Comparison Between Formoterol 12 Mg B.I.D. and On-Demand Salbutamol in Moderate Persistent Asthma

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RESPIRATORY MEDICINE (2001) 95, 64–70 doi:10.1053/rmed.2000.0972, available online at http://www.idealibrary.com on Comparison between formoterol 12 mg b.i.d. and on-demand salbutamol in moderate persistent asthma

{ { { } M. MOLIMARD*,J.BOURCEREAU ,V.LE GROS ,I.BOURDEIX ,F.LEYNADIER AND P. D UROUX} IN ASSOCIATION WITH THE FRENCH FOR-F-01 STUDY GROUP

*Service de Pharmacologie, CHU Pellegrin-Carreire, 33076 Bordeaux Cedex,{CTAR, 75013 Paris, {Novartis Pharma S.A., 92506 Rueil Malmaison Cedex, }Hoˆpital Tenon, 75970 Paris Cedex 20 and }Hoˆpital Antoine Be´cle`re, 92141 Clamart Cedex, France

Inhalation of on-demand salbutamol (ODS) several times daily is sometimes the only b2-agonist prescribed in moderate persistent asthma, whereas a long-acting b2-agonist should be added. This trial aimed to compare the efficacy of formoterol dry-powder capsule 12 mg b.i.d. (Foradil1) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids, in the conditions of real practice. Two hundred and fifty-nine patients were randomized (formoterol; 130; ODS: 129) in this open, parallel-group trial. The mean increases in morning peak expiratory flow (PEF primary variable) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol: +25?7 and +24?1 l min71, respectively vs. +4?5 and +0?5 l min71 respectively with ODS. The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3. Formoterol reduced the use of salbutamol as rescue medication by two-thirds. The percentages of symptom- free days and nights statistically significantly increased with formoterol (+20% and +33% respectively), but did not significantly change with ODS. Clinically relevant and statistically significant improvement in the mean total score of the St George’s Hospital Respiratory Questionnaire was observed in the formoterol group. Adverse events were similar in the two groups. The results show that treatment with formoterol has significant advantages over ODS in patients with moderate persistent asthma.

Key words: asthma; b2-agonists; formoterol; salbutamol; inhalation therapy; eﬃcacy.

RESPIR.MED. (2001) 94, 64–70 # 2000 HARCOURT PUBLISHERS LTD

Introduction The use of long-acting b2-agonists is not questioned in patients with severe persistent asthma. In patients with

Formoterol is a long-acting b2-agonist bronchodilator moderate persistent asthma, on-demand short-acting b2- available as dry-powder capsules containing 12 mgof agonists are sometimes only prescribed whereas long- formoterol fumarate administered via a single dose acting b2-agonists are recommended to be introduced. breath-actuated inhaler (1). It is mainly used in patients Formoterol has never been directly compared with a presenting with moderate or severe persistent asthma short-acting b2-agonist given on an on-demand basis, but [according to the classification of the Global Initiative for with salbutamol given at a fixed dosage of 200 mgor400mg Asthma (2)] not optimally controlled with inhaled corti- two or four times daily (6–11), or indirectly during trials costeroids, i.e. in case of persistent symptoms or in patients comparing formoterol with a placebo matched to formoterol with nocturnal symptoms or using too many puffs of short- in combination with on-demand salbutamol (11,12). How- acting b2-agonists (3). ever in this case, results may not be strictly extrapolated Contrary to long-acting b2-agonists, the use of short- because of the possible interference of the placebo effect. acting b2-agonists at a fixed dosage is not recommended (2), The aim of this pragmatic study was to directly assess the because this has no advantage compared with use on an as- efficacy and the safety of formoterol given at the standard needed basis (4,5). On-demand short-acting b2-agonists such dosage of 12 mg twice daily vs. on-demand (ODS) salbuta- as salbutamol are usually the only b2-agonists used for the mol given in patients with a moderate persistent asthma. treatment of intermittent asthma and mild persistent asthma.

Received 27 June 2000 and accepted in revised form 26 September Methods 2000. Published online 11 December 2000. Correspondence should be addressed to: Prof Mathieu Molimard, STUDY POPULATION Service de Pharmacologie, CHU Pellegrin-Carreire, F-33076 Bordeaux Cedex, France. Fax: (33) 5 56 24 58 89; E-mail: Male and female outpatients aged 18 years or over with [email protected] moderate persistent asthma were eligible for inclusion.

0954-6111/01/010064+07 $35?00/0 # 2000 HARCOURT PUBLISHERS LTD FORMOTEROL VERSUS ON -DEMAND SALBUTAMOL IN ASTHMA 65

These patients had to take daily treatment with an inhaled mini-Wright peak flow meter; night-time asthma symptom corticosteroid (the same product at a stable dose for at least score (0¼no breathing problems; 1=one waking up 1 month prior to the first visit) and require daily treatment because of breathing problems, but no use of rescue with inhaled bronchodilators (taken regularly or on- medication; 2¼one waking up because of breathing demand). The inhaled corticosteroid was kept at a constant problems, controlled by rescue medication; 3¼more than dose throughout the trial, up to the maximal daily dose one waking up because of breathing problems, controlled permitted in moderate persistent asthma (i.e. 1000 mgof by rescue medication; 4¼difficult sleep because of breathing beclomethasone, 800 mg of budesonide, 500 mg of flutica- problems, despite use of rescue medication); daytime sone). However in case of asthma exacerbation, a transient asthma symptom score (0¼no breathing problems at all, increase in the daily dose of the inhaled corticosteroid activity not restricted; 1¼breathing problems with little or therapy, a course of oral corticosteroid therapy or a no discomfort, and no activity restriction; 2¼breathing symptomatic b2-agonist nebulization therapy were allowed. problems with some discomfort and limitation of strenuous Asthma was defined according to the criteria of the activity; 3¼breathing problems with discomfort and limita- American Thoracic Society (13). The FEV1 had to be tion of routine activity; 4¼breathing problems at rest with superior or equal to 60% of the predicted normal value for major discomfort and limitation of routine activity); the patient. Reversibility test (increase in FEV1 510% of number of inhalations of rescue medication (salbutamol) the predicted value) had to be documented at the first visit used during the night and during the day. or within 3 months prior to this visit. Patients had to refrain A spirometry was performed at each visit before the from taking salbutamol 6 h before each spirometry. morning dose of trial medication and the best of three The patients were excluded if they presented one of the determinations of FEV1 was recorded. following criteria: known hypersensitivity to sympathic The St George’s Hospital Respiratory Questionnaire amines or to lactose; pregnancy or breast-feeding; women (SGRQ) was used to measure quality of life. The SGRQ of childbearing potential who did not use a reliable was self-administered by the patient at the investigator’s contraceptive method; significant change in the regular site at visits 2 (baseline) and 5 (after 3 months). The total asthma medication, asthma exacerbation or respiratory score was calculated, just as the three sub-scores: ‘Activity’ tract infection in the month prior to the first visit; (assessing the effects of breathlessness on mobility and incapacity to use a metered-dose inhaler correctly or to physical activity), ‘impacts’ (assessing the psychosocial complete the patient diary. Concomitant treatments with impact of disease), ‘Symptoms’ (assessing distress due to theophylline, anticholinergic bronchodilators and inhaled respiratory symptoms). A change of 4 units was considered or oral b2-agonists other than the trial medications were not to be clinically relevant (14,15). allowed. The safety of the treatments was assessed by measuring the vital signs (heart rate and blood pressure) before each spirometry, and by recording adverse experiences (AE) STUDY DESIGN (nature, severity and causal relationship), as well as reasons for premature treatment discontinuations. This multicentre study was performed by 42 specialists in France, from February 1998 to March 1999, as a randomized, open, parallel-group trial in two groups of asthmatic patients who were treated for 3 months with STATISTICAL ANALYSIS either one dry-powder capsule containing 12 mg of for- 1 Data processing and statistical analyses were performed moterol fumarate every morning and evening (Foradil , using SAS under Windows release 6?12. The primary Novartis Pharma S.A) with salbutamol as rescue medica- efficacy variable was the mean change in morning predose tion, or ODS via a metered-dose inhaler (100 mg puff 71). PEF for the entire treatment period. The calculation of the The trial had two periods. The first period was a 2- to 3- minimum sample size required for the study was based on week run-in, baseline period during which all patients this variable. Assuming an upper limit for the true standard received ODS. The second period was a 3-month treatment deviation of mean morning PEF of 50 l min71 and the use period in which patients were assigned at random to one of of a two-sided significance test at the 5% level, then a total the two treatment groups. Centralized phone randomiza- of 198 patients (99 per treatment) would have given the tion was used to avoid inclusion bias. Patients underwent study a power of 80% to detect a difference of 20 l min71 five visits during the trial: one at the start of study (visit 1), between formoterol and ODS. Secondary efficacy end- a randomization visit (visit 2), then three monthly visits points included mean increase in evening predose PEF for during treatment (visits 3, 4 and 5). An Ethics Committee the entire treatment period, mean morning and evening pre- approved the study protocol and all participants gave their dose PEF averaged 1-monthly, changes in morning pre- written consent. dose FEV1 at visits 3, 4 and 5, day- and night-time use of salbutamol, day- and night-time symptom scores and CLINICAL ASSESSMENTS SGRQ scores. The analyses were carried out in the intent-to-treat Patients completed a diary card twice daily throughout the population, i.e. in all randomized patients with a post- whole trial. The following data were recorded: pre-dose baseline efficacy measurement. Peak expiratory flow, use of peak expiratory flow (PEF) (morning and evening) using a salbutamol and symptom scores were analysed by analysis 66 M. MOLIMARD ET AL. of covariance (ANCOVA) with treatment, centre and sex as induced a significantly higher mean increase in evening factors, and with the baseline value (run-in average) as a predose PEF: +24?1(+35?3) l min71 and +0?5(+31?5) covariate. For the primary variable (morning predose PEF l min71 respectively (P50?0001). The mean changes in for the entire treatment period), treatment-by-centre, morning and evening PEF compared with baseline values treatment-by-baseline and treatment-by-sex interactions are shown in Fig. 1. were also tested. The same ANCOVA model as specified above (without interactions) was used for predose FEV1 and vital signs.

Results A total of 266 patients were screened, of whom 259 were randomized at visit 2. Of the seven patients who discontinued before the randomization, three failed to fulfill the selection criteria, two withdrew their consent and two were lost to follow-up. Thirty patients withdrew from the study prematurely after the randomization (formoterol, 12; ODS, 18). The reasons for these premature discontinuations were lost to follow-up (formoterol, five; ODS, seven), adverse events (formoterol, three; ODS, three), withdrawal of consent (formoterol, one; ODS, two), not meeting protocol criteria (formoterol, one; ODS, three), unsatisfac- tory therapeutic effect (formoterol, 0; ODS; three) and administrative problems (formoterol, two; ODS, 0). Six patients were excluded from the intent-to-treat efficacy analysis because of the absence of efficacy data. The two treatment groups were similar with respect to demographics, asthma history and lung function (Table 1).

LUNG FUNCTION

The mean increase (+SD) in morning PEF over the 3 FIG. 1. Mean (+SEM) changes from baseline in morning months was signiﬁcantly higher in the formoterol group and evening peak expiratory ﬂow (PEF) (* * * than in the ODS group: +25?7(+36?5) l min71 and +4?5 P50?0001). &: formoterol; &: on demand salbutamol. (+32?7) l min71 respectively (P50?0001). Formoterol also

TABLE 1. Patient demographics, asthma duration, baseline lung function

Formoterol (n¼130) On-demand salbutamol (n¼129)

Demographics Mean age + SD (years) 38.5+14.9 39.5+15.0 Sex (F:M) 76:54 71:58 Mean height +SD (cm) 167?3+9?5 167?3+9?6 Mean weight +SD (kg) 67?3+15?167?0+11?8 Smoking status: n(%) Never 91 (70) 88 (68) Past 20 (15) 23 (18) Current 19 (15) 18 (14) Mean asthma duration +SD (years) 14?7+13?015?1+11?5 Baseline lung function Mean FEV1+SD (% of predicted value) 72?7+10?073?7+9?4 71 Mean PEF+SD (l min ) Morning 387?4+108?2 396?2+85?0 Evening 399?1+111?0 406?0+89?0 Mean reversibility +SD (% of predicted FEV1)15?1+5?615?8+7?8 FORMOTEROL VERSUS ON -DEMAND SALBUTAMOL IN ASTHMA 67

FIG. 2. Mean (+SEM) changes from baseline in FEV1 (* * P50?01, * P50?05). &: formoterol; &: on demand salbutamol.

Improvement in predose FEV1 was signiﬁcantly greater with formoterol at visits 3 and 5 (P50?01 and P50?05, respectively). The mean changes in FEV1 compared with baseline values are shown in Fig. 2.

SALBUTAMOL USE

Over the 3 months, the mean (+SD) number of puffs of FIG. 3. Mean (+SEM) percentages of days and nights with salbutamol during the day decreased from 1?2(+1?46) to no puffs of salbutamol (* * * P50?0001 vs. baseline). &: 0?4(+0?65) in the formoterol group and increased from 1?0 formoterol; &: on demand salbutamol. (+1?24) to 1?1(+1?29) in the ODS group. Similarly, the mean (+SD) number of puffs of salbutamol during the night changed from 0?7(+0?85) to 0?2(+0?46) and from 0?5 (+0?76) to 0?7(+0?88), respectively. The mean (+SD) changes from baseline in the number of puffs of salbutamol during day and night respectively, were 70?8(+1?32) and 70?4(+0?72) with formoterol, and +0?1(+0?85) and + 0?1(+0?69) with ODS (P50?0001 for day and night). The percentages of days and nights with no puff of salbutamol are shown in Fig. 3 and the rescue use patterns in Fig. 4. During the run-in period, 91% of the patients used salbutamol at least once in the formoterol group and 85% in the ODS group. Of these patients, 54% of the formoterol patients and 20% of the ODS patients did not use salbutamol FIG. 4. Patterns of salbutamol use as rescue medication. throughout the 3-month treatment period or used it less than &: formoterol; &: on demand salbutamol. once monthly. Conversely, 45% of the ODS patients used salbutamol daily or at least once a week compared with only 15% of the patients in the formoterol group. changes vs. baseline: 70?1+0?43 and 0?0+0?35, respectively) (P50?0001). ASTHMA SYMPTOM SCORES Over the 3 months, the increase in the mean (+SD) percentage of symptom-free days was significantly higher in The mean (+SD) baseline daytime symptom score was 0?7 the formoterol group (from 53?5+38?2% to 71?3+35?0%, (+0?66) in the formoterol group and 0?6(+0?66) in the i.e. a 20% increase in symptom-free days) than in the ODS ODS group. Over the 3-month treatment period, the mean group (from 56?8+38?2% to 63?4+36?0%) (P50?0001). decrease in this score was significantly higher with The respective values of the mean (+SD) percentages of formoterol (70?3+0?48) than with ODS (70?1+0?43) symptom-free nights were 68?2 + 33?8% to 81?7 + 28?4% (P50?0001). Similar changes were observed in night-time (i.e. a 33% increase in symptom-free nights) and symptom scores (baseline values: 0?5+0?54 and 0?3+0?54, 78?0+30?0% to 76?4+29?7% (P=0?003). 68 M. MOLIMARD ET AL.

QUALITY OF LIFE results of this study demonstrate that, in patients with a moderate persistent asthma, the addition of formoterol After 3 months, the mean decreases in the SGRQ total 12 mg b.i.d. to treatment with inhaled corticosteroid and score and in the ‘activity’ and ‘symptoms’ sub-scores ODS, reduces use of salbutamol, asthma symptoms and statistically significantly exceeded the threshold for a improves lung function and quality of life. clinically relevant change in the formoterol group. The Reduction in short-acting b2-agonist use is balanced by mean decrease in the total SGQR score was significantly the use of a long-acting b2-agonist so that the overall b2- higher with formoterol (76?4+10?0) than with ODS agonist consumption is not reduced by addition of (73?5+13?7) (P=0?05). The changes in the mean sub- formoterol. However, as opposed to on-demand inhalation and total SGRQ scores are shown in Fig. 5. of salbutamol, use of formoterol may be scheduled only in the morning and evening, making it more convenient. The time of requirement of on-demand therapy is not pre- SAFETY dictable. Consequently patients with only on-demand salbutamol therapy take their treatment frequently and At least one AE was reported by 47 (36%) and 46 (36%) of only when dyspnoea is present. More than the absolute b2- the formoterol and ODS patients, respectively. Five agonist consumption, the frequency of rescue medication patients of the formoterol group (4%) and four patients requirement is one of the major handicaps for patients. So of the ODS group (3%) presented at least one drug-related 54% of patients in the formoterol group vs. 20% of patients AE with no relevant differences between the two groups. in the ODS group had to take rescue salbutamol less than Drug-related AE induced premature withdrawal of the once a month, allowing a quite normal life. This contributes treatment in two patients (2%) of the formoterol group and to the clinically significant improvement in quality of in three patients (2%) of the ODS group. Bronchitis or life observed in the formoterol group. The reduction in asthma worsening was reported in 17 patients (13%) and 20 rescue medication requirement observed with formoterol patients (15%), respectively. No drug-related serious AE may be partly explained by a protective effect of was reported. No clinically relevant changes in heart rate or formoterol. Indeed, ODS treatment being taken after blood pressure were observed in any group throughout the the beginning of chest discomfort has no protective study. effect whereas a sustained bronchoprotective effect over a 6-month period has been demonstrated for formoterol (12). Subsequently Fitzgerald et al. demonstrated a reduc- Discussion tion in the exacerbation rate in the formoterol group compared to the salbutamol group in agreement with Although a treatment with a long-acting bronchodilator is the reduction in the exacerbation rate observed with recommended in patients with moderate persistent asthma formoterol in the FACET study (18). The pattern of in addition to inhaled corticosteroids (2), some physicians exacerbation was however no different with or without are reluctant about a continuous treatment with a long- formoterol (19), confirming the lack of interaction of acting b2-agonist and prefer to limit the bronchodilator formoterol on rescue medication observed on human therapy to a short-acting b2-agonist used on an on-demand bronchi (20). basis. The causes for the reticence about regular use of a To the authors’, knowledge, this is the first study in long-acting b2-agonist are various (safety, tolerance, loss of which formoterol has been compared with ODS only and asthma control, etc.) (16,17), despite the fact they have not with ODS in combination with a placebo matched to never been demonstrated in large clinical studies. The formoterol. The open design of the study made this comparison possible. Whereas the improvements in lung function, symptom scores and salbutamol use observed with formoterol are similar to those presented in previously published studies (11,12,21,22), the results observed with the ODS confirm the elimination of the placebo effect. In a double-blind study comparing formoterol with ODS plus placebo matched to formoterol, the reduction in salbutamol use during the entire treatment period was 60% with formoterol and 27% with ODS, i.e. almost half the effect of formoterol (12). In the present study no change in salbutamol use was found in the ODS group throughout the 3-month treatment period. Comparable results in symptom scores suggest the existence of a significant placebo effect for these criteria of asthma control. FIG. 5. Mean (with 95% confidence interval) changes in The improvement in quality of life observed in the sub- and total St George Hospital Respiratory Quest formoterol group at the end of this 3-month study (SGRQ) scores. The horizontal dotted line is the threshold complement the traditional indicators of asthma efficacy. of clinically significant change in SGRQ scores. &: A significant improvement in the total score of the St formoterol; &: on demand salbutamol. George’s Hospital Respiratory Questionnaire has already FORMOTEROL VERSUS ON -DEMAND SALBUTAMOL IN ASTHMA 69 been found after longer treatment with formoterol (6 6. Arvidsson P, Larsson S, Lo¨ fdahl C-G, et al. Formoter- months) (23). ol, a new long-acting bronchodilator for inhalation. In conclusion, this study carried out in the conditions of Eur Resp J 1989; 2: 325–330. real practice shows that adding formoterol to treatment in 7. Wallin A, Melander B, Rosenhall L, et al. Formoterol, patients with moderate persistent asthma treated with ODS a new long acting b2 agonist for inhalation twice daily, and inhaled corticosteroid, results in improved lung compared with salbutamol in the treatment of asthma. function, reduced symptoms and rescue salbutamol use, Thorax 1990; 45: 259–261. and an improved quality of life. 8. Arvidsson P, Larsson S, Lo¨ fdahl C-G, et al. Inhaled formoterol during one year in asthma: a comparison with salbutamol. Eur Resp J 1991; 4: 1168–1173. Acknowledgements 9. Midgren B, Milander B, Persson G. Formoterol, a new long-acting b2 agonist, inhaled twice daily, in stable The authors sincerely acknowledge the French FOR-F-01 asthmatic subjects. Chest 1992; 101: 1019–1022. Study Group, Dr Gae¨ tan Boublil and GECEM Clinical 10. Kesten S, Chapman KR, Broder I, et al. A three-month Research Organisation for their contribution in the comparison of twice daily inhaled formoterol versus implementation and reporting of this study. four times daily inhaled albuterol in the management of Supported by a grant from Novartis pharma S.A. The stable asthma. Am Rev Respir Dis 1991; 144: 622–625. French FOR-F-01 Study Group is as follows: M. Ange- 11. Steffensen I, Faurschou P, Riska H, et al. Inhaled bault (Chevilly-Larue), P. Beaumont (Saint-Maur des formoterol dry powder in the treatment of patients with Fosses), A. Berthier (Saint-Nazaire), P. Bihet (Saint- reversible obstructive airway disease. A 3-month, Brieuc), T. Bodez (Paris), D. Boz (La Teste de Buch), C. placebo-controlled comparison of the efficacy and Chalhoub (Saint-Denis), D. Chaˆteau-Waquet (Paris), P. safety of formoterol and salbutamol, followed by a Chaumier (Les Mureaux), L. Colas des Francs (Paris), P. 12-month trial with formoterol. Allergy 1995; 50: Collineau (Saint-Maur des Fosses), M. Corap (Fontaine- 657–663. bleau), X. d’Arcot (Saint-Nazaire), M. Denis (La Teste de 12. FitzGerald JM, Chapman KR, Della Cioppa G, et al. Buch), C. Douillet (Montereau), C. Duarte-Risselin (Paris), and The Canadian FO/OD1 Study Group. Sustained M. Epstein (Paris), G. Fadlallah (Langon), J.-C. Farouz bronchoprotection, bronchodilation, and symptom (Bordeaux), J. Garnier (Saint-Nazaire), S. Graba (Paris), control during regular formoterol use in asthma of M.-T. Guinnepain (Paris), G. Haddad (La Rochelle), J.-P. moderate or greater severity. J Allergy Clin Immunol Hommasson (Chevilly-Larue), P. Joudiou (Saint-Denis), J.- 1999; 103: 427–435. P. Ledoux (Rennes), D. Legallais (Asnie` res sur Seine), F. 13. American Thoracic Society. (American Lung Associa- Marmouz (Cergy Pontoise), B. Medina (Paris), E. Michaud tion). Standards for the diagnosis and care of patients (Saint-Nazaire), M. Montchartre (Ermont), D. Noblet with chronic obstructive pulmonary disease (COPD) (Bourg-la-Reine), D. Ortolan (Villejuif), A. Perche (Or- and asthma. Am Rev Resp Dis 1987; 136: 225–244. le´ ans), J. Petit (Angouleˆme), S. Pham (Paris), Y. Plantard 14. Jones PW, Quirk FH, Baveystock CM. The St George’s (Libourne), P. Reboud (Paris), P. Rufin (Paris), F. Saada- Respiratory Questionnaire. Respir Med 1991; 85(Suppl Buisson (Arpajon), F. Saint-Martin (Villebon sur Yvette), B): 25–31. C. Sauvan-Pistof (Paris), S. Silcret (Paris), L. Tassou- 15. Jones PW, Bosh TK. Quality of life changes in COPD Villette (Maurepas). patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155: 1283–1289. 16. Busse WW. Long- and short-acting b2-adrenergic References agonists. Effects on airway function in patients with asthma. Arch Intern Med 1996; 156: 1514–1520. 1. Faulds D, Hollingshead LM, Goa KL. Formoterol. a 17. Crane J, Pearce N, Burgess C, Beasley R. Asthma and review of its pharmacological properties and therapeu- the b2-agonist debate. Thorax 1995; 50(Suppl.1): tic potential in reversible obstructive airways disease. S5–S10. Drugs 1991; 42: 115–137. 18. Pauwels RA, Lo¨ fdahl C-G, Postma DS, et al. on behalf 2. National Heart Lung and Blood Institute. Global of the FACET International Study Group. Additive strategy for asthma management and prevention. effects of inhaled formoterol and budesonide in NHLBI/WHO workshop report. National Heart, Lung reducing asthma exacerbations: a 1-year, controlled and Blood Institute, 1995; 1–48. study. N Engl J Med 1997; 337: 1405–1411. 3. Maesen FPV, Smeets JJ, Gubbelmans HLL, Zweers 19. Tattersfield AE, Postma DS, Barnes PJ, et al. On behalf PGMA. Bronchodilator effect of inhaled formoterol vs. of the FACET International Study Group. Exacerba- salbutamol over 12 hours. Chest 1990; 97: 590–594. tions of asthma. a descriptive study of 425 severe 4. Chapman KR,, Kesten S, Szalai JP. Regular vs. as- exacerbations. Am J Respir Crit Care Med 1999; 160: needed inhaled salbutamol in asthma control. Lancet 594–599. 1994; 343: 1379–1382. 20. Molimard M, Naline E, Zhang Y, et al. Long- and 5. Drazen JM, Israel E, Boushey HA, et al. Comparison short-acting b2-adrenoceptor agonists interactions in of regularly scheduled with as-needed use of albuterol human contracted bronchi. Eur Resp J 1998; 11: in mild asthma. New Engl J Med 1996; 335: 841–847. 583–588. 70 M. MOLIMARD ET AL.

21. Vervloet D, Ekstro¨ m T, Pela R, et al. A 6-month via a single-dose inhaler in 1380 asthmatic patients. comparison between formoterol and salmeterol in Invest Allergol Clin Immunol 1998; 8: 265–270. patients with reversible obstructive airways disease. 23. Jones PW, Brambilla R, Till MD. Quality of life in Respir Med 1998; 92: 836–842. patients treated with two long-acting b2-agonists: 22. Clauzel A-M, Molimard M, Le Gros V, et al. Use of Formoterol and salmeterol [Astract]. Eur Resp J formoterol dry powder administered for three months 1997; 10(Suppl.25): 3S.