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Eur Respir J 2007, doi:10.1183/09031936.00104606
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ORIGINAL ARTICLE |
Premature discontinuation of patients: a potential bias in COPD clinical trials
1 Boehringer Ingelheim Corporation, Ingelheim, Germany
2 Kansas City VA Medical Center and University of Kansas Medical Center, Kansas City, MO
3 VA Medical Center, Omaha Division and University of Nebraska Medical Center, Omaha, NE
4 Southern Arizona VA Healthcare System and University of Arizona, Tucson, AZ
5 Minneapolis VA Medical Center and University of Minnesota, Minneapolis, MN, USA.
* To whom correspondence should be addressed. E-mail: skesten{at}rdg.boehringer-ingelheim.com.
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Abstract |
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Premature discontinuation from clinical trials may bias results against effective therapies.
We retrospectively reviewed mortality rates in a 6-month, randomized, placebo-controlled trial where tiotropium 18mcg daily was shown to decrease COPD exacerbations. Patients participated for 6 months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for 1)randomization–end trial(0–ET); 2)randomization–end trial drug(0–ED); 3)end trial drug–end trial(ED–ET).
Of 1, 829 patients (FEV1=1.04L [36%predicted], age=68years, 99%men), 16%tiotropium and 27%placebo patients prematurely stopped trial medication. Number of fatal events for entire cohort: all cause=62, cardiac=16, lower respiratory=16. IRs for fatal events/100 patient-years were higher in discontinued period [1.9(0–ED) vs. 23.0(ED–ET)(tiotropium) and 1.8 vs. 19.0 (placebo)]. Respective IRs for fatal cardiac events were 0.7 vs. 2.8 (tiotropium) and 0.5 vs. 6.2 (placebo); for fatal lower respiratory events were 0.7 vs. 2.8 (tiotropium) and 0.8 vs. 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in discontinued period: 1.4 vs. 0.5 for cardiac; 0.9 vs. 0.5 for lower respiratory.
Higher IRs of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs from failure to consider outcomes of patients who discontinue early from clinical trials.
Keywords: Adverse events, bronchodilators, chronic obstructive pulmonary disease, clinical trials, discontinuation, tiotropium
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