© 2008 American Thoracic Society
Methodologic Shortcomings of the INSPIRE Randomized TrialFrom the Authors:Professor Suissa raises two issues with regard to the mortality finding in INSPIRE, as reported in our article (1). The first refers to the fact that some patients randomized into the study were receiving inhaled corticosteroids (ICS) prior to entry, and the concern is that the apparent difference in mortality may be due to withdrawal of ICS rather than a true benefit of treatment. This concern, although interesting, is based on a post hoc subset analysis of data from another study (2) involving 30% of subjects in that study (3). We previously addressed the issue of treatment withdrawal when responding to the letter of Drs. Lanes and Jara (4). Briefly, among those with no prior use of ICS, there were 13 deaths in the salmeterol/fluticasone propionate (SFC) arm compared with 26 in the tiotropium arm, a similar percentage reduction to that seen overall. Therefore, prior use of ICS is not the explanation for the observed survival benefit with SFC in our study. The second issue raised by Prof. Suissa is whether intent-to-treat analysis is possible when there is incomplete follow-up of patients who withdrew from the study. We agree with Professor Suissa that the finding of reduced mortality needs to be seen in the context of a lack of follow-up of patients off-treatment, and this is acknowledged in the discussion section of the article. However, the assertion regarding intent-to-treat analysis is incorrect. Intent-to-treat analysis requires inclusion of all available subjects in the analysis, but the principle allows for missing data. The CONSORT statement (5) is the standard guideline for reporting randomized clinical trials adopted by major medical journals. In an accompanying article to the latest revision, the authors state: "It is common for some patients not to complete a study—they may drop out or be withdrawn from active treatment—and thus are not assessed at the end. Although these patients cannot be included in the analysis, it is customary still to refer to analysis of all available participants as an intent-to-treat analysis" (6). In the analysis of INSPIRE, all available patients were included in the analysis, and therefore the results presented are from a valid intent-to-treat analysis.
Royal Free and University College Medical School
University Hospital Aintree
The University of the West Indies
GlaxoSmithKline
University Hospital Birmingham NHS FOOTNOTES Conflict of Interest Statement: In the past 3 years, J.A.W. received research funding from GlaxoSmithKline (GSK), Boehringer Ingelheim, and AstraZeneca; she also received honoraria for lectures and/or attendance at advisory boards from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis. P.M.A.C. received funding from GlaxoSmithKline (GSK), Altana/Nycomed, Boehringer Ingelheim, Roche, and Chiesi to conduct clinical research trials in COPD; he led several large sponsored studies including those by GSK, Roche, Chiesi, and Altana, and has spoken at meetings supported by these companies and by AstraZeneca, Pfizer/Boehringer Ingelheim, and BOC/Linde. T.A.S. is a full-time consultant of the University of The West Indies. G.H. retired as an employee from GlaxoSmithKline in August 2008; he was employed by GlaxoSmithKline from 1996. Z.A. was employed by GlaxoSmithKline between October 2002 and November 2006 as a full-time employee; his salary started at £24,250, and when he left the company, his salary was £33,850. R.A.S. has received funding to attend international conferences from Boehringer Ingelheim and Talecris and for speaking at conferences organized by GlaxoSmithKline and AstraZeneca; he served on advisory panels from Roche, GlaxoSmithKline, and Merck Sharpe & Dohme ($5,000 in 2006); he received an unrestricted noncommercial grant from AstraZeneca (£100,000 in 2006–2007) and Talecris (£634,000 in 2006–2007). REFERENCES
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