Discontinuing LABAs in combination therapy may increase asthma symptoms, meta-analysis suggests

In asthma patients receiving combination therapy with an inhaled corticosteroid (ICS) and a long-acting β₂-agonist (LABA), discontinuing the latter after asthma is controlled may worsen outcomes, according to a new meta-analysis.

Because of safety concerns, the FDA issued a black-box warning in 2010 stating that LABAs should be withdrawn in patients receiving combination therapy with an ICS once their asthma is controlled. However, there is concern that this approach may increase risk for asthma-related complications. The authors of the current study performed a meta-analysis to answer the following clinical question: “Should LABAs be discontinued after achieving control of symptoms in patients with asthma who required combined therapy with an ICS and a LABA because of inadequate control of symptoms with an ICS alone?”

The meta-analysis included randomized, controlled trials published through August 2010 involving asthma patients age 15 and older who required combination therapy for symptom control. Included trials compared discontinuation of a LABA but continued therapy with an ICS after symptom control versus no change in treatment. The study results were published online Aug. 27 by Archives of Internal Medicine.

A total of 1,492 articles were evaluated, but only five trials met prespecified inclusion criteria. Compared with no change in treatment, discontinuing the LABA resulted in increased asthma-related impairment, as shown by worse scores on the Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire, fewer days without symptoms, and higher risk for study withdrawal because of lack of efficacy or asthma control (risk ratio, 3.27; 95% CI, 2.16 to 4.96). Patients whose LABA was discontinued also required a mean of 0.71 more puffs of a rescue bronchodilator per day (95% CI, 0.29 to 1.14). Not enough data were available to evaluate risk for exacerbations or death.

“In contrast to FDA recommendations of stepping off LABA therapy when asthma is controlled, our analysis supports the continued use of LABAs to maintain asthma control,” the authors wrote. They noted that their results are limited by the limitations of the included studies, including short duration, high withdrawal rates, and little information on treatment adherence, among others. They also noted that only a small number of existing trials address this subject, and stressed that more studies are needed to help settle the question of whether withdrawing LABAs is safe.

“Until those data are available, physicians need to evaluate the risk-benefit ratio of LABAs for their individual patients,” the authors wrote.

The authors of an accompanying invited commentary wrote that the study's findings “help to shift the burden of proof” in the debate about LABA safety. “The core issue of this debate is not how to completely eliminate risk but rather how to manage and value competing risks,” they wrote.

The commentary authors also noted that although a large FDA trial on the safety of LABAs is currently under way, physicians need to make decisions now about how to manage their patients. “We hope that this meta-analysis helps to lift some of the black clouds in the debate surrounding LABAs,” they wrote. “Physicians must now reevaluate the contents of the black box for LABAs, particularly in individuals whose asthma is well controlled with combination LABA and ICS therapy.”

In other news, a related industry-funded study in the Sept. 2 New England Journal of Medicine found that adding tiotropium to combination therapy with inhaled glucocorticoids and LABAs appeared to increase time to first exacerbation and promote modest, sustained bronchodilation in patients with poorly controlled asthma. The full text of the study is available online.