Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study
Open Access
- 15 December 2010
- journal article
- Published by Wiley in The Clinical Respiratory Journal
- Vol. 5 (1), 44-49
- https://doi.org/10.1111/j.1752-699x.2010.00198.x
Abstract
Introduction: Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates. Objectives: We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial. Methods: We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal. Results: There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal. Conclusion: Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal. Please cite this paper as: Vestbo J, Anderson JA, Calverley PMA, Celli B, Ferguson GT, Jenkins C, Yates JC, Jones PW. Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study. Clin Respir J 2011; 5: 44–49.Keywords
This publication has 19 references indexed in Scilit:
- A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary DiseaseNew England Journal of Medicine, 2008
- Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological studyBMJ, 2008
- Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary DiseaseAnnals of Internal Medicine, 2007
- Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary DiseaseNew England Journal of Medicine, 2007
- Inhaled Corticosteroids in Chronic Obstructive Pulmonary DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2005
- The TORCH (TOwards a Revolution in COPD Health) survival study protocol: Fig. 1.—European Respiratory Journal, 2004
- Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary diseaseEuropean Respiratory Journal, 2003
- Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trialThe Lancet, 2003
- Effectiveness of Fluticasone Propionate and Salmeterol Combination Delivered via the Diskus Device in the Treatment of Chronic Obstructive Pulmonary DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2002
- Fundamentals of Clinical TrialsPublished by Springer Science and Business Media LLC ,1998