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Invited Commentary
Oct 8, 2012

Black Clouds and Black BoxesComment on “Long-Acting β2-Agonist Step-off in Patients With Controlled Asthma”

Author Affiliations

Author Affiliations: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington Hospital Center, Washington, DC.

Arch Intern Med. 2012;172(18):1375-1376. doi:10.1001/archinternmed.2012.3650

For more than a decade, black clouds have surrounded the safety of long-acting β2-agonists (LABAs) for asthma. Several studies1,2 indicate that these agents are associated with an increased risk for asthma-related morbidity and mortality. Although these trials were flawed and the absolute increase in mortality risk with LABAs was small, it persisted in multiple analyses. Thus, there is consensus that these agents have no role as monotherapy in asthma.3 Qualms remain, however, about their use in combination with inhaled corticosteroids (ICSs).4 Despite performing their own meta-analysis illustrating that coadministration of ICSs and LABAs essentially eliminated the enhanced risk related to LABA exposure, the US Food and Drug Administration (FDA) instituted a black box warning on LABAs.5 The warning states that LABAs, when given with ICSs, should be discontinued as soon as asthma control is achieved. The authors of the third Expert Panel Report of the National Asthma Education and Prevention Program guidelines3 interpreted the data differently and did not endorse such an approach. With more than 25 million Americans having asthma, clinicians are left facing the quandary of how to manage these patients, many of whom receive suboptimal control with ICSs alone.6

Brozek et al7 report a meta-analysis examining the implications of discontinuing LABAs in patients whose asthma is controlled with LABA and ICS combinations. Most strikingly, they found that few trials have addressed this important topic. Furthermore, each trial evaluated had substantial limitations, particularly with respect to duration of follow-up. The pooled data reveal that withdrawal of LABAs results in loss of stability in multiple domains that capture different aspects of asthma control. Most worrisome was the trend toward a greater need for rescue systemic corticosteroids among patients in whom LABAs were stopped. Their observations help to shift the burden of proof in this debate.

The history of LABAs serves as a case study for precisely how not to make public policy for complicated diseases. The core issue of this debate is not how to completely eliminate risk but rather how to manage and value competing risks. In general, regulatory agencies are incentivized to be cautious. Bureaucratic and political pressures reinforce each other to discourage a true balancing of issues that arise during the drug development and approval process. In the case of LABAs, the FDA played a trump card by placing its warning in a black box, which is rarely revised to less strict forms of labeling concerns. In this instance, the failure to consider the patient-level implications of uniformly discontinuing LABAs in persons whose asthma is controlled by LABA and ICS combinations is worrisome. In the clinic, physicians do not have the freedom to discount that changing a medication regimen might seriously worsen asthma control and the sequelae associated with poor control.

The essential question remains: will regulatory authorities ever consider reevaluating their recommendations as the evidence evolves? Medicine is not a static field, as the results of Brozek and colleagues7 illustrate. The current FDA-mandated megatrial to evaluate the safety of LABAs may not even be able to conclusively evaluate the hypothesis it was designed to address.4 In light of the fact that such a trial will take years to complete, coupled with the reality that clinicians must make decisions about if and how to use LABAs now, will the FDA seriously examine the results of the analysis performed by Brozek et al or will it merely criticize the analysis given several of the flaws noted in the study? We hope that this meta-analysis helps to lift some of the black clouds in the debate surrounding LABAs. Similarly, 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.

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Article Information

Correspondence: Dr Shorr, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Room 2a-68D, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010 (andrew.shorr@gmail.com).

Published Online: August 27, 2012. doi:10.1001/archinternmed.2012.3650

Financial Disclosure: None reported.

References
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National Asthma Education and Prevention Program.  Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.  J Allergy Clin Immunol. 2007;120(5):(suppl)  S94-S138PubMedArticle
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Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma.  N Engl J Med. 2011;364(26):2473-2475PubMedArticle
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Levenson M. Long-acting beta-agonists and adverse asthma events meta-analysis. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-01-FDA.pdf. Published November 12, 2008. Accessed June 1, 2012
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Akinbami LJ, Moorman JE, Bailey C,  et al.  Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010.  NCHS Data Brief. 2012;24(94):1-8PubMed
7.
Brozek JL, Kraft M, Krishnan JA,  et al.  Long-acting β2-agonist step-off in patients with controlled asthma: systematic review with meta-analysis [published online August 27, 2012].  Arch Intern Med. 2012;172(18):1365-1375
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