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Communications to the Editor |

Withdrawal From and Study Design of the ISOLDE Trial FREE TO VIEW

Eric Marchand, MD, PhD
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Cliniques Universitaires UCL de Mont-Godinne Yvoir, Belgium

Correspondence to: Eric Marchand, MD, PhD, Service de Pneumologie, Cliniques Universitaires UCL de Mont-Godinne, B-5530 Yvoir, Belgium; e-mail: eric.marchand@pneu.ucl.ac.be



Chest. 2004;126(2):659. doi:10.1378/chest.126.2.659
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Published online

To the Editor:

In a recent article, Calverley et al1 provide us with further very interesting data from the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. In their article, the authors insist on the fact that the decline of both FEV1 and health status was more rapid in patients who withdrew from follow-up. They also argue that the loss of these patients reduced the power of the ISOLDE study to show a difference for various outcome measures.

The authors did not provide a statistical analysis comparing the fluticasone- and the placebo-treated groups in both completers and withdrawers. It is, however, quite clear from the data that much of the differences observed between the placebo and the fluticasone groups in the intention-to-treat analysis published earlier2 came from withdrawers.

In this context, two points are critical for a proper understanding of the intention-to-treat analysis of the ISOLDE trial2: the statistical handling of withdrawers, and the potential influence of the study design on early withdrawals.

The issue of withdrawals in long-term trials including patients with COPD is certainly difficult to deal with, and makes these studies difficult to perform. Undoubtedly, these withdrawers must be included in the analysis. How they are statistically handled is important, and is not always clearly explained in the methodology of various trials. The random coefficients hierarchical model used in the ISOLDE trial is not familiar to most of us. More details on this particular statistical analysis was provided in another article by the same group,3 in which they stated that patients withdrawn contributed less weight in the statistical model. But what the exact relative weight of withdrawers was in the intention-to-treat analysis2 remains unclear.

One might argue that this is irrelevant, since a lesser weight—whatever its extent—certainly lowers the power of the study to find a statistical difference. Nevertheless, the design of the study had the potential to influence early withdrawals. Indeed, patients received oral prednisolone, 0.6 mg/kg/d, for 14 days in the run-in phase of the trial. One might suspect that after this oral prednisolone treatment, patients randomized to the placebo group had a more rapid decline in FEV1 during the first weeks of the treatment phase than patients allocated to fluticasone (this is indeed suggested by Fig 2 in the original article2). Thus, this prednisolone test could have favored—and more so in the placebo group—the occurrence of early exacerbations, of an early and rapid decline of health status, and of early withdrawals. This is critical since the raw contribution of these early withdrawers to the annualized decline of FEV1 and health status as well as to the annualized exacerbation rate could be very important.

Accordingly, it would be useful to know to what extent the fluticasone- and the placebo-treated groups differed in terms of early withdrawals due to respiratory causes (at 3 months, 6 months, and 12 months), and the exact weight attributed to withdrawers in the statistical model. Interestingly, the only two studies2,4 (lasting ≥ 1 year) that showed a statistically significant effect of inhaled steroids on health-related quality of life in COPD included a run-in with oral steroids.

In their discussion, Calverley et al1state that avoiding premature withdrawals is a difficult problem. However, in previous trials,2,45 some early withdrawals were probably due to the design of the study itself. One could suggest that further studies in COPD should avoid oral steroids run-in, and that when needed inhaled steroids should be withdrawn for at least 4 weeks6 before the treatment phase.

Calverley, PM, Spencer, S, Willits, L, et al (2003) Withdrawal from treatment as an outcome in the ISOLDE study of COPD.Chest124,1350-1356. [CrossRef] [PubMed]
 
Burge, PS, Calverley, PM, Jones, PW, et al Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.BMJ2000;320,1297-1303. [CrossRef] [PubMed]
 
Spencer, S, Calverley, PMA, Burge, PS, et al Health status deterioration in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med2001;163,122-128. [PubMed]
 
Calverley, PM, Boonsawat, W, Cseke, Z, et al Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.Eur Respir J2003;22,912-919. [CrossRef] [PubMed]
 
Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2003;361,449-456. [CrossRef] [PubMed]
 
Jarad, NA, Wedzicha, JA, Burge, PS, et al An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease: ISOLDE study group.Respir Med1999;93,161-166. [CrossRef] [PubMed]
 

Figures

Tables

References

Calverley, PM, Spencer, S, Willits, L, et al (2003) Withdrawal from treatment as an outcome in the ISOLDE study of COPD.Chest124,1350-1356. [CrossRef] [PubMed]
 
Burge, PS, Calverley, PM, Jones, PW, et al Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.BMJ2000;320,1297-1303. [CrossRef] [PubMed]
 
Spencer, S, Calverley, PMA, Burge, PS, et al Health status deterioration in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med2001;163,122-128. [PubMed]
 
Calverley, PM, Boonsawat, W, Cseke, Z, et al Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.Eur Respir J2003;22,912-919. [CrossRef] [PubMed]
 
Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2003;361,449-456. [CrossRef] [PubMed]
 
Jarad, NA, Wedzicha, JA, Burge, PS, et al An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease: ISOLDE study group.Respir Med1999;93,161-166. [CrossRef] [PubMed]
 
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