Samuel M. Brown, MD
Potential Financial Conflicts of Interest: None disclosed.
Brown S.; Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Chronic Obstructive Pulmonary Disease: Possible Confounding Effect of Treatment Withdrawal?. Ann Intern Med. 2007;147:882. doi: 10.7326/0003-4819-147-12-200712180-00011
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Published: Ann Intern Med. 2007;147(12):882.
TO THE EDITOR:
Aaron and colleagues (1) present a study designed to answer a clinically relevant question of whether 2 expensive therapies are better than 1 when the individual components seem to be separately efficacious. Unfortunately, the authors failed to consider the extent to which clinical practice had already outstripped the evidence. They report that as many as 63.6% of tiotropium–placebo recipients (the control group) were taking long-acting β-agonists (LABAs), usually in combination with inhaled corticosteroids at the time of enrollment, and perhaps 25% more were taking inhaled corticosteroids without LABAs. In an important sense, this control group thus represented a trial of the withdrawal of LABA and/or inhaled corticosteroid therapy, a question that is distinct from the proposed clinical question. The observed 40% dropout rate may well reflect this withdrawal of therapy, as clinical deterioration resulting from withdrawal of therapy has been demonstrated (2, 3), although spirometric variables did not clearly worsen in the study. We should not be surprised that sensitivity analysis seems to favor the addition of LABA or inhaled corticosteroids therapy to tiotropium, but the extent to which this is confounded by withdrawal effects is uncertain. Although not definitive, an analysis of patients not taking LABA or inhaled corticosteroids at baseline could perhaps give a sense of the sample size required to evaluate this effect. Although such a study would be expensive, the clinical question would probably be better answered by enrolling patients at the time that their treating physician would ordinarily consider additional therapy. Unfortunately, the current study was not designed to accurately assess the question posed.
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