To the Editor: The study by the American Lung Association AsthmaClinical Research Centers (May 17 issue)1 showed that for patientswith mild persistent asthma who were receiving twice-daily fluticasone,switching to treatment with once-daily fluticasone plus salmeterolwas as effective as continuing treatment with twice-daily fluticasone.Asthma control often worsens over time because compliance witha twice-daily medication regimen decreases, which is an impetusfor once-daily treatment. Since all participants used inhalerstwice daily in this study, the findings do not allow one todetermine whether once-daily treatment improves compliance andleads to better control. To determine whether once-daily treatmentwith fluticasone and salmeterol leads to better compliance andimproved asthma control, we also need to undertake randomizedstudies that are unblinded and in which participants are monitoredless closely, even if this approach is not as objective as thatof a double-blind, placebo-controlled trial.
Peter N. Black, M.B., Ch.B. University of Auckland Auckland 1023, New Zealand pn.black{at}auckland.ac.nz
Dr. Black reports receiving payment from GlaxoSmithKline forundertaking contract research. No other potential conflict ofinterest relevant to this letter was reported.
References
The American Lung Association Asthma Clinical Research Centers. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027-2039. [Free Full Text]
To the Editor: In the study by the American Lung AssociationAsthma Clinical Research Centers, the patients had asthma thatwas well controlled with twice-daily inhaled fluticasone. Duringthe run-in period, patients were treated with fluticasone twicedaily; at the onset of randomized treatment, the dose of inhaledcorticosteroids was sharply decreased in two of the three groups.This approach did not take into account the clinical deteriorationthat can occur after cessation or reduction of inhaled corticosteroidsin patients with asthma, as reported in previous investigations,1,2which could have led to the remarkably higher cumulative percentageof patients with treatment failure during the first 4 weeksin the montelukast group. In future studies, there should bea dose-tapering interval between the run-in period and the double-blindtreatment period.
Rui Chen, M.D. Union Hospital Wuhan 430061, China unioncr{at}gmail.com
References
Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-705. [Free Full Text]
Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003;326:1115-1120. [Free Full Text]
To the Editor: The study by the American Lung Association AsthmaClinical Research Centers did not include an important treatmentgroup. Although the fluticasone dose was reduced in the groupfor which treatment with salmeterol was added, the additionof salmeterol cannot be considered part of a step-down approach.Special attention should be paid to the package warning —mandated by the Food and Drug Administration on the basis ofstudy findings1,2 — that long-acting β2-agonistsshould be used only in patients whose asthma is inadequatelycontrolled with low-dose or medium-dose inhaled corticosteroids.3To evaluate a true step-down approach, the study should haveincluded a treatment group that received a low dose of a once-dailyinhaled corticosteroid.
Myron J. Zitt, M.D. Queens–Long Island Medical Group North Babylon, NY 11703 myron.zitt{at}gmail.com
Gary S. Rachelefsky, M.D. UCLA School of Medicine Los Angeles, CA 90095
Dr. Zitt reports serving on advisory boards for Aerocrine, Alcon,Greer, Sanofi-Aventis, Schering-Plough, Teva, and Verus andserving on speakers' bureaus for Aerocrine, AstraZeneca, Genentech–Novartis,Merck, Sanofi-Aventis, Schering-Plough, Teva, and Verus. Dr.Rachelefsky reports serving as a consultant and on speakers'bureaus for AstraZeneca, Schering-Plough, Merck, Teva, and GlaxoSmithKlineand on speakers' bureaus for Genentech. No other potential conflictof interest relevant to this letter was reported.
References
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]
Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-1037. [Free Full Text]
Food and Drug Administration. Serevent Diskus, Advair Diskus, and Foradil information (long acting beta agonists). Bethesda, MD: Department of Health and Human Services, 2006. (Accessed July 12, 2007, at http://www.fda.gov/cder/drug/infopage/LABA/default.htm.)
The authors reply: Black correctly points out that our trial,like most randomized, double-dummy trials, examined the efficacyof three approaches to the treatment of mild, persistent asthma.We decided that blinding was more important for making a faircomparison of these treatments than was incorporating into thedesign the "added value" that once-daily treatment might conferin the fluticasone–salmeterol group. Our study populationwas diverse, however, with an age range from 6 to 76 years andnonwhite patients accounting for more than 30% of the participants,which enhances the generalizability of our results.
Chen suggests that our protocol should have included an intermediatestep-down in the twice-daily dose of fluticasone (100 µg)before the initiation of either once-daily treatment with fluticasone–salmeterolor montelukast, citing Haahtela et al.1 and Hawkins et al.2Both of those studies involved patients with asthma of greaterseverity (defined on the basis of the forced expiratory volumein 1 second), and much higher doses of inhaled corticosteroids(1200 µg of budesonide per day and a mean of 1430 µgof beclomethasone per day, respectively) before the therapywas stepped down. Those stepped-down doses were more similarto the dose of inhaled corticosteroids at which our patientsdocumented good asthma control than to our stepped-down doses.Therefore, we suggest that a step-down had already occurredin our trial. A step-down approach like the one suggested byChen is probably not necessary in a closely monitored study.
Zitt and Rachelefsky raise two important issues: whether changingtherapy from twice-daily inhaled corticosteroids to once-dailyinhaled corticosteroids at one half the dose, with the additionof a long-acting beta-agonist, is really a "step down," andwhether our approach is a departure from current guidelinesthat recommend use of long-acting beta-agonists only in patientswhose asthma is not adequately controlled by an inhaled corticosteroidalone. Whether a change from twice-daily fluticasone to once-dailyfluticasone–salmeterol represents a step across ratherthan a step down is a semantic issue we do not wish to debate;the once-daily therapy is certainly simpler and involves halfthe dose of inhaled corticosteroids used in the twice-dailyregimen. Our goal was to evaluate alternatives to twice-dailyfluticasone. Once-daily montelukast was an obvious choice, andcombination treatment with fluticasone and salmeterol once dailywas a reasonable choice, given the results of the SalmeterolMulticenter Asthma Research Trial (SMART).3
We agree that our approach of using once-daily fluticasone–salmeterolis at odds with current recommendations. It is based on thefirm scientific rationale that in persons with mild asthma,the bronchodilation produced by once-daily fluticasone–salmeterollasts for at least 24 hours4 and involves an intervention thatminimizes the need for the regular use of long-acting beta-agonistsand should result in increased adherence. Furthermore, mountingevidence suggests that a reduced dose of inhaled corticosteroidsmay maintain control in patients with mild asthma.5 A goal ofclinical investigation should be to provide new informationand a firm scientific rationale from which to devise the nextset of guidelines.
Stephen P. Peters, M.D., Ph.D. Wake Forest University Winston-Salem, NC 27157
Mario Castro, M.D. Washington University St. Louis, MO 63110-1093
Janet T. Holbrook, M.P.H., Ph.D. Johns Hopkins University Baltimore, MD 21205 jholbroo{at}jhsph.edu
References
Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-705. [Free Full Text]
Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003;326:1115-1120. [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]
Masoli M, Weatherall M, Ayling J, Williams M, Beasley R. The 24 h duration of bronchodilator action of the salmeterol/fluticasone combination inhaler. Respir Med 2005;99:545-552. [CrossRef][Web of Science][Medline]
Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528. [Free Full Text]
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