Correspondence

Benefits of combination therapy on exacerba-tions in nonsmoking patients with asthma

To the Editor:The subgroup analysis from the Gaining Optimal Asthma

controL study reported by Pederson et al1 revealed some impor-tant findings about which factors might influence exacerbation re-ductions with combination inhalers. In particular, the response tocombination therapy with fluticasone/salmeterol versus flutica-sone alone appears to be heavily influenced by smoking status,with 8% of the total population smokers, 18% former smokers,and 74% nonsmokers. In this regard, there were significant differ-ences (ie, between combination therapy vs inhaled steroid alone)in the mean exacerbation rate per patient per year, amounting to adifference of 0.04 in nonsmokers, 0.09 in former smokers, and0.15 in current smokers when pooling data for all strata. To putthis into a clinical context, for example, in the majority of patientswho were nonsmokers, it would take 25 years to obtain an addi-tional benefit to prevent an exacerbation by taking fluticasone/salmeterol versus fluticasone alone. In smokers, it would take6.66 years to see the same benefit conferred by using combinationtherapy. The greater difference in response for exacerbations tocombination therapy versus inhaled steroid alone in smokerswith asthma suggests that for such patients, the salmeterol respon-sive smooth muscle component is relatively more important thanin nonsmoking patients with asthma. This in turn highlights thatcurrent guidelines should take into account smoking status instepwise treatment recommendations, because for the majorityof patients who are nonsmokers, the benefits of such combinationtherapy on exacerbations are clearly less impressive.

Catherine Jackson, MDa

Brian Lipworth, MDb

From athe Tayside Center for General Practice and bthe Asthma and Allergy Research

Group, Ninewells Hospital, University of Dundee, Dundee, United Kingdom.

E-mail: brianlipworth@googlemail.com.

B.L. and the Asthma and Allergy Research Group have received financial support from

Neolab, Cipla, Innovata, Teva, Nycomed, AstraZeneca, GlaxoSmithKline, Schering-

Plough, and Merck Sharp & Dohme.

Disclosure of potential conflict of interest: B. Lipworth has served as a consultant for

Innovata, Mundipharma, Teva, and AstraZeneca; has served on the speakers’ bureau

for Nycomed; has received grants from Neolab Ltd, MSA Ltd, and AstraZeneca; and

has served as an expert witness for Teva Pharmaceuticals for Formoterol at the

European Medicines Agency. C. Jackson has declared that she has no conflict of

interest.

REFERENCE

1. Pedersen SE, Bateman ED, Bousquet J, Busse WW, Yoxall S, Clark TJ. Determi-

nants of response to fluticasone propionate and salmeterol/fluticasone propionate

combination in the Gaining Optimal Asthma controL study. J Allergy Clin Immunol

2007;120:1036-42.

Available online February 13, 2008.

doi:10.1016/j.jaci.2007.12.1144

Reply

To the Editor:We thank Drs Jackson and Lipworth1 for their thoughtful com-

ments about our article.2 As they point out, an important finding inour article is that continued smoking (and former smoking, to alesser extent) reduces but does not negate the benefit of the com-bination of fluticasone propionate/salmeterol over fluticasone

780

propionate alone in reducing exacerbations in patients withasthma.

The main reason for this seems to be the reduced efficacy ofinhaled (and systemic) corticosteroids in former and currentsmokers. The resulting differences in efficacy are best expressedas a comparison of numbers-needed-to-treat for 1 year to prevent1 severe exacerbation when using fluticasone propionate/salme-terol compared with fluticasone propionate alone. This number is25 for nonsmokers, 12 for former smokers, and 7 for currentsmokers, very much greater in nonsmokers. However, becauseexacerbations are dramatic events that are important to patientsand expensive for society, any reduction should be consideredworthwhile, and these numbers-needed-to-treat with fluticasonepropionate/salmeterol are quite acceptable as a measure ofsuperior clinical benefit.

Where we differ from Jackson and Lipworth1 is in the sugges-tion that these results call for a revision of current recommenda-tions for choice of drug when stepping up asthma treatment.First, although reduced, the benefits of fluticasone propionate/salmeterol in reducing exacerbations remained. Second, as nowrecommended in guidelines,3 the aim of the GOAL study was toachieve asthma control, of which exacerbations form only apart. However judged, the combination achieved higher levels ofcontrol in more patients and at a lower dose of inhaled corticoste-roid than fluticasone propionate alone.4 Finally, these data cannotbe applied noncritically in an algorithm of escalating treatment,because it is the result of a post hoc analysis of a trial of a particulardesign. We must wait instead for results from prospective trialscomparing the 2 treatments in the clinical context referred to inguidelines. We agree however, that this deserves further study.

Søren E. Pedersen, MD, DMSca

Eric D. Bateman, MDb

From athe University of Southern Denmark, Pediatric Research Unit, Kolding Hospital,

Kolding, Denmark; and bthe Division of Pulmonology, Department of Medicine,

University of Cape Town, Cape Town, South Africa. E-mail: spconsult@post1.tele.dk.

Disclosure of potential conflict of interest: S. E. Pedersen has served as a consultant for

AstraZeneca, GlaxoSmithKline, Nycomed, and Merck and has received research

grants from AstraZeneca, GlaxoSmithKline, and Nycomed. E. D. Bateman has given

lectures for Altana; has served on the advisory board for Nycomed, Almirall, Merck,

Pfizer, Sanofi-Aventis, GlaxoSmithKline, Kyowa Hakko, AstraZeneca, and Boeh-

ringer Ingelheim; has served as the DSMB Chair for Hoffman le Roche; has partici-

pated in clinical trials sponsored by Altana, AstraZeneca, Boehringer Ingelheim,

GlaxoSmithKline, Novartis, AlmirallMerck, Nycomed, Schering-Plough, Pfizer,

Chiesi, Eli Lilly, and Sanofi-Aventis; has served as a legal consultant for Glaxo-

SmithKline; and has served as a committee member on the Global Initiative for

Asthma Science Committee.

REFERENCES

1. Jackson C, Lipworth B. Benefits of combination therapy on exacerbations in non-

smoking patients with asthma. J Allergy Clin Immunol 2008;121:780.

2. Pedersen SE, Bateman ED, Bousquet J, Busse WW, Yoxall S, Clark TJ. Determi-

nants of response to fluticasone propionate and salmeterol/fluticasone propionate

combination in the Gaining Optimal Asthma controL study. J Allergy Clin Immunol

2007;120:1036-42.

3. Global Strategy for Asthma Management and Prevention. Global Initiative for

Asthma (GINA). Available at: http://www.ginasthma.org/Guidelineitem.asp??l15

2&l251&intId560. Accessed January 22, 2008.

4. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al.

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma

controL study. Am J Respir Crit Care Med 2004;170:836-44.

Available online February 13, 2008.

doi:10.1016/j.jaci.2007.12.1143