Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator

A Randomized Trial

  1. Dennis E. Niewoehner, MD;
  2. Kathryn Rice, MD;
  3. Claudia Cote, MD;
  4. Daniel Paulson, MD;
  5. J. Allen D. Cooper, Jr., MD;
  6. Larry Korducki, MS;
  7. Cara Cassino, MD; and
  8. Steven Kesten, MD
  1. From the Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota; Bay Pines Veterans Affairs Medical Center, Bay Pines, Florida; Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia; Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.

    Abstract

    Background: Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications.

    Objective: To prospectively evaluate the effectiveness of a long-acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization.

    Design: Randomized, double-blind study.

    Setting: 26 Veterans Affairs medical centers.

    Patients: 1829 patients with moderate to severe COPD (mean baseline FEV1, 36% predicted).

    Intervention: Once-daily tiotropium (18 µg) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators.

    Measurements: The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.

    Results: Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, −5.7 percentage points [95% CI, −10.4 to −1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, −3.0 percentage points [CI, −5.9 to −0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates.

    Limitations: Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months.

    Conclusions: Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD.

    Article and Author Information

    • Acknowledgments: The authors recognize the contributions of the trial investigators, co-investigators, and study staff (Appendix); P. Arnold, B. Caldwell, S. Johnson, J. Tallman, and D. Chow; and the Duke Clinical Research Institute (which managed the data); and the Minnesota Veterans Research Institute (which furnished administrative support for all study centers).

    • Grant Support: By Boehringer Ingelheim and Pfizer, Inc.

    • Potential Financial Conflicts of Interest: Employment: L. Korducki, C. Cassino, S. Kesten (Boehringer Ingelheim Pharmaceuticals); Consultancies: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals, Chiron Corp., AstraZeneca, Aventis, Sanofi Pasteur), C. Cote (Boehringer Ingelheim Pharmaceuticals); Honoraria: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals), K. Rice (Boehringer Ingelheim Pharmaceuticals), J.A.D. Cooper Jr. (Boehringer Ingelheim Pharmaceuticals); Grants received: D.E. Niewoehner (Boehringer Ingelheim Pharmaceuticals, Chiron Corp., Sanofi Pasteur), K. Rice (Boehringer Ingelheim Pharmaceuticals), C. Cote (Boehringer Ingelheim Pharmaceuticals), D. Paulson (Boehringer Ingelheim Pharmaceuticals); Grants pending: C. Cote (Boehringer Ingelheim Pharmaceuticals).

    • Requests for Single Reprints: Dennis E. Niewoehner, MD, Pulmonary Section (111N), Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, MN 55417; e-mail, niewo001{at}umn.edu.

    • Current Author Addresses: Drs. Niewoehner and Rice: Pulmonary Section (111N), Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, MN 55417.

    • Dr. Cote: Respiratory Diseases (111A), Veterans Affairs Medical Center, PO Box 5005, Bay Pines, FL 35294.

    • Dr. Paulson: Sanofi-Aventis Research, 9 Great Valley Parkway, Malvern, PA 19355.

    • Dr. Cooper: Veterans Affairs Medical Center, Pulmonary Division/215 THT, 1900 University Boulevard, Birmingham, AL 35294.

    • Mr. Korducki and Drs. Cassino and Kesten: 900 Ridgebury Road, Ridgefield, CT 06877.

    • Author Contributions: Conception and design: D.E. Niewoehner, K. Rice, J.A.D. Cooper Jr., S. Kesten.

    • Analysis and interpretation of the data: D.E. Niewoehner, K. Rice, D. Paulson, J.A.D. Cooper Jr., L. Korducki, C. Cassino, S. Kesten.

    • Drafting of the article: D.E. Niewoehner, K. Rice, D. Paulson, L. Korducki, C. Cassino, S. Kesten.

    • Critical revision of the article for important intellectual content: D.E. Niewoehner, K. Rice, C. Cote, D. Paulson, J.A.D. Cooper Jr., C. Cassino, S. Kesten.

    • Final approval of the article: D.E. Niewoehner, K. Rice, C. Cote, D. Paulson, J.A.D. Cooper Jr., C. Cassino, S. Kesten.

    • Provision of study materials or patients: K. Rice, D. Paulson, J.A.D. Cooper Jr.

    • Statistical expertise: L. Korducki.

    • Obtaining of funding: D.E. Niewoehner, J.A.D. Cooper Jr., S. Kesten.

    • Administrative, technical, or logistic support: D.E. Niewoehner, C. Cote, C. Cassino, S. Kesten.

    • Collection and assembly of data: D.E. Niewoehner, D. Paulson.

    Responses to this article

    • Tiotropium Letter
      • Nadia K. Janjua and
      • Kendra D. Sheppard MD
      Ann Intern Med published online October 26, 2009
    • Response
      • Dennis E Niewoehner and
      • Kathryn Rice, Stephen Kesten
      Ann Intern Med published online October 26, 2009
    • Two Major Bias in this Study
      • Oreste Capelli and
      • Armando Capelli, Giulio Formoso, Nicola Magrini.
      Ann Intern Med published online October 26, 2009
    • Is This Study Design Ethical?
      • Alec B. O'Connor
      Ann Intern Med published online October 26, 2009
    • Tiotropium for COPD
      • Chester B Good and
      • Lisa Longo
      Ann Intern Med published online October 26, 2009
    • A Therapeutic Gain?
      • Michael H. Monroe and
      • J. Matthew Blackwell and Arnold Frazier
      Ann Intern Med published online October 26, 2009
    • Do bronchodilators produce a clinically meaningful reduction in COPD-related exacerbations?
      • S. Troy McMullin
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Tiotropium and the Treatment of Chronic Obstructive Lung Disease Ann Intern Med September 6, 2005 143:I-20
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    1. Ann Intern Med September 6, 2005 vol. 143 no. 5 317-326
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