111397 effect of inhaled formoterol and budesonide

C o py r ig h t , 1 9 9 7, by t h e Ma s s a c h u s e t t s Me d i c a l S o c i e t y V O L U M E 3 3 7
N U M B E R 2 0
EFFECT OF INHALED FORMOTEROL AND BUDESONIDE ON EXACERBATIONS ROMAIN A. PAUWELS, M.D., CLAES-GÖRAN LÖFDAHL, M.D., DIRKJE S. POSTMA, M.D., ANNE E. TATTERSFIELD, M.D., PAUL O’BYRNE, M.B., PETER J. BARNES, D.M., AND ANDERS ULLMAN, M.D., FOR THE FORMOTEROL AND CORTICOSTEROIDS ESTABLISHING THERAPY (FACET) INTERNATIONAL STUDY GROUP* ABSTRACT
NHALED glucocorticoids are considered the The role of long-acting, inhaled b - first-line treatment for patients with moderate- agonists in treating asthma is uncertain. In a double- to-severe, persistent asthma.1-3 However, many blind study, we evaluated the effects of adding in- patients taking an inhaled glucocorticoid con- haled formoterol to both lower and higher doses of tinue to have symptoms and need additional treat- the inhaled glucocorticoid budesonide.
ment. Inhaled b -agonists are widely used for symp- After a four-week run-in period of treat- tomatic relief in patients with asthma, but their ment with budesonide (800 mg twice daily), 852 pa- regular use has been the subject of recent controver- tients being treated with glucocorticoids were ran- sy.4-6 Treatment with the long-acting, inhaled b - domly assigned to one of four treatments given agonists formoterol and salmeterol provides better twice daily by means of a dry-powder inhaler (Turbu- control of symptoms and improves lung function haler): 100 mg of budesonide plus placebo, 100 mg of budesonide plus 12 mg of formoterol, 400 mg of bu- more than short-acting b -agonists. Combining a desonide plus placebo, or 400 mg of budesonide plus long-acting, inhaled b -agonist with an inhaled glu- 12 mg of formoterol. Terbutaline was permitted as cocorticoid led to a greater improvement in the con- needed. Treatment continued for one year; we com- trol of symptoms and in lung function than dou- pared the frequency of exacerbations of asthma, bling the dose of the inhaled glucocorticoid.9,10 symptoms, and lung function in the four groups. A However, some studies have suggested that long-term severe exacerbation was defined by the need for oral treatment with long-acting, inhaled b -agonists might glucocorticoids or a decrease in the peak flow to result in tolerance to its effects or mask an increase more than 30 percent below the base-line value on We studied the hypothesis that the addition of tions were reduced by 26 percent and 40 percent, re- regular treatment with the long-acting, inhaled b - spectively, when formoterol was added to the lower agonist formoterol to a lower or higher dose of the dose of budesonide. The higher dose of budesonide inhaled glucocorticoid budesonide would result in alone reduced the rates of severe and mild exacer- improved control of symptoms and lung function, bations by 49 percent and 37 percent, respectively.
without any long-term deterioration in the control Patients treated with formoterol and the higher dose of asthma over a 12-month period. The primary out- of budesonide had the greatest reductions — 63 per- comes evaluated were the rates of severe and mild cent and 62 percent, respectively. Symptoms of asth-ma and lung function improved with both formoteroland the higher dose of budesonide, but the improve-ments with formoterol were greater.
From the Department of Respiratory Diseases, University Hospital, Ghent, Belgium (R.A.P.); the Department of Respiratory Medicine, Uni- symptoms of asthma despite treatment with inhaled versity Hospital, Lund, Sweden (C.-G.L.); the Division of RespiratoryDisease, University Hospital, Groningen, the Netherlands (D.S.P.); the Di- glucocorticoids, the addition of formoterol to budes- vision of Respiratory Medicine, City Hospital, Nottingham, United King- onide therapy or the use of a higher dose of budes- dom (A.E.T.); the Department of Respirology, McMaster University, onide may be beneficial. The addition of formoterol Hamilton, Ont., Canada (P.O.); the National Heart and Lung Institute, to budesonide therapy improves symptoms and lung Imperial College, London (P.J.B.); and Clinical Research and Develop-ment, Astra Draco, Lund, Sweden (A.U.). Address reprint requests to Dr.
function without lessening the control of asthma.
Pauwels at the Department of Respiratory Diseases, University Hospital, De Pintelaan 185, B9000 Ghent, Belgium.
1997, Massachusetts Medical Society.
*The members of the study group are listed in the Appendix.
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T h e New E n g l a n d Jo u r n a l o f Me d i c i n e exacerbations of asthma. Secondary outcomes in- erbation was defined as one requiring treatment with oral gluco- cluded lung function, symptoms, and the need for corticoids, as judged by the investigator, or a decrease in the peakexpiratory flow as measured in the morning to more than 30 per- b -agonists for rescue therapy.
cent below the base-line value on two consecutive days. Seventy-three percent of severe exacerbations were identified clinically by the investigators. The base-line peak expiratory flow was defined Patients
as the mean peak expiratory flow in the morning during the last10 days of the run-in period. All severe exacerbations had to be Patients 18 to 70 years old, who had had asthma for at least six treated with a 10-day course of oral glucocorticoids (30 mg of months and had been treated with an inhaled glucocorticoid for prednisolone or prednisone or 24 mg of methylprednisolone per at least three months were enrolled. The forced expiratory vol- day). Patients who had three severe exacerbations within three ume in one second (FEV ) at base line had to be at least 50 per- months or a total of five severe exacerbations were withdrawn cent of the predicted value,21 with an increase of at least 15 per- from the study. Days with mild exacerbations were defined as days cent in FEV from the base-line value after the inhalation of 1 mg when one of the following occurred: a peak expiratory flow in the of terbutaline. Patients taking more than 2000 mg of beclometh- morning that was more than 20 percent below the base-line val- asone or 1600 mg of budesonide daily by pressurized metered- ue; the use of more than three additional inhalations of terbuta- dose inhaler, 800 mg of budesonide daily by Turbuhaler dry-pow- line per 24 hours as compared with the base-line period; or awak- der inhaler (Astra, Södertällje, Sweden), or 800 mg of fluticasone ening at night due to asthma. Single, isolated days of mild daily were excluded. They were also excluded if they had had exacerbations were not counted. The base-line value was the three or more courses of oral glucocorticoids or had been hospi- mean value for the variable during the last 10 days of the run-in talized for asthma during the previous six months.
period. Days included in a severe exacerbation were excludedfrom the count of days with mild exacerbations.
Study Design
The study was a double-blind, randomized, parallel-group study Diary-Card Data
with four treatment groups. It was carried out at 71 centers innine countries (Belgium, Canada, the Netherlands, Israel, Italy, Patients filled in a daily diary during the run-in and treatment Luxembourg, Norway, Spain, and the United Kingdom). Ap- periods, recording the best of three measurements of peak expir- proval from regulatory agencies and ethics committees was ob- atory flow made with a Vitalograph Peak Flow Meter (Vitalo- tained in all countries and at all centers. All patients gave wit- graph, Buckingham, United Kingdom) in the morning and nessed oral or written informed consent.
evening before medication; symptoms of asthma during the night The study had a 4-week run-in period, followed by 12 months or the daytime (according to a 4-point scale, with 0 indicating no of randomized treatment. There were nine scheduled visits to the symptoms and 3 incapacitating symptoms); awakening due to clinic: at the start of the run-in period, at the start of treatment, asthma; use of inhalations of terbutaline for rescue therapy (at and after 2 weeks and 1, 2, 3, 6, 9, and 12 months of treatment.
night or during the day); and the use of oral glucocorticoids.
In addition, telephone contacts were scheduled with the patientsafter 2 weeks of the run-in period, after 2 to 5 days of treatment, Clinic Visits
and after 4, 5, 7, 8, 10, and 11 months of treatment.
At scheduled clinic visits, clinical measures, adverse events, All patients entering the run-in phase received inhaled budes- withdrawals, or changes in medication were recorded, diary cards onide (Pulmicort, Astra Draco, Lund, Sweden) at a dose of 800 were reviewed, and FEV was measured.
mg twice daily (total daily dose, 1600 mg), plus 250 mg of inhaled terbutaline (Bricanyl, Astra Draco) as needed. At the end of the Episode-free Days
run-in period, patients were eligible for randomization if they hadcomplied with the run-in treatment and had stable asthma. Com- An episode-free day was defined as a day with optimally con- pliance was defined as the use of 75 to 125 percent of the rec- trolled asthma — that is, no need for rescue therapy with inhaled ommended number of doses of inhaled budesonide, as indicated b -agonists, an asthma-symptom score of 0, a morning peak ex- on a hidden mechanical counter built into the dry-powder inhaler piratory flow that was 80 percent or more of the base-line value, that could be read only by the investigators. Asthma was defined as stable if none of the following occurred during the last 10 daysof the run-in period: diurnal variation of more than 20 percent Statistical Analysis
in the peak expiratory flow on 2 consecutive days; use of four or The data analysis followed a factorial design, and pairwise com- more inhalations of b -agonist per day on 2 consecutive days; parisons were made by appropriate contrasts. Rates of exacerba- awakening due to asthma on 2 consecutive nights; or the need to tion were analyzed by applying a Poisson regression model. Other variables were analyzed with use of analysis of covariance, with Eligible patients were randomly assigned to receive one of the base-line variables as covariates. For data from the diaries, mean following treatments (each dose was given twice daily) for a period values for the last 10 days before each visit were used. The analysis of 12 months: 100 mg of budesonide (total daily dose, 200 mg) included all randomized patients (intention-to-treat approach).
plus placebo; 100 mg of budesonide plus 12 mg of formoterol (Ox- Data for patients who withdrew or discontinued therapy were in- is, Astra Draco; total daily dose, 24 mg); 400 mg of budesonide (to- cluded up to the time of their withdrawal. The number of days tal daily dose, 800 mg) plus placebo; or 400 mg of budesonide plus when treatment was received was entered as a covariate.
12 mg of formoterol. Terbutaline (250 mg per inhalation) was usedas rescue medication. All medications were inhaled by means ofa multidose Turbuhaler. The stated doses of budesonide, formo- terol, and terbutaline are the metered doses. The patients were From April 1994 to April 1995, consecutive po- randomly assigned to treatment groups in balanced blocks of fourat each center.
tentially eligible patients were identified at the par-ticipating institutions. Of the 1114 patients entering Outcome Measures
the run-in period, 262 were excluded before ran- Exacerbations of Asthma
domization because they were determined to be in- The primary outcomes studied were the rates of severe and eligible. The remaining 852 patients (436 women mild exacerbations of asthma per patient per year. A severe exac- and 416 men) were randomly assigned to treatment Downloaded from www.nejm.org by CONTARDO CORBETTA on September 08, 2004.
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E F F E C T O F I N H A L E D FO R M OT E RO L A N D B U D E S O N I D E O N EX AC E R BAT I O N S O F AST H M A
groups. Base-line demographic and spirometric char- and formoterol in terms of either severe or mild ex- acteristics and diary-card data are presented in Table acerbations. Formoterol and the higher dose of bu- 1. The differences in base-line data among the groups desonide produced additive reductions in severe and were minor and nonsignificant. Of the 852 patients randomly assigned to receive treatment, 694 (81 The rate of severe exacerbations was reduced by percent) completed the 12-month study. Of the 158 26 percent when formoterol was added to the lower patients who did not complete the study, 44 did not dose of budesonide and by 49 percent when the fulfill the entry criteria and were incorrectly ran- higher dose of budesonide was given alone. The domized, 30 had worsening of asthma, 29 had ad- combination of formoterol and the higher dose of verse events, and 55 left the study for other reasons budesonide reduced the estimated rate of severe ex- (13 because of noncompliance with study proce- acerbations by 63 percent, from 0.91 per year per dures, 5 because they intended to become pregnant, patient to 0.34 (PϽ0.001). Giving the higher dose 5 because they relocated, 20 for personal reasons, of budesonide resulted in a greater reduction in the and 12 because they were lost to follow-up). Most rate of severe exacerbations than did the addition of of the incorrectly randomized patients were with- formoterol (Pϭ0.03). Altogether, 80.8 percent of drawn in the initial part of the study after a visit to the patients receiving both formoterol and the high- the clinic for monitoring. Only three remained in er dose of budesonide were free of severe exacerba- tions during the study, as compared with 61.4 per-cent of the patients receiving the lower dose of Exacerbations of Asthma
budesonide without formoterol. Of the 30 patients Table 2 shows the two primary outcome variables, who left the study because their asthma worsened, the rate of severe exacerbations and the rate of mild 21 were withdrawn because they had frequent severe exacerbations, according to treatment group. The exacerbations: 10 receiving the lower dose of budes- lowest rates were among the patients who received onide alone, 7 receiving the lower dose of budeso- the higher dose of budesonide plus formoterol. There nide plus formoterol, 4 receiving only the higher was no significant interaction between budesonide dose of budesonide, and none receiving the higher TABLE 1. BASE-LINE CHARACTERISTICS OF THE STUDY PATIENTS.*
LOWER-DOSE
LOWER-DOSE
HIGHER-DOSE
HIGHER-DOSE
BUDESONIDE
BUDESONIDE
BUDESONIDE
BUDESONIDE
PLUS PLACEBO
PLUS FORMOTEROL
PLUS PLACEBO
PLUS FORMOTEROL
CHARACTERISTIC
(N؍213)
(N؍210)
(N؍214)
(N؍215)
*The lower dose of budesonide was 100 mg given twice a day (total, 200 mg per day); the higher dose was 400 mg twice a day (total, 800 mg per day). Formoterol was given at a dose of 12 mg twice aday (total, 24 mg). FEV denotes forced expiratory volume in one second, and PEF peak expiratory flow.
†Symptoms were scored from 0 (no symptoms) to 3 (very severe symptoms interfering with activity Downloaded from www.nejm.org by CONTARDO CORBETTA on September 08, 2004.
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T h e New E n g l a n d Jo u r n a l o f Me d i c i n e TABLE 2. CLINICAL OUTCOMES.*
LOWER-DOSE
LOWER-DOSE
HIGHER-DOSE
HIGHER-DOSE
BUDESONIDE
BUDESONIDE PLUS
BUDESONIDE
BUDESONIDE PLUS
VARIABLE
PLUS PLACEBO
FORMOTEROL
PLUS PLACEBO
FORMOTEROL
Patients withdrawn from study because of *The lower dose of budesonide was 100 mg given twice a day (total, 200 mg per day); the higher dose was 400 mg twice a day (total, 800 mg per day). Formoterol was given at a dose of 12 mg twice a day (total, 24 mg).
†Episode-free days were defined as days with no symptoms, no use of rescue medication, and a peak expiratory flow more than 80 percent ‡Symptoms were scored from 0 (no symptoms) to 3 (very severe symptoms interfering with activity or sleep).
dose of budesonide plus formoterol (Pϭ0.01 for increase in symptom scores as compared with the the difference among the treatment groups).
The rate of mild exacerbations was reduced by 37 The need for rescue medication was reduced sig- percent when the higher dose of budesonide, rather nificantly by adding formoterol, during both the day than the lower dose, was given and by 40 percent and the night, and by the use of the higher dose of when formoterol was added to the lower dose of bu- budesonide, during the night but not during the desonide. The combination of budesonide and the day. The addition of formoterol to budesonide ther- higher dose of formoterol reduced the estimated apy was associated with a significantly increased num- rate of mild exacerbations by 62 percent, from 35.4 ber of episode-free days; the higher dose of budeso- per patient per year to 13.4 (PϽ0.001). There was nide was not associated with a significant increase no significant change in the rate of severe or mild exacerbations in any treatment group during thecourse of the study.
Lung Function
FEV increased significantly in all groups during Symptoms
the run-in period and increased further with the ad- At the end of the run-in period, when patients re- dition of formoterol (Fig. 1). The higher dose of bu- ceived 800 mg of budesonide twice a day, clinical- desonide was associated with a significantly higher symptom scores, the rate of use of rescue medica- FEV than the lower dose. Peak expiratory flow in tion, and the frequency of nighttime awakening the morning and evening increased considerably were low in all four groups (Table 1). The addition when formoterol was added (Fig. 2). The higher of formoterol to budesonide therapy was associated dose of budesonide was associated with a significant with a significant further improvement in both day- increase in peak expiratory flow, although less than time and nighttime symptom scores (Table 2). The that associated with the addition of formoterol.
higher dose of budesonide was significantly better In the formoterol groups, the peak expiratory than the lower dose in controlling symptoms during flow in the morning was higher during the first the day, but patients in both treatment groups that days of treatment than subsequently (i.e., after day received budesonide without formoterol had a slight 3; PϽ0.001). For the rest of the 12-month treat- Downloaded from www.nejm.org by CONTARDO CORBETTA on September 08, 2004.
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E F F E C T O F I N H A L E D FO R M OT E RO L A N D B U D E S O N I D E O N EX AC E R BAT I O N S O F AST H M A
ment period, the peak expiratory flow remained sta-ble and considerably higher than the value in the groups treated with budesonide alone (Fig. 2).
Adverse Events
All treatments were well tolerated throughout the study. The proportion of patients reporting adverseevents was similar in the four treatment groups.
Eleven patients were hospitalized because of asthma: Lower-dose budesonide plus formoterolHigher-dose budesonide three receiving the lower dose of budesonide plus placebo, one receiving the lower dose of budesonideplus formoterol, five receiving the higher dose of bu- desonide plus placebo, and two receiving the higher dose of budesonide plus formoterol. Twenty-nine Figure 1. Forced Expiratory Volume in One Second (FEV ) dur-
patients withdrew because of adverse events: six re- ceiving lower-dose budesonide plus placebo, six FEV is shown as a mean percentage of the predicted value receiving lower-dose budesonide plus formoterol, during the run-in period (shaded area) and the treatment peri- eight receiving higher-dose budesonide plus place- od. The bars indicate 2 SE. During the run-in period, all pa- bo, and nine receiving higher-dose budesonide plus tients received 800 mg of budesonide twice daily. Patients werethen randomly assigned to twice-daily treatment with 100 mg formoterol. Seven withdrawals were due to pharma- of budesonide, 100 mg of budesonide plus 12 mg of formoterol, cologically predictable adverse events: three in the 400 mg of budesonide, or 400 mg of budesonide plus 12 mg of group receiving lower-dose budesonide plus formo- terol (one with headache and two with tremor) andfour in the group receiving higher-dose budesonideplus formoterol (two with tremor, one with tachy- cardia, and one with oral candidiasis). The other 22 withdrawals were due to throat irritation (2 patients), gastrointestinal effects (5), and miscellaneous side ef- We examined the hypothesis that adding regular treatment with the long-acting inhaled b -agonist formoterol to therapy with the inhaled glucocorti- coid budesonide would improve symptoms of asth- ma without a long-term worsening of the disease, asindicated by the rates of severe and mild exacerba- tions. We found no evidence of deterioration in thecontrol of asthma over the course of a year when formoterol was added to budesonide therapy. In fact, the addition of formoterol decreased the inci- dence of both severe and mild exacerbations. This effect was independent of the dose of budesonide.
The rates of severe and mild exacerbations were also Figure 2. Changes in Mean Peak Expiratory Flow (PEF) in the
lower among the patients given the higher dose of Morning during the Run-in Period, on Days 1 through 14 of budesonide; this effect was independent of the ad- Treatment, and at Months 1 through 12 of Treatment. dition of formoterol. For severe exacerbations, the During the run-in period all patients received 800 mg of budes- effect of the higher dose of budesonide was sig- onide twice daily. Patients were then randomly assigned to nificantly more pronounced than the effect of for- twice-daily treatment with 100 mg of budesonide, 100 mg of bu-desonide plus 12 mg of formoterol, 400 mg of budesonide, or 400 mg of budesonide plus 12 mg of formoterol.
Regular treatment with long-acting, inhaled b - agonists has not been shown to modify chronic air-way inflammation in patients with asthma.22,23 Thereason for the reduction in the rate of severe exacer-bations with formoterol is not clear. Possible expla-nations include an inhibitory effect on the acuteinflammatory changes that occur during a severe ex-acerbation; an inhibitory effect on airway smooth- Downloaded from www.nejm.org by CONTARDO CORBETTA on September 08, 2004.
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T h e New E n g l a n d Jo u r n a l o f Me d i c i n e muscle contraction, plasma extravasation, or both — tion from a Turbuhaler delivers twice as much bu- assuming that these are important to the develop- desonide to the airways as inhalation from pressurized ment of severe acute exacerbations; and an increased deposition of budesonide in the airways after the in- Our results support therapeutic guidelines that halation of formoterol. Acute exacerbations of asthma recommend the addition of a long-acting inhaled are associated with an influx of eosinophils, neutro- b -agonist to low doses of inhaled glucocorticoids in phils, or both.24,25 Formoterol has been shown to in- patients with persistent symptoms of asthma or less hibit the influx of inflammatory cells in animal mod- than optimal lung function.3 Increasing the mainte- els of acute airway inflammation.26 Formoterol is a nance dose of inhaled glucocorticoids might be a potent functional antagonist of airway smooth-mus- more appropriate initial therapeutic step in patients cle stimulants and inhibits plasma extravasation.27-30 with repeated severe exacerbations of asthma.
In our study, the addition of formoterol to either the lower or the higher dose of budesonide also im- Supported by a grant from Astra Draco, Lund, Sweden.
proved asthma-symptom scores and lung functionand reduced the need for rescue medications. The improvement in the control of symptoms is in agree- The following physicians, listed according to country, enrolled patients: ment with the results of other studies, which have Belgium — W. DeBacker, M. Decramer, P.-M. Mengeot, L. Siemons, shown better control of symptoms when long-act- J. Verhaert, and W. Vinken; Canada — M. Alexander, J. Bouchard, A. Day, A. Knight, J.-L. Malo, D. Marciniuk, J.G. Martin, S. Peters, B. Sanders, b -agonists are added to the treatment B. Sproule, and D. Stubbing; the Netherlands — A. Baas, T.A. Bantje, J. Creemers, H. Sinninghe Damsté, W. Evers, S. Gans, A. Greefhorst, The control of asthma symptoms and lung func- H. Hassing, F. Maesen, M.J. Möllers, H.R. Pasma, Z. Pelikan, P.E. Post-mus, J. Prins, B.M. Santana, M. Schrijver, A.P. Sips, R. Stallaert, L. van der tion were better in the higher-dose budesonide Maas, and A.J. van Harreveld; Israel — J. Greif, D. Heimer, A.H. Rubin, groups than in the lower-dose groups, although the and A. Wollner; Italy — F. Bariffi, F. Bonifazi, V. Brusasco, G. D’Amato, effect of increasing the dose of budesonide on these L. Fabbri, C. Franco, L. Gandola, C. Giuntini, E. Gramiccioni, V. Grassi,L. Marazzini, A. Rossi, A.M. Santolicandro, and C. Sturani; Luxembourg measures was less marked than that of adding for- — J.-P. Parini; Norway — L. Bjermer and N. Ringdal; Spain — J.L. Alvarez moterol. The relative effects of adding formoterol or Sala, P.L. Cabrera Navarro, S. Romero, J. Sanchis, V. Sobradillo, and giving a higher dose of budesonide on the control H. Verea; United Kingdom — G. Basran, L.M. Campbell, D. Franklin,G.J. Gibson, R.C. Joshi, A. Knox, A.B. MacLean, R. Scott, R. Smith, of symptoms and on lung function in this study A. Tattersfield, and J.P. Vernon. The following Astra employees were in- are in keeping with observations made with salme- volved in the study: C.-A. Bauer (project leader), M. Best (data entry),C. Hultquist (medical advisor), F. Jackson (safety evaluation), A. Lennon (medical coordinator), S. Lindgren (safety evaluation), H. MacFarlane Regular treatment with formoterol combined with (computing), A. McLean (deputy project leader), M. Nevinson (medical budesonide did not cause any long-term loss of con- coordinator), M.-Å. Persson (computing), and K. Svensson (statistician).
The national medical monitors were: F. Bellemans, T. Ben-Or, S. Bordo- trol of asthma. There were no signs of worsening of naro, M. Chiesa, I. Garcia, J. Haddon, S. Holthe, M. Huybrechts, A. Ning, disease or tolerance to the effects of medication with H. Rijskamp, F. Stafford, and M. van den Dobbelsteen.
regard to any clinical or functional variable exam- ined, except for a decrease in the effect of formo-terol on peak expiratory flow in the morning after 1. Haahtela T, Järvinen M, Kava T, et al. Comparison of a b -agonist, ter-
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expiratory flow in the morning during the first one cock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled cor- to two days of treatment, followed by a slight de- ticosteroids and/or beta-2-agonists on lung function, airway responsive-ness, and symptoms in children with asthma. Am Rev Respir Dis 1992;146: crease in both budesonide groups. The peak expira- tory flow then remained stable and significantly 3. Global Initiative for Asthma. Global strategy for asthma management
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7. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salme-
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