This Article Full Text Full Text (PDF) All Versions of this Article: 200508-1338PPv1 173/8/842    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suissa, S. Search for Related Content PubMed PubMed Citation Articles by Suissa, S.

Statistical Treatment of Exacerbations in Therapeutic Trials of Chronic Obstructive Pulmonary Disease

Division of Clinical Epidemiology, Royal Victoria Hospital; McGill University Health Centre; and Departments of Epidemiology and Biostatistics and Medicine, McGill University, Montreal, Canada

Correspondence and request for reprints should be addressed to Samy Suissa, Ph.D., Division of Clinical Epidemiology, Royal Victoria Hospital, 687 Pine Avenue West, Ross 4.29, Montreal, PQ, H3A 1A1 Canada. E-mail: samy.suissa{at}clinepi.mcgill.ca

ABSTRACT

Randomized trials and a meta-analysis suggesting that inhaled corticosteroids reduce exacerbation rates in patients with chronic obstructive pulmonary disease (COPD) show major discrepancies that may be due to different approaches to data analysis. These trials used statistical techniques that were either weighted or unweighted for follow-up time, with p values and confidence intervals estimated with or without accounting for between-patient variability in exacerbation rates. We illustrate the validity of these methods using data from a cohort of 5,454 patients with COPD structured to emulate a randomized trial. The "reference" group was defined as patients with a history of exacerbations before cohort entry (n = 1,137), whereas the "treated" group included an equal number (n = 1,137) of patients with no prior exacerbation. Random samples of 100 and 200 subjects were selected three times from each of two groups to further illustrate the variability in the findings. Exacerbations during follow-up were identified from prescriptions for systemic antibiotics. The correct rate ratio of 0.75 estimated by the weighted approach was underestimated as 0.57 by the unweighted approach. When the weighted approach did not, however, also account for between-patient variability, the p value was greatly underestimated (e.g., rate ratio, 0.79; p = 0.0007 instead of p = 0.12) and confidence intervals were much narrower than after properly accounting for this variability. In conclusion, the reports from randomized trials and the meta-analysis that inhaled corticosteroids reduce COPD exacerbation rates are the result of improper statistical analysis techniques. The only two studies that used the correct statistical approach found insignificant effects with these drugs.

Key Words: biases • data analysis • drug effectiveness • inhaled corticosteroids • methods

This article has been cited by other articles:

				C.-L. Tsai Temporal Clustering of Exacerbations of COPD: Not-So-Surprising Findings Am. J. Respir. Crit. Care Med., August 1, 2009; 180(3): 283 - 283. [Full Text] [PDF]

				H. Gardarsdottir, T. C. Egberts, J. J. Stolker, and E. R. Heerdink Duration of Antidepressant Drug Treatment and Its Influence on Risk of Relapse/Recurrence: Immortal and Neglected Time Bias Am. J. Epidemiol., August 1, 2009; 170(3): 280 - 285. [Abstract] [Full Text] [PDF]

				S. Suissa and P. J. Barnes Inhaled corticosteroids in COPD: the case against Eur. Respir. J., July 1, 2009; 34(1): 13 - 16. [Full Text] [PDF]

				H. K. Reddel, D. R. Taylor, E. D. Bateman, L.-P. Boulet, H. A. Boushey, W. W. Busse, T. B. Casale, P. Chanez, P. L. Enright, P. G. Gibson, et al. An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations: Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice Am. J. Respir. Crit. Care Med., July 1, 2009; 180(1): 59 - 99. [Abstract] [Full Text] [PDF]

				C. Laurin, M. Labrecque, G. Dupuis, S. L. Bacon, A. Cartier, and K. L. Lavoie Chronic Obstructive Pulmonary Disease Patients With Psychiatric Disorders Are at Greater Risk of Exacerbations Psychosom Med, July 1, 2009; 71(6): 667 - 674. [Abstract] [Full Text] [PDF]

				F. M. Ducharme, C. Lemire, F. J.D. Noya, G. M. Davis, N. Alos, H. Leblond, C. Savdie, J.-P. Collet, L. Khomenko, G. Rivard, et al. Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young Children N. Engl. J. Med., January 22, 2009; 360(4): 339 - 353. [Abstract] [Full Text] [PDF]

				W. Xu, J.-P. Collet, S. Shapiro, Y. Lin, T. Yang, R. W. Platt, C. Wang, and J. Bourbeau Independent Effect of Depression and Anxiety on Chronic Obstructive Pulmonary Disease Exacerbations and Hospitalizations Am. J. Respir. Crit. Care Med., November 1, 2008; 178(9): 913 - 920. [Abstract] [Full Text] [PDF]

				D. P. Tashkin, B. Celli, S. Senn, D. Burkhart, S. Kesten, S. Menjoge, M. Decramer, and the UPLIFT Study Investigators A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease N. Engl. J. Med., October 9, 2008; 359(15): 1543 - 1554. [Abstract] [Full Text] [PDF]

				S. Suissa Exacerbations and intent-to-treat analyses in randomised trials Eur. Respir. J., October 1, 2008; 32(4): 1117 - 1118. [Full Text] [PDF]

				O. N. Keene, P. M. A. Calverley, P. W. Jones, J. Vestbo, and J. A. Anderson Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited Eur. Respir. J., July 1, 2008; 32(1): 17 - 24. [Abstract] [Full Text] [PDF]

				P. Albert and P. M. A. Calverley Drugs (including oxygen) in severe COPD Eur. Respir. J., May 1, 2008; 31(5): 1114 - 1124. [Abstract] [Full Text] [PDF]

				S. Suissa, P. Ernst, K. L. Vandemheen, and S. D. Aaron Methodological issues in therapeutic trials of COPD Eur. Respir. J., May 1, 2008; 31(5): 927 - 933. [Abstract] [Full Text] [PDF]

				M. Cazzola, W. MacNee, F. J. Martinez, K. F. Rabe, L. G. Franciosi, P. J. Barnes, V. Brusasco, P. S. Burge, P. M. A. Calverley, B. R. Celli, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur. Respir. J., February 1, 2008; 31(2): 416 - 469. [Abstract] [Full Text] [PDF]

				S D Aaron, D Fergusson, G B Marks, S Suissa, K L Vandemheen, S Doucette, F Maltais, J F Bourbeau, R S Goldstein, M Balter, et al. Counting, analysing and reporting exacerbations of COPD in randomised controlled trials Thorax, February 1, 2008; 63(2): 122 - 128. [Abstract] [Full Text] [PDF]

				G. R. Washko, V. S. Fan, S. D. Ramsey, Z. Mohsenifar, F. Martinez, B. J. Make, F. C. Sciurba, G. J. Criner, O. Minai, M. M. DeCamp, et al. The Effect of Lung Volume Reduction Surgery on Chronic Obstructive Pulmonary Disease Exacerbations Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 164 - 169. [Abstract] [Full Text] [PDF]

				J. A. Wedzicha, P. M. A. Calverley, T. A. Seemungal, G. Hagan, Z. Ansari, R. A. Stockley, and for the INSPIRE Investigators The Prevention of Chronic Obstructive Pulmonary Disease Exacerbations by Salmeterol/Fluticasone Propionate or Tiotropium Bromide Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 19 - 26. [Abstract] [Full Text] [PDF]

				S. Suissa, R. McGhan, D. Niewoehner, and B. Make Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, October 1, 2007; 4(7): 535 - 542. [Abstract] [Full Text] [PDF]

				S. Suissa On the Correct Statistical Analysis of Exacerbation Rates in Clinical Trials Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 522 - 522. [Full Text] [PDF]

				P. Kardos, M. Wencker, T. Glaab, and C. Vogelmeier Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 522 - 522. [Full Text] [PDF]

				P. Ernst, A. V. Gonzalez, P. Brassard, and S. Suissa Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease and the Risk of Hospitalization for Pneumonia Am. J. Respir. Crit. Care Med., July 15, 2007; 176(2): 162 - 166. [Abstract] [Full Text] [PDF]

				K. F. Rabe, B. Beghe, F. Luppi, and L. M. Fabbri Update in Chronic Obstructive Pulmonary Disease 2006 Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1222 - 1232. [Full Text] [PDF]

				S. D. Aaron, K. L. Vandemheen, D. Fergusson, F. Maltais, J. Bourbeau, R. Goldstein, M. Balter, D. O'Donnell, A. McIvor, S. Sharma, et al. Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial Ann Intern Med, April 17, 2007; 146(8): 545 - 555. [Abstract] [Full Text] [PDF]

				K. F. Rabe Treating COPD -- The TORCH Trial, P Values, and the Dodo N. Engl. J. Med., February 22, 2007; 356(8): 851 - 854. [Full Text] [PDF]

				D. E. Niewoehner and T. J. Wilt Inhaled Corticosteroids for Chronic Obstructive Pulmonary Disease: A Status Report Am. J. Respir. Crit. Care Med., January 15, 2007; 175(2): 103 - 104. [Full Text] [PDF]

				P. Kardos, M. Wencker, T. Glaab, and C. Vogelmeier Impact of Salmeterol/Fluticasone Propionate versus Salmeterol on Exacerbations in Severe Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., January 15, 2007; 175(2): 144 - 149. [Abstract] [Full Text] [PDF]