To the Editor: In her Perspective article, Kramer (April 16issue)1 succinctly summarizes the decisions of the Food andDrug Administration (FDA) regarding the continued availabilityof single-agent long-acting beta-agonist (LABA) inhalers foruse in patients with asthma. She further clarifies that thesedrugs would remain on the market for patients with chronic obstructivepulmonary disease (COPD), even if the asthma indication wereremoved.
As a practicing pulmonary physician, I have a different perspectiveto offer for debate. A not insignificant number of patientsthat my colleagues and I see do not correctly differentiatebetween asthma and COPD, and therefore, it is quite possiblethat single-agent LABAs would end up being used in patientswith asthma. Also, separate single-agent LABAs and corticosteroidprescriptions can often be used separately in real life, eitherbecause of a misunderstanding or because the inhaled corticosteroidruns out before the inhaled single-agent LABA does. Given theready availability of two combined LABA–corticosteroidagents, the absence of evidence that single-agent LABAs aresuperior to single-agent corticosteroid inhalers in patientswith asthma, and the well-defined risk of death from single-agentLABAs among patients with asthma, I submit that single-agentLABAs should be removed from the market as a public safety measure.
Arun Agarwal, M.D. Putnam Hospital Center Carmel, NY 10512 arun.agarwal.md{at}gmail.com
Dr. Agarwal reports receiving lecture fees from GlaxoSmithKlineand Boehringer Ingelheim. No other potential conflict of interestrelevant to this letter was reported.
References
Kramer JM. Balancing the benefits and risks of inhaled long-acting beta-agonists -- the influence of values. N Engl J Med 2009;360:1592-1595. [Free Full Text]
To the Editor: We respectfully disagree with the implicationin the editorial by Drazen and O'Byrne1 on the risks of LABAsin achieving asthma control that a large study on the safetyof LABAs has not been performed because of financial considerations.GlaxoSmithKline has rigorously explored the conduct of a studyof mortality associated with LABAs in patients with asthma.However, such a study is not feasible. Because of the low rateof asthma-related deaths, a study designed to rule out a 20%increase in mortality (relative risk, 1.2) would require approximately700,000 subjects per group. If an appropriately powered mortalitystudy had been feasible, we would have done it.
Recognizing that limitation, since the Salmeterol MulticenterAsthma Research Trial (SMART)2 was completed, GlaxoSmithKlinehas sponsored important research on LABA safety, including ayear-long study of asthma exacerbations in blacks,3 the largestprospective study to date examining asthma genotype and responseto salmeterol,4 and epidemiologic studies of more than 80,000patients receiving salmeterol. None of these varied approachesshowed an increased risk of asthma-related death.5 At GlaxoSmithKline,patient safety is our highest priority. We continue to conductstudies with LABAs that are scientifically sound and feasibleand that can provide information that has clinical and statisticalsignificance.
Katharine Knobil, M.D. GlaxoSmithKline Research Triangle Park, NC 27709
References
Drazen JM, O'Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med 2009;360:1671-1672. [Free Full Text]
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26. [Erratum, Chest 2006;129:1393.] [CrossRef][Web of Science][Medline]
Bailey W, Castro M, Matz J, et al. Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone. Curr Med Res Opin 2008;24:1669-1682. [CrossRef][Web of Science][Medline]
Bleecker ER, Nelson H, Corren J, et al. ARG16Gly polymorphism of the β2-adrenergic receptor gene does not modulate clinical response to salmeterol in subjects with asthma. J Allergy Clin Immunol 2008;121:Suppl:S143-S143.
The author replies: In response to Agarwal's letter: it is importantto clarify that the December 2008 joint meeting of the Pulmonary–AllergyDrugs Advisory Committee, the Drug Safety and Risk ManagementAdvisory Committee, and the Pediatric Advisory Committee wasconvened to consider the safety of LABAs for the asthma indicationonly, since that is where a safety signal had been detected.No concerns about the safety of LABAs in patients with COPDwere raised. Briefing materials prepared by the FDA stated thatif the asthma indication for single-agent LABAs is withdrawn,"the actual products will remain in the market [because of]the COPD indication these products carry."1 Thus, no scenariowas described in which single-agent LABAs could be removed fromthe market completely.
It is also important to note that the "decisions" summarizedin my Perspective article were not decisions of the FDA. Theywere recommendations by the advisory committee for FDA consideration.The FDA's opinions referred to in the briefing materials forthe December 2008 meeting were preliminary interpretations.To date, the FDA has not yet publicly issued any decisions basedon the advice received at the December 2008 meeting.
Judith M. Kramer, M.D. Duke University Medical Center Durham, NC 27715
References
Long-acting beta-agonists and adverse asthma events meta-analysis: statistical briefing package for a joint meeting of the Pulmonary–Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee, and Pediatric Advisory Committee, December 10–11, 2008. (Accessed June 18, 2009, at http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-01-FDA.pdf.)
The editorialists reply: Knobil is correct that a study to provethe absence of a small increased risk of death among patientswith asthma with the use of inhaled corticosteroid–LABAcombinations would need to be large. However, she misses thepoint. The persisting concern is that the use of LABAs causesan increased mortality, which may be as high as 1 death in 700patient-years of treatment; exclusion of a level of risk ofthis magnitude should be possible in a manageable study. Weremain convinced that a study of similar scope to that of theoriginal SMART study, but executed with a better design andcomparing inhaled corticosteroid–LABA combinations withinhaled corticosteroids alone, would provide the data neededto establish the range of risk of death from asthma that existswith these combinations. Sometimes, in an effort to achieveperfection, we do nothing at all; we believe that this is unacceptable.
In our editorial, we said that the cost of executing these studieswould be "about 2 weeks of gross profits." This should haveread "about 2 weeks of gross sales."
Paul M. O'Byrne, M.B. McMaster University Hamilton, ON L8N 3Z5, Canada
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