Tolerance to bronchodilating effects of beta-agonists has been described in asthma but is not well described in COPD. We evaluated spirometric response to bronchodilators over time in COPD trials in which albuterol was regularly administered to note whether tolerance was observed. A comparison to an anticholinergic was sought to identify class differences.
A retrospective review of an existing database comparing albuterol (ALB), ipratropium (IB) and the combination of both in patients with COPD was undertaken. Two double-blind, parallel-group, randomized, 85-day multicenter trials were previously conducted in patients with COPD. Two of the treatment arms included ALB or IB MDI at 2 actuations qid. Spirometry (pre and serially post study drug over 8 hours) was measured at day 1, 29, 57, and 85. Persistence of bronchodilation was determined using ANCOVA with day 1 baseline as the covariate. The response on each test day was compared to the first test day. Only patients with day 85 data were included.
Mean day 1 predrug FEV1 in the ALB group (n=277) and the IB group (n=283) were 0.92 and 0.91 L. On day 1, mean peak improvement, and normalized AUC0–4 and AUC0–8 hours responses for ALB were 0.33, 0.21, and 0.15 L. For IB, the respective responses were 0.27, 0.17, and 0.12 L. Percent differences in mean FEV1 (L) responses from day 1 to either day 29 or day 85 are shown in the tableDayDrugPeakAUC 0–4 hrsAUC 0–8 hrsDay 29ALB−12.1*−17.9*−21.5*IB7.412.18.3Day 85ALB−12.1*−16.7*−22.3*IB126.96.36.199*
p<0.01below. Results on day 57 were similar to results on day 29 and day 85.CONCLUSIONS: The observed reduction in bronchodilator response over time, after regular administration of inhaled beta-agonist is consistent with the development of tolerance. This effect was observed within four weeks of treatment initiation. However, this effect is not observed with regular use of inhaled anticholinergics.
Serial declines in postbronchodilator FEV1 in COPD patients receiving regular inhaled beta-agonists may represent tolerance rather than a clinical deterioration of status.
S.C. Campbell, Boehringer Ingelheim, Industry.