Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity,☆☆,

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Abstract

Background: Recent studies have raised concern that regular inhalation of β2 -agonists may cause a worsening of asthma control compared with on-demand dosing regimens. Objective: The objective of this study was to compare the effect of twice daily formoterol (Foradil), 4 times daily albuterol, and on-demand albuterol on bronchial hyperresponsiveness (BHR), lung function measurements, symptoms, and other indicators of disease control over 6 months inpatients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids. We also looked for occurrence of rebound BHR on discontinuation of treatment. Methods: This was a multicenter, parallel-group, double-blind, clinical trial. Methacholine PC20 was the primary outcome variable. Other outcome variables included symptom scores, use of rescue medication, morning peak expiratory flow (PEF), serial FEV1 measurements, and asthma exacerbations. Results: Of the 271 randomized patients, 217 completed the study. Formoterol was significantly superior to on-demand albuterol with regard to methacholine PC20 , FEV1 , PEF, symptom scores, and use of rescue medication at each measured time point/interval. Regular albuterol was superior to on-demand albuterol with regard to PC20 and FEV1 , but not PEF or various clinical scores. After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after randomization, there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment. The formoterol group had the lowest number of exacerbation days, as defined by high intake of rescue bronchodilator and/or symptom scores, whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups. Conclusion: In patients with asthma of moderate or greater severity receiving inhaled corticosteroids, formoterol taken twice daily resulted in superior bronchoprotection, bronchodilatation, and clinical control compared with on-demand albuterol over 6 months. Four times daily albuterol was superior to on-demand albuterol for only some of the end points. Progressive tolerance and a rebound increase in BHR on discontinuation of β-agonists were not found (J Allergy Clin Immunol 1999;103:427-35.)

Section snippets

Trial design and treatments

This was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 15 Canadian centers. Written informed consent was obtained from each participant, and the study protocol was approved by the institutional review board at each clinical center.

After screening, eligible patients entered a 2-week, single-blind, run-in period during which their disease severity was assessed. During this period, patients inhaled placebo dry powder capsules 44 timestimes daily with albuterol

Patient demographic and baseline characteristics

Of 374 patients screened, 271 were randomized, and 217 completed the study. Twenty percent of patients withdrew from the study prematurely, primarily due to adverse events (7%) and protocol violations (5%), with no meaningful differences among treatments (formoterol, 19%; regular albuterol, 21%; and on-demand albuterol, 20%). The 3 treatment groups were similar with respect to demographics, pulmonary function, and daily intake of inhaled corticosteroids at the start of the study (Table I).

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DISCUSSION

There is debate in the medical community as to whether long-term, regular use of β2 -agonists (ie, every day at fixed times) is associated with instability or deterioration of asthma control compared with β2 -agonists taken for symptomatic relief only (on demand, as needed, as required).1, 2, 3, 4, 5, 15, 17, 34, 35, 36, 37, 38 Our data show that when patients with asthma of moderate or greater severity inhale formoterol twice daily or albuterol 4 times daily, both regular β2 -agonist

Acknowledgements

We wish to thank the FO/OD1 Study Group and Drs Erhard Quebe-Fehling, Nozhat Chowdry,* Patrick Manning,* Antonia Wang,* and Roger Pierce of Novartis (* = former employees) and Dan Anbar and Izabela Roman of Target Research (Scotch Plains) for their contribution to the design, implementation, and reporting of this trial.

The Canadian FO/OD1 Study Group is as follows: Hôpital Laval Sainte-Foi (Montreal, Quebec): L. P. Boulet, P. Leblanc, F. Maitain (investigators), M. J. Breton, J. Milot

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    Supported in part by a grant from Ciba-Geigy Inc (now known as Novartis Inc).

    ☆☆

    Reprint requests: Mark FitzGerald, MD, Department of Respiratory Medicine, Mater Misericordiae Hospital, Eccles St, Dublin 7.

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