When is it legitimate to exclude randomised patients from the analysis of data in clinical trials? Basing their analysis on the desirability of minimising bias and random error, the authors consider the circumstances when it may be possible to exclude patients, even in an intention to treat trial
Objective To examine the reporting and success of double blinding in a sample of randomised, placebo controlled trials from leading general medicine and psychiatry journals.
Background: Clinical trials measure exacerbations of chronic obstructive pulmonary disease (COPD) inconsistently. A study was undertaken to determine if different methods for ascertaining and analysing COPD exacerbations lead to biased estimates of treatment effects. Methods: Information on the methods used to count, analyse and report COPD exacerbation rates was abstracted from clinical trials of long-acting bronchodilators or long-acting bronchodilator/inhaled steroid combination products published between 2000 and 2006. Data from the Canadian Optimal Therapy of COPD Trial was used to illustrate how different analytical approaches can affect the estimate of exacerbation rates and their confidence intervals. Results: 22 trials (17 156 patients) met the inclusion criteria and were reviewed. None of the trials adjudicated exacerbations or determined independence of events. 14/22 studies (64%) introduced selection bias by not analysing outcome data for subjects who prematurely stopped study medications. Only 31% of trials used timeweighted analyses to calculate the mean number of exacerbations/patient-year and only 15% accounted for between-subject variation. In the Canadian Optimal Therapy of COPD Trial the rate ratio for exacerbations/ patient-year was 0.85 when all data were included in a time-weighted analysis, but was overestimated as 0.79 when data for those who prematurely stopped study medications were excluded and was further overestimated as 0.46 when a time-weighted analysis was not conducted; p values ranged from 0.03 to 0.24 depending on how exacerbations were determined and analysed. Conclusions: Clinical trials have used widely different methods to define and analyse COPD exacerbations and this can lead to biased estimates of treatment effects. Future trials should strive to include blinded adjudication and assessment of the independence of exacerbation events, and trials should report time-weighted intentionto-treat analyses with adjustments for between-subject variation in COPD exacerbations.Patients with chronic obstructive pulmonary disease (COPD) exhibit slow progressive deterioration in airflow and respiratory status that can be punctuated by acute episodes of clinical deterioration known as COPD exacerbations. Acute exacerbations of COPD are characterised clinically by acute or subacute worsening of respiratory symptoms and may include abrupt increases in cough, sputum production, sputum purulence and breathlessness.
1COPD exacerbations have an important negative impact on health-related quality of life 2-4 and generate considerable economic costs. 5 The prevention of exacerbations is now recognised as a primary goal of COPD therapy. 6 Earlier trials of COPD therapy considered lung function as the primary outcome and analysed exacerbations as secondary outcomes.7 8 More recently, many clinical trials of maintenance medications for COPD have evaluated COPD exacerbation rates as a primary outcome. Unfortunately, clinical trials have not been consistent in how they count, record or anal...
The present randomized, placebo-controlled trial offers a unique opportunity to answer the question, what is the best combination of inhaled medications to use for COPD patients? It is hoped that optimal use of inhaled medications will improve patient health and quality of life, reduce patient respiratory exacerbations, and ultimately, reduce health care resource use.
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