The US Food and Drug Administration and long-acting β2-agonists: The importance of striking the right balance between risks and benefits of therapy?
Authors: Robert F. Lemanske, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2010)

“When E. F. Hutton speaks, people listen” was the catchy and memorable slogan of this brokerage house decades ago and was based on the premise that E. F. Hutton knew what he was speaking about: “Well, my broker is E. F. Hutton, and he says….” The same can be said for the US Food and Drug Administration (FDA). The FDA must protect the public by initially and then prospectively evaluating and monitoring the safety of medications, thereby providing a trusted service to clinicians and patients alike. Because of their knowledge, experience, and access to information, clinicians and the public listen closely when the FDA speaks. On February 18, 2010, exercising new authority under the FDA Amendments Act of 2007, the FDA announced a set of updated recommendations that subsequently will require a class-labeling change on all United States–manufactured long-acting β2-agonists (LABAs).1Chowdhury B.A. Dal P.G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma.N Engl J Med. 2010; 362: 1169-1171Crossref PubMed Scopus (223) Google Scholar The precise language to be used in the labeling changes, particularly in the black box warning section, was subsequently released in the public domain (Table I) and is deserving of comment. For clinicians involved in the care of asthmatic patients, particularly those with more severe disease, and for those of us involved in the development, promotion, or both of evidence-based clinical practice guidelines, the new recommendations from the FDA have caused concern, as well as confusion. There is confusion because of the apparent lack of new data to warrant revising recommendations on this issue unless the FDA has new safety data information that has not yet appeared in the public domain. There is concern because aspects of the FDA's recommendations on long-term use of LABAs run counter to information in the National Asthma Education and Prevention Program's Expert Panel Report 3 (EPR-3).2NAEPP3 Science base committeeExpert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google ScholarTable INew recommendations for labeling changes for LABAs1. Use of a LABA alone without use of a long-term asthma control medication, such as an ICS, is contraindicated (absolutely advised against) in the treatment of asthma.2. LABAs should not be used in patients whose asthma is adequately controlled with low- or medium-dose ICSs.3. LABAs should only be used as additional therapy for patients with asthma who are currently taking but whose symptoms are not adequately controlled by a long-term asthma control medication, such as an ICS.4. Once asthma control is achieved and maintained, patients should be assessed at regular intervals, and step-down therapy should begin (eg, discontinue the LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an ICS.5. Pediatric and adolescent patients who require the addition of a LABA to an ICS should use a combination product containing both an ICS and a LABA to ensure adherence with both medications. Open table in a new tab The FDA's first recommendation (Table I) appropriately restates their position that LABAs should not be used alone for asthma treatment in patients of all ages without concomitant use of an asthma controller medication, such as an inhaled corticosteroid (ICS). This recommendation is based in large part on findings from the Salmeterol Multicenter Asthma Research Trial,3Nelson H.S. Weiss S.T. Bleecker E.R. Yancey S.W. Dorinsky P.M. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.Chest. 2006; 129: 15-26Crossref PubMed Scopus (1059) Google Scholar which raised concerns that the use of salmeterol alone has associated risks for severe asthma outcomes, including death. Although this study had serious design problems, the findings, especially in high-risk groups, were a red flag and were duly heeded. Other trials have supported the FDA's concern on “solo” use of salmeterol. Two such studies conducted by the National Heart, Lung, and Blood Institute–funded Asthma Clinical Research Network also demonstrated that monotherapy with salmeterol significantly increased rates of asthma exacerbations4Lazarus S.C. Boushey H.A. Fahy J.V. Chinchilli V.M. Lemanske Jr., R.F. Sorkness C.A. et al.Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.JAMA. 2001; 285: 2583-2593Crossref PubMed Scopus (353) Google Scholar and treatment failures.5Lemanske Jr., R.F. Sorkness C.A. Mauger E.A. Lazarus S.C. Boushey H.A. Fahy J.V. et al.Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.JAMA. 2001; 285: 2594-2603Crossref PubMed Scopus (262) Google Scholar Therefore no one disagrees with this recommendation, and the FDA's reminder is duly noted. Indeed, the use of the term contraindicated is clearly appropriate. In addition, it has not been established why the LABA treatment group experienced more serious adverse events in the Salmeterol Multicenter Asthma Research Trial: whether it is some inherent feature of the LABA used chronically or whether it is because more patients in the LABA treatment arm relied on LABAs as their only asthma treatment when they needed an anti-inflammatory medication as well. Several appropriately conducted meta-analyses appear to support the latter explanation: comparing patients taking LABAs and ICSs with patients taking ICSs alone has not shown an increased risk of adverse events (hospitalizations or deaths) in patients taking LABAs plus ICSs.6Jaeschke R. O'Byrne P.M. Mejza F. Nair P. Lesniak W. Brozek J. et al.The safety of long-acting β-agonists among patients with asthma using inhaled corticosteroids.Am J Respir Crit Care Med. 2008; 178: 1009-1016Crossref PubMed Scopus (99) Google Scholar, 7Weatherall M. Wijesinghe M. Perrin K. Harwood M. Beasley R. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy.Thorax. 2010; 65: 39-43Crossref PubMed Scopus (106) Google Scholar We also agree with the FDA's reminder that LABAs are not recommended as adjunct therapy in patients whose asthma is adequately controlled with low-dose ICSs. Indeed, this use of LABAs is neither necessary nor appropriate. The goal of treatment is to maintain control with the least amount of medication possible, and there is substantial evidence that most patients who have mild persistent asthma can maintain control of asthma on low-dose ICSs alone or, for some patients, leukotriene receptor antagonists. It is the proposed FDA points 2, 3, and 4 (Table I) that center on the long-term use of LABAs in patients with moderate and severe asthma that are the source of concern and confusion for us, our colleagues who conduct and review clinical research, and other clinicians. The FDA's recommendations for label change and use of LABAs are in clear contrast to the EPR-3 report, for which a systematic review of the scientific literature regarding the use of LABAs in patients with asthma was conducted and discussed at length.2NAEPP3 Science base committeeExpert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google Scholar The FDA's recommendation to use LABAs as additional therapy with “a long-term asthma control medication, point #3, such as an inhaled corticosteroid” is counter to EPR-3 because it implies that any other long-term controller medication would be appropriate to combine with LABAs. EPR-3 cites studies demonstrating that use of LABAs plus ICSs is superior to use of LABAs plus leukotriene modifiers and concludes that LABAs should be used as adjunctive therapy with ICSs.2NAEPP3 Science base committeeExpert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google Scholar Regarding proposed rule change point 4, the FDA's rule change implies that once adequate control is achieved after the addition of a LABA to ICS therapy, initial consideration should be given to stepping down therapy by discontinuing the LABA. EPR-3 and the international guidelines developed by the Global Initiative for Asthma8Global Initiative for Asthma, National Heart, Lung, and Blood Institute. Global strategy for asthma management and prevention. Available at: http://www.ginasthma.com. Accessed 2009.Google Scholar do recommend that consideration be given to stepping down therapy but only after asthma control is achieved and maintained for several months. Although the guidelines suggest that the possibility of stepping down therapy might be considered after 3 months of asthma control, there can be no precision to this time frame because asthma can vary over time in individual patients, especially in response to exposures to allergens or viral respiratory tract infections. We can hope, but not assume, that such individual consideration is accounted for in the FDA's rule to stop use of LABAs “if possible.” However, the recommendation to stop use of LABAs “once control is achieved” strongly conveys a precipitous withdrawal of therapy as soon as control is achieved and that the medication to withdraw should preferably be the LABA. This position is of considerable concern. As emphasized in EPR-3, there are few data available to effectively guide treatment step down and the decision of what controller medication to select for the reduction. The few studies available focus on reducing the dose of the ICS, given the documented potential for adverse effects that are of serious concern to patients and clinicians alike. In children, often the parents and clinician might try to reduce the ICS, particularly if medium to high doses are being used, to minimize effects on growth. In adults side effects, such as osteoporosis, cataracts, immune suppression, and skin changes, might be of concern and prompt the clinician to reduce the corticosteroid load. In other circumstances the advice might be simply to withdraw the last medication added, whatever that was. In any case, the selection of medicine to reduce is not clearly defined and, to date, has not been adequately studied. Many factors need to be considered in approaching a step down of therapy. The most important outcome to maintain is acceptable asthma control in both the domains of impairment (eg, current levels of symptoms, activity limitations, and lung function experienced by the patient) and risk (of future events, particularly exacerbations). When EPR-3 introduced the concept of these 2 distinct domains of control, the importance of monitoring exacerbations was highlighted as an integral part of asthma control. EPR-3 also noted that control of markers of impairment can be achieved at lower treatment steps than might be required to prevent future risks. Furthermore, different medications might affect the impairment and risk domains differently. Consequently, the approach for a step down in treatment is complex, particularly for patients with more severe disease. Our concerns are not meant to say that stepping down therapy should not be tried but do indicate a reservation that the issue of step-down therapy has not been sufficiently studied to warrant the FDA's recommendation that LABAs should be the first target in treatment reduction. Indeed, 3 separate studies found that stepping off LABAs after the establishment of acceptable asthma control resulted in the patient's asthma becoming less well controlled.9Bateman E.D. Jacques L. Goldfrad C. Atienza T. Mihaescu T. Duggan M. Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down.J Allergy Clin Immunol. 2006; 117: 563-570Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10Godard P. Greillier P. Pigearias B. Nachbaur G. Desfougeres J.L. Attali V. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study.Respir Med. 2008; 102: 1124-1131Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 11Koenig S.M. Ostrom N. Pearlman D. Waitkus-Edwards K. Yancey S. Prillaman B.A. et al.Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are “stepped-down.”.J Asthma. 2008; 45: 681-687Crossref PubMed Scopus (44) Google Scholar Although confirmatory studies are needed, these initial results do not support the FDA's proposed recommendation that the step down be withdrawal of LABAs. Other studies provide insight into the complexity of “when” and “in whom” step-down treatment should be considered. The Gaining Optimal Asthma Control study was designed to evaluate the effect of trying to achieve asthma control based on the Global Initiative for Asthma's goals for treatment and to compare combination treatment (ie, ICSs and LABAs) versus ICSs alone.12Bateman E.D. Boushey H.A. Bousquet J. Busse W.W. Clark T.J. Pauwels R.A. et al.Can guideline-defined asthma control be achieved?: The gaining optimal asthma control study.Am J Respir Crit Care Med. 2004; 170: 836-844Crossref PubMed Scopus (1505) Google Scholar A number of key observations arose from this large trial that might speak directly to LABA use and the complexity of step-down approaches, including the timing for this change. First, particularly in patients with more severe disease, combination treatment achieved asthma control in a greater portion of patients than ICSs alone. This observation has now been confirmed in a number of other studies.12Bateman E.D. Boushey H.A. Bousquet J. Busse W.W. Clark T.J. Pauwels R.A. et al.Can guideline-defined asthma control be achieved?: The gaining optimal asthma control study.Am J Respir Crit Care Med. 2004; 170: 836-844Crossref PubMed Scopus (1505) Google Scholar, 13Bateman E. Nelson H. Bousquet J. Kral K. Sutton L. Ortega H. et al.Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events.Ann Intern Med. 2008; 149: 33-42Crossref PubMed Scopus (107) Google Scholar, 14Nelson H. Bonuccelli C. Radner F. Ottosson A. Carroll K.J. Andersson T.L. et al.Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials.J Allergy Clin Immunol. 2010; 125: 390-396Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Second, a greater level of asthma control was achieved with a lower dose of ICS when combination treatment was used, and this differential was seen in both the domains of impairment and future risk (ie, exacerbations). Finally, the percentage of patients in the Gaining Optimal Asthma Control study who achieved “well-controlled” asthma did not plateau over the 52 weeks of treatment. These findings suggest that the time required to achieve a desired level of asthma control varies from patient to patient. Therefore decisions on the timing of a treatment step down will need to be carefully considered and made on an individual basis. In sum, choosing the best step down for patients is complex, and physicians must weigh the advantages and disadvantages of potential effects of LABAs or continued higher doses of ICSs against the individual needs and circumstances of the patient; step-down approaches have not been sufficiently studied; some initial studies suggest that either precipitous withdrawal or withdrawal of LABAs might put patients at increased risk of losing asthma control; and there is no evidence of increased risk of serious adverse events when LABAs are used in conjunction with therapeutic doses of ICSs.6Jaeschke R. O'Byrne P.M. Mejza F. Nair P. Lesniak W. Brozek J. et al.The safety of long-acting β-agonists among patients with asthma using inhaled corticosteroids.Am J Respir Crit Care Med. 2008; 178: 1009-1016Crossref PubMed Scopus (99) Google Scholar, 7Weatherall M. Wijesinghe M. Perrin K. Harwood M. Beasley R. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy.Thorax. 2010; 65: 39-43Crossref PubMed Scopus (106) Google Scholar In an era of promoting evidence-based medicine, it is puzzling why the FDA would recommend a clinical practice for step-down therapy that lacks supporting evidence. Similar concerns are raised regarding that part of the FDA's proposed rule change 2 that recommends “… against LABA use in patients whose asthma is adequately controlled with a low-or medium-dose ICS” (Table I, italics are ours). The issue of step-up therapy in asthma care is also complex, but there are considerable data to guide the choice when asthma is not adequately controlled with low-dose ICSs. EPR-3 made the choices of either increasing the dose of an ICS or adding a LABA as equal options for preferred step-up therapy. This was a result of weighing the considerable advantages of combination LABA and low-dose ICS therapy and the risk, albeit uncommon, of serious adverse events with LABAs. As noted above, there is a large body of data demonstrating the superior effectiveness of adding LABAs to low-dose ICSs rather than increasing the dose of ICSs in adults who have asthma. Studies also indicate a dose-response curve for ICSs in which the benefits might plateau for some patients in even low to moderate doses, yet the risks of toxicity continue to increase with increasing doses.15Martin R.J. Szefler S.J. Chinchilli V.M. Kraft M. Dolovich M. Boushey H.A. et al.Systemic effect comparisons of six inhaled corticosteroid preparations.Am J Respir Crit Care Med. 2002; 165: 1377-1383Crossref PubMed Scopus (233) Google Scholar, 16Szefler S.J. Martin R.J. King T.S. Boushey H.A. Cherniack R.M. Chichilli V.M. et al.Significant variability in response to inhaled corticosteroids for persistent asthma.J Allergy Clin Immunol. 2002; 109: 410-418Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar For the same reasons, it might be advisable to reduce the ICS dose in a step down, and patients and clinicians might need to avoid increasing the dose when a low dose is not sufficient to control asthma. Furthermore, the FDA's approach implies that a patient must try and fail medium-dose ICS therapy before starting a LABA. In patients who present with more severe disease, starting with obviously suboptimal therapy is inappropriate. The current black box warning accounts for this group of patients; this should not be deleted in the proposed rule change. One additional concern raised by the FDA, particularly in their meeting in December 2008, was the efficacy and safety of LABAs in children. Ironically, at the time, the National Heart, Lung, and Blood Institute–funded Childhood Asthma Research and Education Network was conducting a trial in children that had the potential of addressing these concerns. This trial, given the acronym BADGER (Best Add-on Therapy Giving Effective Responses), was designed to evaluate what choice of step-up therapy was the best in children whose symptoms were not acceptably controlled with low doses of ICS (step 2 care). BADGER has now been completed, and the results were recently published.17Lemanske Jr., R.F. Mauger D.T. Sorkness C.A. Jackson D.J. Boehmer S.J. Martinez F.D. et al.Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids.N Engl J Med. 2010; 362: 975-985Crossref PubMed Scopus (374) Google Scholar Children (6-17 years of age) who had uncontrolled asthma while receiving 100 μg of fluticasone twice daily each received 3 blinded step-up therapies in random order for 16 weeks: 250 μg of fluticasone twice daily (ICS step-up), 100 μg of fluticasone plus 50 μg of a LABA twice daily (LABA step-up), or 100 μg of fluticasone twice daily plus 5 or 10 mg of a leukotriene receptor antagonist daily (leukotriene receptor antagonist step-up). BADGER used a triple-crossover design and a composite of 3 outcomes (exacerbations requiring oral corticosteroids, asthma control days, and FEV1) to determine whether the frequency of a differential response to the step-up regimens was greater than 25%. A striking study finding was that a differential response occurred in more than 95% of the children. The response to LABA step-up therapy was more than 1.5 times as likely to produce the best overall response compared with responses to either leukotriene receptor antagonist or ICS step-up therapy. BADGER provided novel evidence for the efficacy of LABA plus ICS combination therapy in children by using an outcome that included components of both the impairment and risk domains of asthma control. Although BADGER was neither designed nor powered to evaluate long-term safety, it is noteworthy that the numbers of prednisone-requiring exacerbations were numerically the smallest when the children were receiving LABA step-up therapy. Finally, recommendation 5 is inconsistent with concerns regarding overall LABA-associated risk because it might apply to all age groups. There are no data to indicate that potential risk is disproportionately greater in the pediatric population. As such, why recommend the use of combination products only in children and adolescents and not in adults? Adherence to treatment regimens is a potential complicating issue for all asthmatic patients, and there is no reason to believe that 2 separate inhalers to deliver an ICS and a LABA as opposed to a single combination device will be used more consistently in adults than it would be in children and adolescents. Asthma is clearly a complex disease with variable phenotypes, variation in individual response to therapy, and variability within patients over time and varying exposures. Evidence-based guidelines provide general approaches to therapy that are intended to assist, not replace, the clinical decision making that must account for individual patients' needs and circumstances. Unnecessarily limiting treatment options with such across-the-board practice requirements as the FDA is considering would pose undue restrictions to individualizing and optimizing patient care. We understand the concerns raised by a number of persons regarding the potential for increased risk of asthma morbidity and mortality with LABAs.18Kramer J.M. Balancing the benefits and risks of inhaled long-acting beta-agonists—the influence of values.N Engl J Med. 2009; 360: 1592-1595Crossref PubMed Scopus (97) Google Scholar However, these events are obviously rare and do not appear to be attributable to the use of LABAs with ICSs. More emphasis needs to be placed on the benefits that this class of drugs provides for many of our patients. Treatment of any disease requires an appropriate balancing of risk/benefit ratios for all the medication options available. We believe that the FDA's proposed changes for labeling and use of LABAs take the concern about a rare risk too far in one direction without any new supporting evidence and that the pendulum needs to start moving in the opposite direction (ie, with appropriate recognition of benefits and acknowledgment of the complexity of decision making among different treatment options in asthmatic patients) so that clinicians are not inappropriately limited in their ability to provide adequate asthma control to both their adult and pediatric patients. What will be the outcomes of the recent recommendations? At present, the consequences are not clear, but they could have a tremendous effect on care for patients, particularly those with more severe disease in whom combination therapy has, for many, provided control. Indeed, these recommendations have the potential of restricting pharmacy and reimbursement practices that could alter the landscape of coverage for asthma medications. The FDA's position that LABAs should not be used as monotherapy or for patients whose asthma can be controlled with low-dose ICSs or leukotriene modifiers is shared by evidence-based guidelines. So is the statement that the FDA concluded, after comprehensive review, that “the benefits of LABAs continue to outweigh the risks when the drugs are used appropriately.”1Chowdhury B.A. Dal P.G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma.N Engl J Med. 2010; 362: 1169-1171Crossref PubMed Scopus (223) Google Scholar The divergence of the FDA's proposed label changes from evidence-based guidelines is in the treatment of patients with more severe disease. A substantial body of scientific literature documents that the addition of a LABA leads to improved control and improved quality of life in a large portion of these patients. Epidemiologic data show a decrease in asthma-related deaths in the United States at the same time use of combination therapy (ie, LABAs and ICSs) has increased.19DiSantostefano R.L. Davis K.J. Yancey S. Crim C. Ecologic analysis of asthma-related events and dispensing of inhaled corticosteroid- and salmeterol-containing products.Ann Allergy Asthma Immunol. 2008; 100: 558-565Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In this regard we believe that current data are not sufficient or convincing to mitigate against the long-term use of LABAs as adjunctive therapy. Such a restriction of LABA use could set back effective asthma care and its sustained control in the United States. We doubt that this is a desired outcome. An open discussion with transparent examination of data will be critical to an appropriate conclusion and will provide for the safest and most effective asthma care in the United States, as in the rest of the world. Moreover, re-examination of treatment use can also ensure that combination therapy is prescribed to those who need it and will most benefit from this approach. This should be the goal of all involved in the care of asthmatic patients. Like the ad for E. F. Hutton, people have and will continue to listen when the FDA speaks. We, however, are concerned that the FDA's position on LABA use does not appear fully evidence based. For clinicians to listen and accept the FDA's recommendation on LABAs, substantial and significant evidence is an essential component of this discussion.