Chest
Volume 124, Issue 4, October 2003, Pages 1350-1356
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Clinical Investigations
Copd
Withdrawal From Treatment as an Outcome in the ISOLDE Study of COPD

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Objectives

To investigate the determinants of patient withdrawal from our study, and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD.

Design

A double-blind, placebo-controlled, randomized trial.

Setting

Eighteen outpatient centers in the United Kingdom.

Participants

Seven hundred fifty-one patients with stable COPD defined clinically and as baseline postbronchodilator FEV1 ≥ 0.8 L and < 85% predicted, FEV1/FVC ratio < 70%, and FEV1 change after albuterol < 10% of predicted.

Intervention

Random assignment of either 500 μg bid of inhaled fluticasone propionate (FP) using a spacer device or an identical placebo inhaler. Treatment was continued for 3 years or until patients withdrew from follow-up.

Measurements and results

Postbronchodilator FEV1 was measured on three occasions before randomization and every 3 months thereafter. Health status was assessed by the disease-specific St. George Respiratory Questionnaire (SGRQ) and the modified short-form 36 questionnaire (SF-36) at baseline and every 6 months. Three hundred thirty-nine patients withdrew, of whom 156 patients received FP. Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol (69 patients in the FP group withdrew due to respiratory symptoms, compared with 93 patients in the placebo group). This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV1 was < 50% predicted. Patients withdrawing had a significantly more rapid decline in health status, measured by both the SGRQ and the SF-36 (p < 0.001). Those withdrawing from the placebo group had a more rapid decline in FEV1 and more exacerbations than the FP-treated groups. Baseline FEV1 was lower in dropouts than in patients completing the study receiving placebo, but there was no difference between the respective groups receiving FP.

Conclusions

Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function. Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point.

Section snippets

Patients

Details of the trial design and patient recruitment have been presented previously.8All patients had a clinical diagnosis of nonasthmatic COPD, met the established diagnostic criteria for this disorder,1213were aged 40 to 75 years inclusive, and had a history of current or previous smoking. At baseline, postbronchodilator (400 μg albuterol) FEV1 was ≥ 0.8 L and < 85% predicted, (FEV1/FVC) ratio was < 70%, and the FEV1 change after albuterol was < 10% of predicted. Patients with a clinical

Demographic and Baseline Characteristics

The demographic and baseline characteristics of the patients categorized into those completing and withdrawing and by treatment allocation are presented in Table 1. At the beginning of the study, there were no significant differences in gender, atopy, smoking status, or pack-years of tobacco exposure between any of these groups; however, patients who withdrew while receiving placebo were significantly more likely to have been receiving inhaled corticosteroids before entry into the trial. The

Discussion

This is the first prospective COPD study in which large numbers of patients failed to complete the intended follow-up period because of nonrandom withdrawal. Like other studies6789of inhaled corticosteroids, our trial did not show a significant effect on the primary outcome measure, rate of decline of FEV1; however, patients withdrawing from our study had a more rapid deterioration in lung function and health status assessed prior to withdrawal. Loss of these patients from the trial is likely

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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

    Drs. Calverley, Burge, and Jones, and Ms. Spencer were all independent investigators in the ISOLDE study from which this work is derived. This study was supported by a grant from GlaxoSmithKline. Ms. Willits is a statistician working for GlaxoSmithKline. The investigators had unrestricted access to the data and determined its analysis throughout the study.

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