The OPTIMA Randomized Trial |
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The optimal treatment for mild asthma is uncertain. We assessed the effects of adding a long-acting inhaled beta-agonist, formoterol, to low doses of an inhaled corticosteroid, budesonide, for 1 yr in subjects with mild asthma, receiving no or only a small dose of inhaled corticosteroid. The 698 corticosteroid free patients (Group A) were assigned to twice daily treatment with 100 µg budesonide, 100 µg budesonide plus 4.5 µg formoterol, or placebo. The 1,272 corticosteroid-treated patients (Group B) were assigned to twice daily treatment with 100 µg budesonide, 100 µg budesonide plus 4.5 µg formoterol, 200 µg budesonide, or 200 µg budesonide plus 4.5 µg formoterol. The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days. In Group A, budesonide alone reduced the risk for severe exacerbations by 60% and poorly controlled days by 48%; adding formoterol increased lung function with no change in other end points. By contrast, in Group B, adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30%, respectively. Thus, in corticosteroid-free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, and in patients already receiving inhaled corticosteroid, adding formoterol was more effective than doubling the corticosteroid dose.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Keywords: mild asthma; inhaled corticosteroids; budesonide; long acting beta-agonists; formoterol; management
Asthma management has undergone a number of important changes over the past 10 yr. Clinical studies have shown that the regular use of short-acting inhaled beta-agonists does not improve asthma control (1). Also, in patients with more severe asthma, the benefit from a 2- or 2.5-fold increase in the dose of an inhaled corticosteroid is limited, when compared with that achieved by adding a long-acting inhaled beta-agonist (4, 5). In addition, for patients with moderately severe asthma, the addition of formoterol, a fast onset, long-acting inhaled beta-agonist, reduced asthma exacerbations and improved symptoms and lung function when added to low or moderate doses of inhaled budesonide (the FACET study) (6).
The effect of combining a low dose of inhaled corticosteroids with low doses of an inhaled long-acting beta-agonist
is attractive since the benefits are at least additive, as in the
FACET study (6), and the long-term risks from adverse effects of higher doses of inhaled corticosteroids may be reduced. However, the effect of combined treatment has never
been evaluated in patients with mild asthma, although they
account for the majority of patients in primary care. In this
randomized controlled trial, we studied patients with mild
asthma, who experienced symptoms but were either taking no
inhaled corticosteroid or taking low dose inhaled corticosteroids (
400 µg budesonide/d or its equivalent). The aim was
to determine whether regular treatment with low doses of inhaled budesonide, with or without low doses of inhaled formoterol, would reduce severe asthma exacerbations and improve asthma control compared with placebo.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients
Patients were 
12 yr of age with mild asthma. Group A patients (corticosteroid-free) had used no inhaled corticosteroid for 3 mo, had a
FEV1 80% predicted normal (7) after inhaling 1 mg terbutaline
(Bricanyl Turbuhaler; AstraZeneca, Lund, Sweden). Group B patients were taking 400 µg/d of inhaled budesonide or its equivalent
for 3 mo, with a FEV1 70% predicted normal after terbutaline.
Randomized patients demonstrated a need for two or more inhalations per week of rescue medication during the last 2 wk of run-in, a
15% variability in peak expiratory flows (PEF), or a 12% increase in FEV1 after terbutaline.
Study Design
The study was double-blind, randomized, and parallel-group, carried out in 198 centers in 17 countries and conducted in accordance with the principles of good clinical practice. Approval from regulatory agencies and ethics committees was obtained in all countries and centers. All patients gave written, informed consent.
The study had a 4-wk run-in, when Group A patients took placebo and Group B patients took budesonide 100 µg twice daily. Eligible patients were randomly assigned to treatment twice daily for 1 yr: in Group A with 100 µg budesonide, 100 µg budesonide plus 4.5 µg formoterol, or placebo; in Group B with 100 µg budesonide, 100 µg budesonide plus 4.5 µg formoterol, 200 µg budesonide, or 200 µg budesonide plus 4.5 µg formoterol, all delivered by Turbuhaler (Astra Zeneca). The stated doses are metered doses for budesonide and delivered doses for formoterol. Patients attended the clinic on nine occasions, at the same time of day, over the year. No additional treatments were allowed unless the patient had a severe exacerbation, after which medications could be added at the physician's discretion.
Outcome Measures
The primary outcomes were (1) time to the first severe asthma exacerbation, defined as need for treatment with oral corticosteroids, as
judged by the investigator, or hospital admission or emergency treatment for worsening asthma, or a decrease in morning PEF > 25%
from baseline (the mean values during the last 14 d of the run-in) on
two consecutive days. This was chosen because it would not be influenced by a change in the patient's asthma treatment initiated by the
occurrence of the initial exacerbation, which was allowed in the protocol. Patients were not excluded from the study unless they experienced three severe exacerbations during the initial 6 mo or five exacerbations in total; (2) poorly controlled asthma days, defined as days
with morning PEF values 20% below baseline, or the use of rescue
medication was 2 above baseline, or with asthma awakening.
The secondary outcomes were changes in morning PEF, FEV1% predicted, percentage of days with symptoms, percentage of asthma awakenings, number of rescue inhalations, and rate per patient per year of severe asthma exacerbations. Patients completed a daily diary card during the run-in and for the first 7 d after each visit. They recorded morning PEF from a peak flow meter (Vitalograph, Buckingham, UK) before medication, number of rescue inhalations, symptoms, and asthma awakenings. Patients also kept a notebook to record health contacts, changes in medications, asthma-related events, and morning PEF.
Analysis
The study was analyzed using intention-to-treat principles. For Group A, pairwise comparisons were made. For Group B, the data were analyzed using a factorial design by appropriate contrasts. Time to the first severe exacerbation was analyzed using a Cox model for proportional hazards. Poorly controlled asthma days and the rate of severe exacerbations were analyzed using a Poisson regression model. The results are reported as risk ratios (RR) with 95% CI. Other variables were analyzed using analysis of covariance, with baseline values as covariates.
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RESULTS |
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METHODS
RESULTS
DISCUSSION
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A total of 900 patients were enrolled in Group A and 1,625 patients into Group B, of whom 698 and 1,272, respectively, were subsequently randomized to treatment (Table 1). A total of 23 patients were excluded from the efficacy evaluation: eight from Group A, 15 from Group B. There were no significant differences in baseline demographic or spirometric characteristics between the treatment arms in either group (Table 1). The year-long study was completed by 81% in Group A (n = 554) and by 87% in Group B (n = 1,092). Efficacy data were available for 1,947 patients. Of the 301 (15%) patients who did not complete the study, 51 (3%) discontinued because of adverse events, including 14 because of deteriorating asthma, and 250 (13%) were either ineligible for the study or left for personal reasons.
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Group A (Corticosteroid-free Patients)
In the placebo group, 79 of 237 patients had a severe asthma exacerbation, and asthma was poorly controlled in 14.4% of days. Patients receiving budesonide alone showed a 60% reduction in the risk for the first severe asthma exacerbation (RR = 0.40, 95% CI = 0.27 to 0.59) and a 48% reduction in the rate of poorly controlled asthma days (RR = 0.52, 95% CI = 0.40 to 0.67) when compared with patients given placebo (Figure 1A and 1B). There was also a reduction in the rate of exacerbations (RR = 0.38, 95% CI = 0.25 to 0.57), asthma symptoms, nocturnal awakening, and number of rescue inhalations of short-acting inhaled beta agonists in the budesonide group and an increase in FEV1 (Table 2). The addition of formoterol to budesonide provided further benefit over that seen for budesonide alone for FEV1 and morning PEF (Figure 2A), but not for other outcome variables (Table 2).
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Group B (Patients Taking Inhaled Corticosteroids)
In the budesonide 100 µg group, 107 of 317 patients had a severe asthma exacerbation and asthma was poorly controlled on 13% of days. When the groups taking budesonide 100 µg and 200 µg twice daily were compared, the higher dose of budesonide was associated with a 19% reduction in the risk of a first severe exacerbation (RR = 0.81, 95% CI = 0.65 to 1.01) (Figures 3A) and a 13% reduction in the rate of poorly controlled asthma days (RR = 0.87, 95% CI = 0.75 to 1.01) (Figure 3B). There was also a trend towards a reduction in the rate of severe exacerbations (RR = 0.82, 95% CI = 0.67 to 1.01) and small, but significant, improvements in the percentage of days with asthma symptom, FEV1, and morning PEF with the higher dose of budesonide (p < 0.05) (Figure 2B and Table 3).
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Adding formoterol to either the lower or higher dose of budesonide reduced the risk of the first asthma exacerbation by 43% (RR = 0.57, 95% CI = 0.46 to 0.72) (Figure 3A) and the rate of poorly controlled asthma days by 30% (RR = 0.70, 95% CI = 0.60 to 0.82) (Figure 3B). There was also a significant 52% reduction in the rate of severe exacerbations (RR = 0.48, 95% CI = 0.39 to 0.59) on adding formoterol to either the lower or the higher dose of budesonide. Formoterol also increased FEV1 and morning PEF and reduced the percentage of asthma symptom days and the number of rescue inhalations of short-acting inhaled beta-agonists (Table 3). Adding formoterol to the lower dose of budesonide was more effective than doubling the dose of budesonide, in terms of reducing the risk of a severe exacerbation day (RR = 0.71, 95% CI = 0.52 to 0.96) or a poorly controlled asthma day (RR = 0.81, 95% CI = 0.66 to 0.99). In addition, significant improvements were observed for the rate of severe exacerbations (RR = 0.58, 95% CI = 0.44 to 0.76), FEV1, and morning PEF (p = 0.001, p < 0.05, and p < 0.005, respectively).
Adverse Events
All treatments were well tolerated throughout the study. The frequency of reported adverse events, including those described as serious or causing patients to discontinue, was similar in Groups A and B and between the different treatments. Class-specific adverse effects of beta-agonist and inhaled corticosteroid occurred in less than 2% of patients in all treatment arms.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the role of regular treatment with low dose budesonide and low doses of formoterol for patients with mild, but symptomatic, asthma. Our primary end points were the time
to the first severe asthma exacerbation and the percentage of
poorly controlled asthma days. In patients who were not currently taking an inhaled corticosteroid (corticosteroid-free), a
low dose of inhaled budesonide reduced the rate of severe exacerbations and poorly controlled asthma days by more than
half. Adding formoterol resulted in improved lung function,
but no further clinical benefit. In patients taking a low dose of
inhaled corticosteroid ( 400 µg/d budesonide), the addition
of formoterol improved all outcome variables, including reducing severe exacerbations, and this benefit was significantly
superior to that seen with doubling the dose of budesonide.
This is the largest study yet reported to assess management of patients with mild asthma, and it covered a wide age range from 12 yr upwards. The corticosteroid-free asthmatic patients (Group A) had close to normal lung function (mean prebronchodilator FEV1 = 89.5%) and infrequent use of short-acting inhaled beta-agonists. Such patients are treated mainly in the primary care setting, often without inhaled corticosteroids (8, 9). Although such patients are considered to have mild asthma (10), one third of those taking placebo experienced a severe asthma exacerbation during the year of the study and asthma was poorly controlled on 14% of the days, confirming that appreciable morbidity is associated with the label of mild asthma (9). The most common cause of these poorly controlled days was asthma-related nocturnal awakenings (46.5%). In addition, the frequency of severe exacerbations was higher than expected, when planning the study, in this mild population. This reinforces the point that even patients thought to have mild asthma are at risk of severe, and even fatal, asthma exacerbations (11)
Patients in Group B were already taking low doses of inhaled corticosteroids on entry to the study, yet they were still mildly symptomatic and had lower lung function than in Group A. Doubling the budesonide dose produced little clinical benefit, whereas the addition of formoterol was associated with greater efficacy regarding the time to the first severe asthma exacerbation, the rate of asthma exacerbations, and the number of poorly controlled asthma days. The fact that giving a low dose of budesonide to the steroid-free group had a marked effect on asthma exacerbations and poorly controlled days, whereas doubling the dose of budesonide in Group B had a marginal benefit, is of interest. It supports other studies suggesting much of the benefit achieved with inhaled corticosteroids occurs with lower doses and that the dose-response curves are relatively flat thereafter (12).
The doses of inhaled budesonide used in the study are small and long-term adverse effects should be minimal. The two main adverse effects of concern with long-term use of inhaled corticosteroids, growth in children, and bone mineral density in adults, do not appear to be relevant when low doses of inhaled corticosteroids are used for asthma management (13, 14). However, there may be concern, regarding bone mineral density, when higher doses of inhaled corticosteroids are used (15). In addition, the need for oral corticosteroids and other antiasthma drugs was reduced by treatment with budesonide alone in Group A and by the addition of formoterol, but not the increased dose of budesonide, in Group B. Taken together, these results suggest that many patients considered to have mild asthma would benefit from low doses of budesonide and that if asthma control is not achieved, inhaled formoterol would provide further benefit.
A reduction in severe asthma exacerbations has also been demonstrated when formoterol is used as needed, at a similar dose, when compared with the short-acting inhaled beta-agonist, terbutaline (16). Neither the magnitude of this effect on severe asthma exacerbations nor of the effect on exacerbations described in the present study has yet been demonstrated with other long-acting inhaled beta-agonists, or other therapies, added to inhaled corticosteroids. The mechanism by which low-dose inhaled formoterol reduces severe asthma exacerbations in persons with mild asthma, as well as that seen with a double dose of formoterol in the FACET study, in those with more severe asthma (6), is uncertain. Possibilities include a reduction in airway eosinophils (17), or an inhibitory effect on mast cell activation (18).
A strength of this study is its size and general applicability to a large proportion of asthmatic patients and the fact that more than 84% of patients completed the year-long study. Patients' diaries were completed for 1 wk only after each study visit to improve compliance with their completion, although PEF was measured every day. We did not include a formoterol-only treatment arm for Group A since the role for regular bronchodilator therapy as monotherapy in asthma has been questioned (19), and long-acting inhaled beta-agonists used alone are not currently recommended for regular use in this patient group (10).
Additional asthma medications could be added, at the managing physician's discretion, once patients had recovered from their first severe asthma exacerbation during the study. This pragmatic approach mimics what happens in everyday management of asthma. The number of patients receiving additional treatment was highest in the placebo group in Group A and in those patients receiving budesonide 100 µg twice daily with placebo in Group B (Table 4). Despite this, outcomes, such as poorly controlled asthma days, which were measured over the year of the study, were greater in these groups when compared with the other treatment arms.
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Our results suggest that mild asthma may often be undertreated. The corticosteroid-free population had a frequency of severe asthma exacerbations that was approaching that previously reported for moderate to severe asthma (6), as well as symptoms, which were markedly improved by a low dose of inhaled budesonide. The definition of a severe asthma exacerbation in this study was slightly different (a 25% reduction in PEF for 2 consecutive d) from that in the FACET trial (a 30% reduction in PEF for 2 consecutive d) (6). This change from the FACET definition was decided on to increase the sensitivity of the definition because severe exacerbations were believed to be less likely in this milder patient population. In fact, the prevalence of severe exacerbations in the study was much greater than expected. In Group A, in the placebo-treated patients, 56 of the 79 identified as having a severe asthma exacerbation (71%) were identified by the managing physician as needing systemic corticosteroids. In Group B, in the patients receiving budesonide 100 µg twice daily with placebo with 81 of 107 (76%) with a severe exacerbation needed systemic corticosteroids (Table 4).
It is generally recommended that long-acting inhaled beta-agonists be added to moderate doses of inhaled corticosteroids
(generally 500 to 800 µg/d) (20). However, the current study
suggests that better asthma control can be achieved with the
addition of formoterol to lower doses of inhaled corticosteroids
than currently recommended. This may be different for patients with moderate to severe disease, where fourfold higher
doses of budesonide taken for 1 yr did reduce asthma exacerbations, as demonstrated in the FACET study (6). In addition,
the study indicates that for patients with mild persistent asthma,
not using inhaled corticosteroids, the introduction of a low dose
of budesonide alone was sufficient to achieve close to optimal asthma control and only if optimal control is not achieved
should additional therapy with formoterol be considered.
In summary, in corticosteroid-free patients, severe asthma exacerbations and asthma control benefit from a low dose of inhaled budesonide, with no further benefit from adding formoterol, except for lung function. By contrast, in patients already taking a low dose of inhaled corticosteroids, the addition of inhaled formoterol reduced asthma exacerbations and improved asthma control more effectively than doubling the dose of budesonide.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Paul M. O'Byrne, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Ave East, Hamilton, ON, Canada. E-mail: obyrnep{at}mcmaster.ca
(Received in original form April 24, 2001 and accepted in revised form July 27, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org| |
References |
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INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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1. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, et al . . Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-1396 [Medline].
2.
Drazen JM,
Israel E,
Boushey HA,
Chinchilli VM,
Fahy JV,
Fish JE, et al
.
. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma.
N Engl J Med
1996;
335:
841-847
3. Dennis SM, Sharp SJ, Vickers MR, Frost CD, Crompton GK, Barnes PJ, et al . . Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Lancet 2000; 355: 1675-1679 [Medline].
4. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219-224 [Medline].
5. Woolcock AJ, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481-1488 [Abstract].
6.
Pauwels RA,
Lofdahl C-G,
Postma DS,
O'Byrne PM,
Barnes PJ,
Ullman A.
Effect of inhaled formoterol and budesonide on exacerbations of
asthma.
N Engl J Med
1997;
337:
1405-1411
7. Roca J, Burgos F, Sunyer J, Saez M, Chinn S, Anto JM, Rodriguez-Roisin R, Quanjer PH, Nowak D, Burney P. References values for forced spirometry. Group of the European Community Respiratory Health Survey. Eur Respir J 1998; 11: 1354-1362 [Abstract].
8. O'Byrne PM, Cuddy L, Taylor DW, Birch S, Morris J, Syrotiuk J. The clinical efficacy and cost benefit of inhaled corticosteroids as therapy in patients with mild asthma in primary care practice. Can Respir J 1996; 3: 169-175 .
9. Turner-Warwick M. Nocturnal asthma: a study in general practice. J R Coll Gen Pract 1989; 39: 239-243 [Medline].
10. Sheffer AL, Bartal M, Bousquet J, Carrasco E, et al. Global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health 95-3659. 1995;70-114.
11. Robertson CF, Rubinfeld AR, Bowes G. Pediatric asthma deaths in Victoria: the mild are at risk. Pediatr Pulmonol 1992; 13: 95-100 [Medline].
12. Busse WW, Chervinksy P, Condemi J, Lumry WR, Petty TL, Rennard S, et al . . Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998; 101: 457-463 [Medline].
13.
Boulet LP,
Milot J,
Gagnon L,
Poubelle PE,
Brown J.
Long-term influence of inhaled corticosteroids on bone metabolism and density. Are
biological markers predictors of bone loss?
Am J Respir Crit Care Med
1999;
159:
838-844
14.
Agertoft L,
Pedersen S.
Effect of long-term treatment with inhaled
budesonide on adult height in children with asthma.
N Engl J Med
2000;
343:
1064-1069
15. Wong CS, Walsh LJ, Smith CJ, Wisniewski AFZ, Lewis SA, Hubbard R, et al . . Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000; 355: 1399-1403 [Medline].
16. Tattersfield AE, Lofdahl C-G, Postma DS, Ekstrom T, Eivindson A, Schreurs A, Rasidakis A, Karlsson K, Larsson P. On demand treatment: comparison of formoterol and terbutaline in moderate asthma. Eur Respir J 1999; 14: 4S .
17.
Wallin A,
Sandstrom T,
Soderberg M,
Howarth PH,
Lundback B,
Della-Cioppa G, et al
.
. The effects of regular inhaled formoterol, budesonide,
and placebo on mucosal inflammation and clinical indices in mild
asthma.
Am J Respir Crit Care Med
1999;
159:
79-86
18.
Nightingale JA,
Rogers DF,
Barnes PJ.
Differential effect of formoterol
on adenosine monophosphate and histamine reactivity in asthma.
Am
J Respir Crit Care Med
2000;
159:
1786-1790
19.
Lipworth BJ.
Airway subsensitivity with long-acting 
2-agonists: is there
cause for concern?
Drug Safety
1997;
16:
295-308
[Medline].
20. Boulet LP, Becker A, Berube D, et al . . Canadian asthma consensus report. CMAJ 1999; 161: S1-S61 .
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E. D. Bateman, S. S. Hurd, P. J. Barnes, J. Bousquet, J. M. Drazen, M. FitzGerald, P. Gibson, K. Ohta, P. O'Byrne, S. E. Pedersen, et al. Global strategy for asthma management and prevention: GINA executive summary Eur. Respir. J., January 1, 2008; 31(1): 143 - 178. [Abstract] [Full Text] [PDF]
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M. Cazzola and M. G. Matera Review: Safety of long-acting {beta}2 -agonists in the treatment of asthma Therapeutic Advances in Respiratory Disease, October 1, 2007; 1(1): 35 - 46. [Abstract] [PDF]
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P. M. O'Byrne How much is too much? The treatment of mild asthma Eur. Respir. J., September 1, 2007; 30(3): 403 - 406. [Full Text] [PDF]
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 A. Papi, G. W. Canonica, P. Maestrelli, P. Paggiaro, D. Olivieri, E. Pozzi, N. Crimi, A. M. Vignola, P. Morelli, G. Nicolini, et al. Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma N. Engl. J. Med., May 17, 2007; 356(20): 2040 - 2052. [Abstract] [Full Text] [PDF]
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P. J. Barnes Scientific rationale for using a single inhaler for asthma control Eur. Respir. J., March 1, 2007; 29(3): 587 - 595. [Abstract] [Full Text] [PDF]
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 J. Travers, S. Marsh, M. Williams, M. Weatherall, B. Caldwell, P. Shirtcliffe, S. Aldington, and R. Beasley External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax, March 1, 2007; 62(3): 219 - 223. [Abstract] [Full Text] [PDF]
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A. Deykin, M. E. Wechsler, H. A. Boushey, V. M. Chinchilli, S. J. Kunselman, T. J. Craig, E. DiMango, J. V. Fahy, M. Kraft, F. Leone, et al. Combination Therapy with a Long-Acting beta-Agonist and a Leukotriene Antagonist in Moderate Asthma Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 228 - 234. [Abstract] [Full Text] [PDF]
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 P. Ernst, A. McIvor, F. M. Ducharme, L.-P. Boulet, M. FitzGerald, K. R. Chapman, T. Bai, and for the Canadian Asthma Guideline Group Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med, November 7, 2006; 145(9): 692 - 694. [Abstract] [Full Text] [PDF]
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J M FitzGerald and P G Gibson Asthma exacerbations {middle dot} 4: Prevention. Thorax, November 1, 2006; 61(11): 992 - 999. [Abstract] [Full Text] [PDF]
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A. Bell and R. A. McIvor SMART therapy. Can. Med. Assoc. J., August 1, 2006; 175(3): 276 - 277. [Full Text] [PDF]
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S. R. Salpeter, N. S. Buckley, T. M. Ormiston, and E. E. Salpeter Meta-Analysis: Effect of Long-Acting {beta}-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths Ann Intern Med, June 20, 2006; 144(12): 904 - 912. [Abstract] [Full Text] [PDF]
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R. H. Green, C. E. Brightling, S. McKenna, B. Hargadon, N. Neale, D. Parker, C. Ruse, I. P. Hall, and I. D. Pavord Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness Eur. Respir. J., June 1, 2006; 27(6): 1144 - 1151. [Abstract] [Full Text] [PDF]
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A. R. Rubinfeld, R. Scicchitano, A. Hunt, P. J. Thompson, A. Van Nooten, and O. Selroos Formoterol Turbuhaler as reliever medication in patients with acute asthma Eur. Respir. J., April 1, 2006; 27(4): 735 - 741. [Abstract] [Full Text] [PDF]
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D. Cheung, H. C. J. van Klink, R. Aalbers, and for the OZON study group Improved lung function and symptom control with formoterol on demand in asthma. Eur. Respir. J., March 1, 2006; 27(3): 504 - 510. [Abstract] [Full Text] [PDF]
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K. F. Rabe, E. Pizzichini, B. Stallberg, S. Romero, A. M. Balanzat, T. Atienza, P. A. Lier, and C. Jorup Budesonide/Formoterol in a Single Inhaler for Maintenance and Relief in Mild-to-Moderate Asthma: A Randomized, Double-Blind Trial. Chest, February 1, 2006; 129(2): 246 - 256. [Abstract] [Full Text] [PDF]
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P. M. O'Byrne and E. Adelroth {beta}2 Deja Vu Chest, January 1, 2006; 129(1): 3 - 5. [Full Text] [PDF]
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 L. Todorova, E. Gurcan, A. Miller-Larsson, and G. Westergren-Thorsson Lung Fibroblast Proteoglycan Production Induced by Serum Is Inhibited by Budesonide and Formoterol Am. J. Respir. Cell Mol. Biol., January 1, 2006; 34(1): 92 - 100. [Abstract] [Full Text] [PDF]
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A. B. Chang and W. B. Glomb Guidelines for Evaluating Chronic Cough in Pediatrics: ACCP Evidence-Based Clinical Practice Guidelines Chest, January 1, 2006; 129(1_suppl): 260S - 283S. [Abstract] [Full Text] [PDF]
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C. Vogelmeier, A. D'Urzo, R. Pauwels{dagger}, J. M. Merino, M. Jaspal, S. Boutet, I. Naya, and D. Price Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur. Respir. J., November 1, 2005; 26(5): 819 - 828. [Abstract] [Full Text] [PDF]
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K. Maneechotesuwan, S. Essilfie-Quaye, S. Meah, C. Kelly, S. A. Kharitonov, I. M. Adcock, and P. J. Barnes Formoterol Attenuates Neutrophilic Airway Inflammation in Asthma Chest, October 1, 2005; 128(4): 1936 - 1942. [Abstract] [Full Text] [PDF]
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A. Becker, C. Lemiere, D. Berube, L.-P. Boulet, F. M. Ducharme, M. FitzGerald, T. Kovesi, and on behalf of The Asthma Guidelines Working Group o Summary of recommendations from the Canadian Asthma Consensus Guidelines, 2003 Can. Med. Assoc. J., September 13, 2005; 173(6_suppl): S3 - S11. [Full Text] [PDF]
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S. E. Overbeek, P. G. Mulder, S. M. Baelemans, H. C. Hoogsteden, and J.-B. Prins Formoterol Added to Low-Dose Budesonide Has No Additional Antiinflammatory Effect in Asthmatic Patients Chest, September 1, 2005; 128(3): 1121 - 1127. [Abstract] [Full Text] [PDF]
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M Masoli, M Weatherall, S Holt, and R Beasley Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma Thorax, September 1, 2005; 60(9): 730 - 734. [Abstract] [Full Text] [PDF]
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P. M. O'Byrne Daily Inhaled Corticosteroid Treatment Should Be Prescribed for Mild Persistent Asthma Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 410 - 412. [Full Text] [PDF]
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H. A. Boushey Rebuttal from Dr. Boushey Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 415 - 415. [Full Text] [PDF]
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M. B. Stanbrook Is daily inhaled steroid use necessary in the treatment of mild persistent asthma? Can. Med. Assoc. J., May 24, 2005; 172(11): 1439 - 1439. [Full Text] [PDF]
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H. A. Boushey, C. A. Sorkness, T. S. King, S. D. Sullivan, J. V. Fahy, S. C. Lazarus, V. M. Chinchilli, T. J. Craig, E. A. Dimango, A. Deykin, et al. Daily versus As-Needed Corticosteroids for Mild Persistent Asthma N. Engl. J. Med., April 14, 2005; 352(15): 1519 - 1528. [Abstract] [Full Text] [PDF]
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L. M. Fabbri Does Mild Persistent Asthma Require Regular Treatment? N. Engl. J. Med., April 14, 2005; 352(15): 1589 - 1591. [Full Text] [PDF]
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 G. P Currie, G. S Devereux, D. K C Lee, and J. G Ayres Recent developments in asthma management BMJ, March 12, 2005; 330(7491): 585 - 589. [Full Text] [PDF]
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P. J. Barnes A Single Inhaler for Asthma? Am. J. Respir. Crit. Care Med., January 15, 2005; 171(2): 95 - 96. [Full Text] [PDF]
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P. M. O'Byrne, H. Bisgaard, P. P. Godard, M. Pistolesi, M. Palmqvist, Y. Zhu, T. Ekstrom, and E. D. Bateman Budesonide/Formoterol Combination Therapy as Both Maintenance and Reliever Medication in Asthma Am. J. Respir. Crit. Care Med., January 15, 2005; 171(2): 129 - 136. [Abstract] [Full Text] [PDF]
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H Powell and P G Gibson Initial starting dose of inhaled corticosteroids in adults with asthma: a systematic review Thorax, December 1, 2004; 59(12): 1041 - 1045. [Abstract] [Full Text] [PDF]
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P. M. A. Calverley Effect of Corticosteroids on Exacerbations of Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 161 - 166. [Abstract] [Full Text] [PDF]
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E. D. Bateman, H. A. Boushey, J. Bousquet, W. W. Busse, T. J. H. Clark, R. A. Pauwels, S. E. Pedersen, and for the GOAL Investigators Group Can Guideline-defined Asthma Control Be Achieved?: The Gaining Optimal Asthma ControL Study Am. J. Respir. Crit. Care Med., October 15, 2004; 170(8): 836 - 844. [Abstract] [Full Text] [PDF]
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P.G. Cox, J. Miller, W. Mitzner, and A.R. Leff Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations Eur. Respir. J., October 1, 2004; 24(4): 659 - 663. [Abstract] [Full Text] [PDF]
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 D. D. Sin, J. Man, H. Sharpe, W. Q. Gan, and S. F. P. Man Pharmacological Management to Reduce Exacerbations in Adults With Asthma: A Systematic Review and Meta-analysis JAMA, July 21, 2004; 292(3): 367 - 376. [Abstract] [Full Text] [PDF]
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D. A. Stempel, C. S. Roberts, and R. H. Stanford Treatment Patterns in the Months Prior to and After Asthma-Related Emergency Department Visit Chest, July 1, 2004; 126(1): 75 - 80. [Abstract] [Full Text] [PDF]
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W W Busse and R F Lemanske Jr Management of asthma exacerbations Thorax, July 1, 2004; 59(7): 545 - 546. [Full Text] [PDF]
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J M FitzGerald, A Becker, M R Sears, S Mink, K Chung, and J Lee Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations Thorax, July 1, 2004; 59(7): 550 - 556. [Abstract] [Full Text] [PDF]
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S. R. Salpeter, T. M. Ormiston, and E. E. Salpeter Meta-Analysis: Respiratory Tolerance to Regular {beta}2-Agonist Use in Patients with Asthma Ann Intern Med, May 18, 2004; 140(10): 802 - 813. [Abstract] [Full Text] [PDF]
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M. Masoli, S. Holt, M. Weatherall, and R. Beasley Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis Eur. Respir. J., April 1, 2004; 23(4): 552 - 558. [Abstract] [Full Text] [PDF]
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R. A. Pauwels Similarities and Differences in Asthma and Chronic Obstructive Pulmonary Disease Exacerbations Proceedings of the ATS, April 1, 2004; 1(2): 73 - 76. [Abstract] [Full Text] [PDF]
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P. M. O'Byrne Pharmacologic Interventions to Reduce the Risk of Asthma Exacerbations Proceedings of the ATS, April 1, 2004; 1(2): 105 - 108. [Abstract] [Full Text] [PDF]
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T. van der Molen Formoterol and Asthma Exacerbations Chest, April 1, 2004; 125(4): 1591 - 1591. [Full Text] [PDF]
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R.A. Pauwels, M.R. Sears, M. Campbell, C. Villasante, S. Huang, A. Lindh, W. Petermann, M. Aubier, G. Schwabe, and T. Bengtsson Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial Eur. Respir. J., November 1, 2003; 22(5): 787 - 794. [Abstract] [Full Text] [PDF]
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M. Mann, B. Chowdhury, E. Sullivan, R. Nicklas, R. Anthracite, and R. J. Meyer Serious Asthma Exacerbations in Asthmatics Treated With High-Dose Formoterol Chest, July 1, 2003; 124(1): 70 - 74. [Abstract] [Full Text] [PDF]
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U. G. Lalloo, J. Malolepszy, D. Kozma, K. Krofta, J. Ankerst, B. Johansen, and N. C. Thomson Budesonide and Formoterol in a Single Inhaler Improves Asthma Control Compared With Increasing the Dose of Corticosteroid in Adults With Mild-to-Moderate Asthma Chest, May 1, 2003; 123(5): 1480 - 1487. [Abstract] [Full Text] [PDF]
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 R H Green, C E Brightling, I D Pavord, and A J Wardlaw Management of asthma in adults: current therapy and future directions Postgrad. Med. J., May 1, 2003; 79(931): 259 - 267. [Abstract] [Full Text] [PDF]
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G. Strube, C Ward, D Reid, and E H Walters Revision of BTS guidelines for treatment of asthma Thorax, March 1, 2003; 58(3): 280 - 280. [Full Text] [PDF]
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W. Szafranski, A. Cukier, A. Ramirez, G. Menga, R. Sansores, S. Nahabedian, S. Peterson, and H. Olsson Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Eur. Respir. J., January 1, 2003; 21(1): 74 - 81. [Abstract] [Full Text] [PDF]
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A.S. Buist Similarities and differences between asthma and chronic obstructive pulmonary disease: treatment and early outcomes Eur. Respir. J., January 1, 2003; 21(39_suppl): 30S - 35s. [Abstract] [Full Text] [PDF]
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R. B. Hubbard, C. J. P. Smith, L. Smeeth, T. W. Harrison, and A. E. Tattersfield Inhaled Corticosteroids and Hip Fracture: A Population-based Case-Control Study Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1563 - 1566. [Abstract] [Full Text] [PDF]
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B J Lipworth and C M Jackson Marginal benefits of adding formoterol Thorax, December 1, 2002; 57(12): 1089 - 1089. [Full Text] [PDF]
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K. G. Lim Management of Persistent Symptoms in Patients With Asthma Mayo Clin. Proc., December 1, 2002; 77(12): 1333 - 1339. [Abstract] [PDF]
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R. Leigh, D. Vethanayagam, M. Yoshida, R. M. Watson, T. Rerecich, M. D. Inman, and P. M. O'Byrne Effects of Montelukast and Budesonide on Airway Responses and Airway Inflammation in Asthma Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1212 - 1217. [Abstract] [Full Text] [PDF]
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C. Lemiere, A. Becker, L.-P. Boulet, D. Bowie, A. Cartier, D. Cockroft, R. Cowie, P. Ernst, M. Fitzgerald, M. Sears, et al. Should combination therapy with inhaled corticosteroids and long-acting {beta}2-agonists be prescribed as initial maintenance treatment for asthma? Can. Med. Assoc. J., October 29, 2002; 167(9): 1008 - 1009. [Full Text] [PDF]
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P.W. Ind, C. Villasante, R.J. Shiner, A. Pietinalho, N.G. Boszormenyi, S. Soliman, and O. Selroos Safety of formoterol by Turbuhaler(R) as reliever medication compared with terbutaline in moderate asthma Eur. Respir. J., October 1, 2002; 20(4): 859 - 866. [Abstract] [Full Text] [PDF]
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 {blacktriangledown}Seretide and {blacktriangledown}Symbicort in asthma management DTB, August 1, 2002; 40(8): 62 - 64. [Abstract] [Full Text] [PDF]
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 D. Grosser and B. Smith Low dose budesonide improved asthma control in mild asthma; adding formoterol improved control in corticosteroid treated patients Evid. Based Med., July 1, 2002; 7(4): 120 - 120. [Full Text] [PDF]
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B. J. Lipworth, P. M. O'Byrne, P. J. Barnes, R. Rodriguez-Roisin, T. Sandstrom, and A. Tattersfield BUDESONIDE DOSE-RESPONSE IN MILD PERSISTENT ASTHMA Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1188a - 1189. [Full Text]
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M. J. TOBIN Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 598 - 618. [Full Text] [PDF]
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P.J. Barnes Scientific rationale for inhaled combination therapy with long-acting {beta}2-agonists and corticosteroids Eur. Respir. J., January 1, 2002; 19(1): 182 - 191. [Abstract] [Full Text] [PDF]
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J. C. Kips Treating Asthma, or Is Simple Too Simple? Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1336 - 1338. [Full Text] [PDF]
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