Asthma Worsens with Step-Off Therapy
From Medpage Today:
Discontinuation of long-acting beta-agonist therapy in patients whose asthma is well controlled is associated with a worsening of symptom control and quality of life, a systematic review suggested.
Withdrawing a long-acting beta-agonist resulted in a 0.24 point (95% CI 0.13 to 0.35) rise in the seven-point Asthma Control Questionnaire score, according to Jan L. Brozek, MD, PhD, of McMaster University in Hamilton, Ontario, and colleagues.
In addition, the "step-off" approach was associated with a lowering of 0.32 points (95% CI 0.14 to 0.51) on the Asthma Quality of Life Questionnaire, the researchers reported online in Archives of Internal Medicine.
Recommendations from the National Asthma Education and Prevention Program have favored the consideration of step-down therapy for asthma in patients whose disease has been under control "for several months."
And although most research has focused on lowering the doses of inhaled steroids to avoid potential adverse effects, during the past two decades concerns have been raised about potentially severe adverse outcomes associated with treatment with long-acting beta-agonists.
In 2010 the FDA determined that these drugs should carry a black box warning and advised that discontinuation of the drugs should begin once patients gain and maintain adequate asthma control.
But some experts disagreed, arguing that abrupt withdrawal of this component of treatment could result in a loss of symptom control.
To address this controversy, Brozek and colleagues conducted a systematic review of the literature, identifying only five randomized trials that compared step-off therapy with continued maintenance with long-acting beta-agonists in conjunction with inhaled corticosteroids.
Four of the studies had been published in the peer-reviewed literature; the fifth had been presented as an abstract at a conference.
In none of the studies was a benefit seen for withdrawal of the beta-agonist, according to the authors of the review.
Rather, step-off therapy was associated with a difference of 9.15% (95% CI 1.62 to 16.69) in the number of symptom-free days and a greater likelihood of study withdrawal because of symptom persistence (RR 3.27, 95% CI 2.16 to 4.96).
Patients who stopped the long-acting beta-agonist also required 0.71 (95% CI 0.29 to 1.14) more doses of a rescue bronchodilator per day and had a nonsignificant increase in use of oral corticosteroids (RR 1.68, 95% CI 0.84 to 3.38).
A trend also was seen for a lower proportion of nights when patients were awakened, with a mean difference of 1.47% (95% CI -3.18 to 0.23).
A striking finding of this analysis was the few number of studies that had attempted to address the question of whether the long acting bronchodilators should or should not be continued, according to the authors.
They noted that, although the available evidence suggested that better symptom control was maintained with continuation of the bronchodilator, "there is uncertainty about estimated effects because of the risk of bias in the included studies, imprecision of the estimates, and indirectness of the evidence."
Furthermore, they faulted the included studies for brief duration, failure to consider adherence to treatment, and large numbers of patients who withdrew.
There also may have been publication bias, the researchers noted.
The rationale behind the FDA's decision to require the black box warning originated with two studies in which there was an increase in mortality among patients receiving salmeterol.
However, Brozek and colleagues criticized those studies, noting that in one, short-acting beta-agonists may have been overused and inhaled corticosteroids underused.
The other study had "many flaws," including follow-up that included only a single physician visit.
"In contrast to FDA recommendations of stepping off [long-acting beta-agonist] therapy when asthma is controlled, our analysis supports the continued use of [these agents] to maintain asthma control," the researchers stated.
The FDA has requested that manufacturers of long-acting bronchodilators conduct further large safety studies of their products, but the results are unlikely to be available for several more years.
In an invited commentary published with the systematic review, Chee M. Chan, MD, and Andrew F. Schorr, MD, of Washington Hospital Center in Washington, D.C., described the history of long-acting beta-agonists as "a case study for precisely how not to make public policy for complicated diseases."
They argued that the goal of management for a disease such as asthma should not be total elimination of risk, but a balancing of multiple risks.
Furthermore, they called on the FDA to reconsider the black box warning for these agents based on the findings of Brozek and colleagues, particularly in light of the possibility that the mandated safety trial may not even provide conclusive evidence 5 years in the future.
"We hope that this meta-analysis helps to lift some of the black clouds in the debate surrounding [long-acting beta-agonists]," wrote Chan and Shorr.
They further argued that, in the meantime, clinicians themselves "must now reevaluate the contents of the black box," particularly for patients whose disease is currently under control with a regimen of inhaled corticosteroids and long-acting beta-agonists.