Withdrawing long-acting beta-agonist therapy worsened refractory asthma that had been controlled with a combination of LABAs and inhaled corticosteroids, according to a meta-analysis published online Aug. 27 in Archives of Internal Medicine.
The findings run counter to the Food and Drug Administration’s black-box warning that patients should reduce use of LABAs such as salmeterol or formoterol once they achieve asthma control.
Stopping LABAs after achieving asthma control was associated with reduced asthma control, increased symptom frequency, increased use of rescue bronchodilators, decreased asthma-related quality of life, and similar rates of adverse events and serious adverse events, compared with continuing LABAs in combination therapy, according to the meta-analysis’ authors, who focused on the only five randomized, controlled clinical trials (RCTs) to examine this issue.
"Thus, in contrast to FDA recommendations of stepping off LABA therapy [once] asthma is controlled, our analysis supports the continued use of LABAs to maintain asthma control," said Dr. Jan L. Brozek of the department of clinical epidemiology and biostatistics and medicine, McMaster University, Hamilton, Ont., and his associates (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.3250]).
However, they noted that this conclusion is based on the pooled results of only five studies, all of which had substantial limitations.
"An interesting and important finding is the paucity of studies evaluating this issue," Dr. Brozek and his colleagues said.
The researchers undertook the meta-analysis because of the ongoing controversy over whether to withdraw or continue LABA therapy once asthma is adequately controlled, as the FDA recommends in a black-box warning for the drugs.
The five RCTs included in the meta-analysis were all sponsored by the manufacturers of the study drugs. Four were published in peer-reviewed journals, and one was a conference abstract. All the RCTs involved adolescents or adults with at least a 6-month history of mild to moderate asthma, but four of the five trials did not specify whether combined therapy with inhaled corticosteroids and LABAs had been required to control symptoms at enrollment.
Compared with continued combination therapy, LABA step-down therapy was associated with an average 0.24-point drop in Asthma Quality of Life Questionnaire scores for control of asthma, 9.2% fewer symptom-free days, and an average of 0.71 more puffs/day from a rescue bronchodilator.
Despite the meta-analysis results, the investigators cautioned that the duration of well-controlled asthma on combination therapy was shorter than the 3 months that are recommended to adequately judge the treatment effect.
In addition, the studies included only 1,342 patients: 660 who gradually withdrew from LABA therapy, and 682 who continued on it.
None of the RCTs reported emergency department visits, unscheduled office visits for asthma, days missed from work or school, costs, or complications associated with the corticosteroids, the authors said. All were of short duration, none provided information on treatment adherence, and some had high dropout rates.
Nevertheless, "our findings likely represent the current best evidence about stepping off LABA therapy in patients with asthma," the investigators asserted.
The pooled analysis showed "no statistically significant results for any of the reported asthma outcomes of interest showing a benefit from [the] LABA step-off approach, compared with continued use of the same dose of inhaled corticosteroids and LABA," Dr. Brozek and his associates said.
Discontinuing LABA therapy significantly reduced asthma control and asthma-related quality of life. It increased symptom frequency and the use of rescue bronchodilators, and raised the risk that subjects would withdraw from the studies because of lack of efficacy or loss of asthma control. It also increased the need for oral corticosteroids but not to a statistically significant degree.
"Because of the paucity of data, we were unable to assess the critical issue of ... whether LABA use had any effect on catastrophic asthma events," they added.
"There is clearly a need for more properly designed and executed randomized trials aimed at rectifying differences between asthma guideline recommendations and FDA safety concerns," the investigators concluded.
The meta-analysis was supported by McMaster University, the American Academy of Allergy, Asthma, and Immunology, and the American Thoracic Society. The researchers reported ties to Abbott, Asthmatix, Astra-Zeneca, Boehringer Ingelheim, Eumedics, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, and Sanofi-Aventis.