© 2008 American Thoracic Society
Management of Patients with COPD: A Comparison of the INSPIRE and TORCH StudiesFrom the Authors:We appreciate Drs. Gillissen, Marchand, and Middleton's interest in our article, which published the results of the INSPIRE study (1). Dr. Gillissen correctly notes, as specified in the article, that patients included in the INSPIRE study had a post-bronchodilator FEV1 < 50% (classified as severe or very severe by the GOLD criteria). However, we respectfully disagree with Dr. Gillissen and believe that withdrawal rates in INSPIRE were indirect markers of efficacy. There was a significant difference in withdrawal rate between treatments (41.7% in the tiotropium group and 34.5% in the SFC [salmeterol/fluticasone] group; hazard ratio, 1.29; 95% CI [confidence interval], 1.08–1.54; P = 0.005). This differential withdrawal rate was evident by Week 13 and continued to diverge until Week 52, after which the difference was maintained. At 2 years, investigators recorded numerically more withdrawals on tiotropium than on SFC listed as consent withdrawal, COPD exacerbations, and lack of efficacy. Dr. Marchand suggests that the differential withdrawal rate between SFC and tiotropium is driven by patients who discontinued inhaled corticosteroids (ICS) at entry into the trial. Use of ICS may be a marker of disease severity, and severity is associated with increased withdrawal (2). While a greater proportion of patients on ICS at entry withdrew from the tiotropium arm than from the SFC arm, prior use of ICS was associated with increased withdrawal in both arms of INSPIRE, and more patients withdrew on tiotropium than on SFC regardless of prior ICS use, as Table 1 shows.
Finally, Drs. Gillissen and Middleton compare the INSPIRE mortality results with those of TORCH and comment on the apparent lower mortality seen in INSPIRE. Mortality in INSPIRE was a prespecified efficacy and safety endpoint. It is, however, difficult to directly compare these studies as their design, patient population, and duration were different. We did not ascertain the survival status of patients who withdrew from our study as was done in TORCH, and we did not have a placebo arm. Fifty-nine deaths were recorded during the study (38 in the tiotropium group and 21 in the SFC group), and seven deaths were recorded after subjects had left the study (4 from the tiotropium group and 3 from the SFC). In INSPIRE, the on-treatment mortality (up to 2 wk after treatment cessation) for the tiotropium group at end of the study (Week 104) was 6.7%; 6.5% patients from the TORCH placebo group died at Week 108 (the second year of the 3-yr study) using the same analysis. On this basis, the mortality results in INSPIRE and TORCH appear to be consistent. The lower mortality we observed with SFC in INSPIRE would be supportive of the TORCH mortality results, but further studies are required to address this question.
Royal Free and University College Medical School
University Hospital Aintree
The University of the West Indies
GlaxoSmithKline
University Hospital Birmingham NHS Foundation Trust FOOTNOTES Conflict of Interest Statement: In the past 3 years, J.A.W. has received research funding from GlaxoSmithKline (GSK), Boehringer Ingelheim, and AstraZeneca; she has also received honoraria for lectures and/or attendance at advisory boards from GSK, Boehringer Ingelheim, AstraZeneca, and Novartis. P.M.A.C. has received honoraria for serving on study advisory boards for GSK and Pfizer and has received funding to conduct clinical trials by GSK, Altana, and Chiesi. T.A.S. is on the steering committee for the INSPIRE study and has attended meetings of this committee every 3 months. G.H. is an employee of the sponsor, GSK, and has been since 1996; as an employee, he holds stock options in various formats. Z.A. was employed by GSK between October 2002 and November 2006 as a full-time employee, with a starting salary of £24,250 and an ending salary of £33,850. R.A.S. has received funding to attend international conferences from Boehringer Ingelheim and Talecris and for speaking at conferences organized by GSK and AstraZeneca; he has served on advisory panels for Roche, GSK, and Merck, Sharp & Dohme ($5,000 in 2006); he is in receipt of an unrestricted noncommercial grant from AstraZeneca (£30,000 in 2006) and Talecris (£317,000 in 2006). REFERENCES
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