FitzGerald.

    • Provision of study materials or patients: S.D. Aaron, M. Balter, A. McIvor, G. Bishop, J. Anthony, R. Cowie, S. Field, A. Hirsch, P. Hernandez, R. Rivington, V. Hoffstein, R. Hodder, D. Marciniuk, D. McCormack, G. Fox, G. Ford, I. Mayers, K. Chapman, N. Zamel, M. FitzGerald.

    • Statistical expertise: S.D. Aaron, D. Fergusson, J. Road, S. Doucette.

    • Obtaining of funding: S.D. Aaron, K.L. Vandemheen, D. Fergusson, A. McIvor.

    • Administrative, technical, or logistic support: S.D. Aaron, K.L. Vandemheen, A. McIvor, G. Ford, D. Bleskie, M. FitzGerald.

    • Collection and assembly of data: S.D. Aaron, K.L. Vandemheen, M. Balter, A. Hirsch, P. Hernandez, R. Rivington, V. Hoffstein, G. Ford.

    Responses to this article

    • Author's response to Dr. Brown's letter
      • Shawn D. Aaron
      Ann Intern Med published online October 26, 2009
    • Power calculations
      • Ejvind Frausing Hansen
      Ann Intern Med published online October 26, 2009
    • Re: Inhaled Corticosteroid in COPD: safety vs efficacy
      • jaspreet Singh
      Ann Intern Med published online October 26, 2009
    • Possible confounding effect of withdrawal of pre-existing therapy
      • Samuel M. Brown
      Ann Intern Med published online October 26, 2009
    • Editor's reply to Dr. Porat
      • Harold C. Sox
      Ann Intern Med published online October 26, 2009
    • Conflicts of Interest
      • Gil Porat
      Ann Intern Med published online October 26, 2009
    • Inhaled Corticosteroid in COPD: safety vs efficacy
      • Akashdeep Singh
      Ann Intern Med published online October 26, 2009
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