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Review Article |

Long-Acting β2-Agonist Step-off in Patients With Controlled Asthma:  Systematic Review With Meta-analysis FREE

Jan L. Brozek, MD, PhD; Monica Kraft, MD; Jerry A. Krishnan, MD, PhD; Michelle M. Cloutier, MD; Stephen C. Lazarus, MD; James T. Li, MD, PhD; Nancy Santesso, RD, MLIS; Robert C. Strunk, MD; Thomas B. Casale, MD
[+] Author Affiliations

Author Affiliations: Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Brozek and Ms Santesso); Duke Asthma, Allergy and Airway Center, Department of Medicine, Duke University, Durham, North Carolina (Dr Kraft); Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago (Dr Krishnan); Department of Pediatrics, University of Connecticut Health Center, Farmington, and Asthma Center, Connecticut Children's Medical Center, Hartford (Dr Cloutier); Division of Pulmonary and Critical Care Medicine and the Cardiovascular Research Institute, University of California, San Francisco (Dr Lazarus); Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota (Dr Li); Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Missouri (Dr Strunk); and Division of Allergy and Immunology, Creighton University, Omaha, Nebraska (Dr Casale).


Arch Intern Med. 2012;172(18):1365-1375. doi:10.1001/archinternmed.2012.3250.
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Background Because of concerns about the safety of long-acting β2-agonist (LABA) use in patients with asthma, withdrawal of the LABA is recommended by the US Food and Drug Administration once asthma is controlled by combination therapy with a LABA and inhaled corticosteroid (ICS).

Objective To perform a systematic review and meta-analysis assessing evidence supporting the discontinuation of LABA therapy once asthma control has been achieved with a combination of ICS and LABA.

Data Sources MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched (through August 2010), references of identified studies and selected narrative review articles were evaluated, registries of clinical trials were reviewed, and manufacturers of LABAs were contacted.

Study Selection Randomized controlled trials of discontinuation of LABA therapy in patients with asthma controlled with a combination of ICS and LABA.

Data Extraction Two reviewers independently screened each title and abstract in the initial searches and then the full text of each nominated article to extract data for analyses.

Results Of 1492 screened articles, only 5 trials involving patients aged 15 years or older fulfilled a priori–specified inclusion criteria. Results did not favor the LABA step-off approach compared with no change in treatment. The LABA step-off regimen increased asthma impairment, with worse Asthma Quality of Life Questionnaire score (mean difference [95% CI], 0.32 [0.14-0.51] points lower); worse Asthma Control Questionnaire score (0.24 [0.13-0.35] points higher); fewer symptom-free days (9.15% [1.62%-16.69%] less); and greater risk of withdrawal from study resulting from lack of efficacy or loss of asthma control (risk ratio, 3.27 [2.16-4.96]). Risk of exacerbations and deaths after LABA step-off were not evaluable because of the small number of events and short duration of follow-up.

Conclusions Evidence suggests that discontinuing LABA therapy in adults and older children with asthma controlled with a combination of ICSs and LABAs results in increased asthma-associated impairment. Additional trials measuring all long-term patient-important outcomes are needed.

Figures in this Article

Recommendations for asthma therapy have been promulgated through the National Asthma Education and Prevention Program (NAEPP) guidelines, the most recent of which were published in 2007.1 The NAEPP Expert Panel Report 3 (EPR-3) emphasized the importance of assessing asthma control to guide long-term therapy, whether stepping up or stepping down therapy. Asthma severity and control have 2 domains: (1) impairment (ie, severity of symptoms, functional limitations, reduced quality of life, and other manifestations of asthma) and (2) risk of exacerbations or decreased lung function. The primary goal of asthma therapy is to eliminate impairment and reduce the risk.

One major class of medications for asthma therapy is the long-acting β2-agonists (LABAs). Quiz Ref IDIn response to safety concerns, the guidelines recommend that the drugs not be used as monotherapy for long-term control of persistent asthma but should continue to be considered adjunctive therapy to inhaled corticosteroids (ICSs). In making recommendations for preferred medications, the NAEPP EPR-3 tried to balance efficacy and safety for patients with various levels of asthma severity or control.1 For patients with asthma not adequately controlled by low-dose ICSs, the EPR-3 gave equal weight to increasing the ICS dose and adding a LABA. The EPR-3 continued to endorse the use of a combination of ICS and LABA as the most effective therapy for patients with severe persistent asthma or asthma that was not well controlled by ICS monotherapy.1

The EPR-3 recommended that consideration be given to stepping down therapy after asthma control is achieved for several months.1 The timing and strategies of stepping down asthma care have not been well defined and are not well substantiated by data. Most studies focused on reducing the dose of ICSs while continuing other controller medications, including LABAs. This strategy aims to reduce the potential adverse effects of higher dosages of ICSs for children and adults. Appropriate step-down recommendations must be individualized.

In February 2010, the US Food and Drug Administration (FDA) announced a class labeling change for LABAs based on safety concerns.2 The labeling change was prompted primarily by data from the Salmeterol Multicenter Asthma Research Trial (SMART), which raised concerns that the use of salmeterol xinafoate alone has associated risks for severe asthma outcomes.3 The data from the SMART suggested a higher risk for catastrophic asthma events, including hospitalizations, intubations, and deaths, in patients receiving salmeterol. The FDA subsequently published 4 recommendations for labeling changes for LABAs. The fourth recommendation is perhaps the most controversial and states: once asthma control is achieved and maintained, patients should be assessed at regular intervals, and step-down therapy should begin (eg, discontinue the LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid.2

Subsequent to publication of the FDA recommendations, members of the EPR-3 wrote an editorial addressing these recommendations.4 Commenting especially on the fourth recommendation, they voiced a concern that the precipitous withdrawal of LABAs might put patients at risk for worsening asthma and that step-down approaches had not been sufficiently studied.

The American Academy of Allergy Asthma and Immunology and the American Thoracic Society formed a joint task force to address the issue of step-off strategies for patients whose asthma was controlled by combination ICS and LABA treatment. We searched for systematic reviews that addressed step-off strategies but found none. We therefore performed a systematic review and meta-analysis assessing the evidence supporting discontinuation of LABAs once asthma control is achieved. The clinical question is: Should LABAs be discontinued after achieving control of symptoms in patients with asthma who required combined therapy with an ICS and a LABA because of inadequate control of symptoms with an ICS alone?

Our primary objective was to evaluate the effects of the discontinuation of LABA once asthma control has been achieved with a combination of ICS and LABA. We developed and followed a protocol that included several criteria.

CRITERIA FOR CONSIDERING STUDIES

We developed a protocol and determined a priori to include randomized controlled trials that enrolled children aged 4 or more years and adults with asthma who required treatment with a combination of an ICS and LABA to control asthma symptoms. The intervention of interest was the discontinuation of LABA therapy and unchanged dosage of ICSs (LABA step-off) compared with continued use of unchanged dosages of LABAs and ICSs (no change in treatment) in patients who initially received a drug from each class to control symptoms. We reviewed studies that used salmeterol or formoterol fumarate dihydrate. We specified a priori that a target population of interest would have used the combination of an ICS and a LABA twice daily for at least 3 months and that asthma would have been well controlled for at least 3 months before discontinuation of the LABA.

TYPES OF OUTCOME MEASURES

The outcome measures did not constitute criteria for including studies in this review. We selected outcomes of interest following the approach suggested by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group.5 Outcomes that we identified a priori as potentially important for patients are listed in eTable 1. We rated their relative importance on a 9-point scale: critical, 7 to 9; important, 4 to 6; and of limited importance for decision making, 1 to 3.

SEARCH METHODS FOR IDENTIFICATION OF STUDIES

We developed search strategies that were a combination of subject terms (eAppendix 1). We searched OVID MEDLINE (1950 through August week 5, 2010), OVID EMBASE (1980 through 2010 week 36), and The Cochrane Library, including Cochrane Central Register of Controlled Trials; Clinical Trials; Database of Abstracts of Reviews of Effects (DARE); and NHS (National Health Service) Economic Evaluation Database (until August 2010).

We also searched registries of clinical trials provided by the manufacturers of formoterol (http://www.astrazenecaclinicaltrials.com) and salmeterol (http://www.gsk-clinicalstudyregister.com). We reviewed the references of identified studies and selected narrative review articles on the topic. We also asked experts in the field and the manufacturers of salmeterol and formoterol for studies that we might have missed.

SELECTION OF STUDIES

One investigator (J.L.B.) carried out the initial searches, and 2 investigators (J.L.B. and J.A.K.) independently reviewed titles and abstracts of all identified citations and assessed them for eligibility. Decisions were recorded and compared; in cases of disagreement about whether to include a study, we accepted it for full-text screening. Agreement between investigators about inclusion for full-text screening was moderate because one of the reviewers was generally more inclusive than the other (κ = 0.46; 95% CI, 0.42-0.50). Overall, 43 potentially relevant reports of studies were identified from the initial searches. Subsequently, 2 review authors independently screened the full-text articles for eligibility, using a standardized form with explicit inclusion and exclusion criteria. Agreement between review authors about study eligibility was very good (κ = 0.81; 95% CI, 0.50-1.13). Disagreements were resolved by discussion or by consulting a third review author (J.L.B.). Studies that did not fulfill the criteria631 were excluded, and the reasons for exclusion were recorded (eAppendix 2).

DATA EXTRACTION AND MANAGEMENT

We developed, piloted, and used a standardized data extraction form. One author extracted data from each included study, and the other systematically checked the correctness of data extraction. Disagreements were resolved by discussion. Details of the process are reported in eAppendix 3.

ASSESSMENT OF THE RISK OF BIAS AND THE QUALITY OF THE EVIDENCE

We assessed the risk of bias at the outcome level, using The Cochrane Collaboration's tool for assessing risk of bias.32 Subsequently, we assessed the quality of evidence (ie, confidence in the estimated effects) for each of the outcomes of interest, following the GRADE approach.33 The small number of studies did not allow use of a funnel plot or statistical tests to detect the possibility of publication bias.

DATA SYNTHESIS

We calculated the agreement between the 2 reviewing authors for the assessment of trial eligibility using the κ statistic. We calculated risk ratio (RR) of dichotomous outcomes and rate ratios for count data for outcomes that each participant could experience more than once.34 We used mean difference meta-analysis to combine the results for continuous or ordinal outcome data. Commercial software (Review Manager, version 5.1.1)35 was used to conduct the meta-analyses.

ASSESSMENT OF HETEROGENEITY

We assessed heterogeneity between trials by visual inspection of forest plots, by estimation of the percentage of heterogeneity between trials that cannot be ascribed to sampling variation, and by a formal statistical test of the significance of the heterogeneity.36 If there was evidence of substantial heterogeneity (ie, I2 ≥50%), we investigated and reported possible explanations. We intended to explore heterogeneity based on a priori–specified characteristics of participants (age, 4-11, 12-17, and ≥18 years; receiving ICS plus LABA because of inadequate control of symptoms with ICSs alone vs receiving the combination for an unspecified reason; receiving ICSs at a dose of ≥200 μg/d of fluticasone propionate or an equivalent vs a lower dose; and duration of good control of asthma before the step-off phase of 3-5 months vs ≥6 months) and type of the experimental intervention (combination ICS and LABA from a single inhaler vs separate inhalers).

INCLUDED STUDIES

Our electronic searches identified 1497 distinct records; we excluded 1457 on the basis of title and abstract screening (Figure 1). Full-text articles of the remaining 40 articles were assessed for eligibility and 23 were excluded (eAppendix 2). We found 5 randomized controlled trials that examined LABA step-off in patients with asthma compared with no change in use of LABAs and ICSs (Table 1).3751 Four studies were published in peer-reviewed journals37,39,42,47 and 1 was available only as a conference abstract50 and a report in the manufacturer's online register of studies.51

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Figure 1. Flow of information through the different stages of the systematic review (for details about the excluded studies, see eAppendix 2). CENTRAL indicates Cochrane Central Register of Controlled Trials.

Table Graphic Jump LocationTable 1. Characteristics of the Included Trials

All studies included adult or older adolescent patients with a 6-month or longer history of mild to moderate asthma (Table 1). All studies used a combination of ICS and LABA from the same inhaler as study medication. Studies allowed short-acting β2-agonists as rescue medication; no study reported using short-acting anticholinergic agents. Based on the reported information, we were uncertain whether a combination treatment with ICS and LABA was required to control symptoms at study enrollment in 4 of 5 included studies. Also, the duration of asthma that was well controlled with use of the combined treatment before LABA step-off was shorter than the recommendation of at least 3 months.1

QUALITY OF EVIDENCE FROM THE INCLUDED STUDIES

Our assessment of the risk of bias in the 5 randomized trials included in the review is reported in eTable 2. Quiz Ref IDThere was no indication of the serious risk of bias in the studies except for incompleteness of follow-up: 12% to 38% of participants discontinued treatment and were excluded from some analyses. All studies were funded by the manufacturers of study medications.Table 2 presents numerical values for all analyses for all outcomes. Our assessment of the quality of available evidence (ie, confidence in the estimates of the effects) is given in eTable 3.

Table Graphic Jump LocationTable 2. LABA Step-off vs Continued Use of LABAs in Patients With Asthma That Is Well Controlled With a Combination of ICS and LABA
EFFECTS OF INTERVENTIONS

No study measured or reported the number of emergency department visits or unscheduled consultations for asthma, days missed from work or school, resource use (cost), and complications associated with the systemic effects of ICSs. No patient died, was admitted to the hospital, or required intubation or mechanical ventilation during the observation periods of the included studies.

BENEFITS OF LABA STEP-OFF

There were no statistically significant results for any of the reported asthma outcomes of interest showing a benefit from LABA step-off approach compared with continued use of the same dose of ICS and LABA (no change in treatment) (Table 2). The frequency of adverse events not related to asthma was similar between patients undergoing LABA step-off and those with no change in treatment (RR, 0.93; 95% CI, 0.86-1.02) (eFigure 1). Serious adverse events occurred in 7 of 660 patients (1.1%) in the LABA step-off groups and in 9 of 682 patients (1.3%) in the control groups (RR, 0.79; 95% CI, 0.29-2.09). Similarly, 17 of 660 patients (2.6%) in the LABA step-off groups and 19 of 682 patients (2.8%) in the control groups withdrew from the studies because of an adverse event (RR, 0.92; 95% CI, 0.47-1.8).

ADVERSE OUTCOMES OF LABA STEP-OFF

Quiz Ref IDThe LABA step-off approach reduced the quality of life of patients (mean difference [95% CI] in Asthma Quality of Life Questionnaire score, 0.32 [95% CI, 0.14-0.51] points lower) as well as reduced control of asthma (mean difference in Asthma Control Questionnaire score, 0.24 [95% CI, 0.13-0.35] points higher).Quiz Ref IDDiscontinuation of LABAs also increased symptom frequency as measured by the proportion of symptom-free days (mean difference, 9.15% [95% CI, 1.62%-16.69%] fewer symptom-free days) and the risk of withdrawing from the study because of lack of efficacy or loss of asthma control (RR, 3.27 [95% CI, 2.16-4.96]). Patients who discontinued LABAs required a mean of 0.71 (95% CI, 0.29-1.14) more puffs per day of a rescue bronchodilator. The risk of need for oral corticosteroids was increased, but the increase was not statistically significant (RR, 1.68 [95% CI, 0.84-3.38]). Similarly, there were nonsignificant trends for increased risk of loss of asthma control as defined by the investigators (RR, 1.24 [95% CI, 0.79-1.95]) and a reduced proportion of awakening-free nights (mean difference, 1.47% fewer [95% CI, 3.18% fewer to 0.23% more]) (Table 2).

Individual forest plots of some of the asthma impairment measures rated by us as the most important for decision making are shown in Figure 2 and Figure 3. The remainder of the forest plots are shown in eFigure 2.

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Figure 2. Forest plots of the effects of continuing long-acting β2-agonist (LABA) therapy vs stepping off with regard to any use of systemic corticosteroids, asthma control, and quality of life. ACQ indicates Asthma Control Questionnaire; RR, risk ratio. The size of the data marker corresponds to the relative weight assigned in the analysis. *Risk ratio. Mantel-Haenszel method; random effects analysis model. †Data obtained directly from the study sponsor. ‡Inverse variance method; random effects analysis model. §Asthma Quality of Life Questionnaire (AQLQ) (data obtained directly from the study sponsor); higher values indicate better quality of life. Sign of change score was changed to allow same direction of change in both studies. Results favored combination of inhaled corticosteroid plus LABA. ∥Marks AQLQ; higher values indicate better quality of life.

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Figure 3. Forest plots of the effects of continuing long-acting β2-agonist (LABA) therapy vs stepping off with regard to deterioration of symptoms, night-waking due to asthma, and any serious adverse effect. OR indicates odds ratio; RR, risk ratio. The size of the data marker corresponds to the relative weight assigned in the analysis. *Inverse variance method; random effects analysis model. †Change from baseline. ‡Variability obtained directly from the study sponsor. §Final score. ∥Control group: breast cancer in situ, traffic accident, musculoskeletal chest pain; experimental group: tension headache; none was deemed related to study medication. ¶Control group: loss of consciousness, car crash, breast cancer, chest pain; experimental group: pulmonary embolism. #Control group: gallstones, severe respiratory tract infection; experimental group: bleeding hemorrhoids, esophageal narrowing, and a cerebral arteriovenous malformation thought to have been congenital. **Control group: cholecystitis; experimental group: herniated lumbar disc, breast cancer.

To our knowledge, this is the first systematic review and meta-analysis of randomized controlled trials investigating the effects of stepping off LABA use in patients with asthma controlled by combination ICS and LABA therapy. An interesting and important finding is the paucity of studies evaluating this issue. The results of the available studies suggest that discontinuation of LABAs compared with continued use of LABAs and ICSs increases the risk of loss of asthma control in adults. However, there is uncertainty about estimated effects because of the risk of bias in the included studies, imprecision of the estimates, and indirectness of the evidence (Table 2).

Limitations of our review include the methodological quality of the included randomized trials (eTable 2). Potential issues identified included lack of verification of the need for combination ICS and LABA treatment for the patients studied, the short duration of the studies and trial phases, lack of information on treatment adherence, and the relatively high withdrawal rates of patients in some studies. In addition, we did not conduct an explicit search for observational studies to assess the information about outcomes for which there was no evidence from randomized trials or those for which the quality of evidence from randomized trials was very low. We could not exclude the possibility of publication bias. With only 5 studies being available, techniques of estimating the likelihood of publication bias are not reliable. One might suspect publication bias in uniformly small studies showing favorable results and sponsored by the for-profit institution with an interest in the study results. However, we identified one industry-sponsored study that remained unpublished despite showing the same effects as the published studies; we did not identify any other study that would be registered but not published. Quiz Ref IDBecause the quality of the evidence about many critical outcomes was low to very low, any additional downgrading for possible publication bias would have little influence on our confidence in the estimated effects.

The strengths of this systematic review are the very broad search criteria and the paucity of missing information that was obtained directly from the study sponsors, making it unlikely that we missed any relevant information. Thus, our findings likely represent the current best evidence about stepping off LABA therapy in patients with asthma.

Concern over the safety of LABAs was initially raised in 1993 from a study conducted in the United Kingdom.52 The Serevent Nationwide Surveillance Study was a 14-week double-blind, randomized study that enrolled 25 180 individuals, with 16 787 receiving salmeterol twice daily and 8393 receiving albuterol sulfate (salbutamol sulfate) 4 times daily. At entry, more than 80% of the participants had moderate or severe persistent asthma, but less than 70% of patients were receiving ICSs. More asthma deaths occurred in patients receiving salmeterol (12 of 16 787) vs albuterol (2 of 8393), representing a nonstatistically significant increase in mortality (RR, 3.0; 95% CI, 0.7-20). However, those results were very imprecise because of the small number of events in both groups. Twelve of 14 participants who died were using more than 2 short-acting β2-agonist canisters per month. The authors concluded that overuse of β2-agonists and inadequate use of ICSs in patients with severe or unstable asthma, rather than LABA therapy, placed patients at greatest risk of asthma mortality.52

These findings prompted the SMART, which was designed to assess the safety of salmeterol added to usual therapy compared with usual therapy alone.3 In this 7-month placebo-controlled, double-blind study, patients were evaluated by the study physician only once and received a 7-month supply of study medication. Subsequent contact was monthly by telephone from a central office. An interim analysis at 50% of the randomization goal demonstrated an increase in asthma mortality in patients randomized to receive salmeterol. Thirteen of 13 176 patients receiving salmeterol died compared with 3 patients of 13 179 who had received placebo (RR, 4.37; 95% CI, 1.25-15.34). Seven of 13 fatalities occurred in African Americans, who represented 18% of the cohort, suggesting a possibly higher risk in this population. The potential contribution of the use of ICSs was not measured. Although the study was not designed to evaluate whether concurrent ICS use modified the risk of asthma death, 7 participants reporting ICS use at entry died: 4 randomized to receive salmeterol and 3 randomized to receive placebo. Nine patients who were not receiving ICSs died; all were randomized to receive salmeterol. There were many flaws in this study, and patient follow-up was not typical of most controlled trials. Nonetheless, the results prompted a number of varied opinions about the potential risk-benefit ratio of LABAs for asthma. Several authors5355 concluded that the increase in unadjusted risk associated with LABAs may be the result of confounding by severity. Others56 concluded if LABAs were removed from the market in the United States, we might witness a reduction in asthma mortality rates.

The NAEPP EPR-3 had these data prior to formulating the latest asthma guidelines but did not conclude that LABAs put patients at risk for catastrophic asthma events.1 The FDA, however, directed manufacturers to place a black-box warning on all products that contain salmeterol or formoterol and expressed a concern about the safety of LABAs.2

Few new data about the safety of LABAs have been forthcoming, but investigators, including some from the FDA, have pooled data from previous clinical trials to further study the potential risks of LABAs.5769 These analyses have provided contradictory conclusions, putting clinicians in an unsettling role of trying to decide how to best step down therapy. Indeed, the present study was prompted by members of the American Academy of Allergy Asthma and Immunology and American Thoracic Society appealing to the leadership of these professional societies for guidance, especially in regard to how best to step down asthma treatment once asthma is controlled.

We found few randomized controlled trials designed to explore the effects of stepping off LABAs in patients whose asthma was well controlled. Because of the paucity of data, we were unable to assess the critical issue of asthma risk and whether LABA use had any effect on catastrophic asthma events. This issue has been of concern to the FDA and others.2,56 Indeed, there is an FDA mandate for LABA safety studies by manufacturers of these agents involving approximately 50 000 patients of all ages with asthma. The results of these studies will not be available for approximately 5 years. In the interim, the consistent trends that we identified for many asthma impairment factors, some of which were statistically significant, favor the continued use of LABAs (Table 2). Thus, in contrast to FDA recommendations of stepping off LABA therapy when asthma is controlled, our analysis supports the continued use of LABAs to maintain asthma control. Although our results indicate that LABA step-off will, on average, lead to worsening of asthma control, it is possible that step-off can be safe in a subset of patients. Individual-level data from the studies conducted to date could help identify characteristics of these patients; such data were not available for this meta-analysis. There is clearly a need for more properly designed and executed randomized trials aimed at rectifying differences between asthma guideline recommendations and FDA safety concerns and guidance. These studies should include a comparison between stepping off LABAs and decreasing the dose of ICSs and be conducted in a variety of populations, since patients with differing severities of asthma might respond differently. Until those data are available, physicians need to evaluate the risk-benefit ratio of LABAs for their individual patients. Results of this review and many previous studies support the positive effects of LABAs for achieving and maintaining asthma control.

Correspondence: Thomas B. Casale, MD, Creighton University, 601 N 30th St, Ste 5850, Omaha, NE 68131 (tbcasale@creighton.edu).

Accepted for Publication: May 21, 2012.

Published Online: August 27, 2012. doi:10.1001/archinternmed.2012.3250

Author Contributions: Dr Brozek had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Brozek, Kraft, Krishnan, Lazarus, Li, Strunk, and Casale. Acquisition of data: Brozek, Kraft, Cloutier, Lazarus, Li, Santesso, Strunk, and Casale. Analysis and interpretation of data: Brozek, Kraft, Krishnan, Lazarus, Li, Strunk, and Casale. Drafting of the manuscript: Brozek, Kraft, Krishnan, Cloutier, Li, Strunk, and Casale. Critical revision of the manuscript for important intellectual content: Kraft, Cloutier, Lazarus, Li, Santesso, Strunk, and Casale. Statistical analysis: Brozek, Lazarus, and Li. Administrative, technical, and material support: Krishnan and Casale. Study supervision: Kraft and Casale.

Financial Disclosure: Relevant financial activities outside the submitted work include grants from GlaxoSmithKline, Merck, Asthmatix, Eumedics, Novartis, and Genentech (Duke University); personal and family stock ownership in Abbott, Novartis, and Johnson and Johnson (Dr Li); grants from AstraZeneca, Merck, Novartis, Genentech, and sanofi-aventis (Creighton University): and consultation for Boehringer Ingelheim on unrelated topics (Dr Casale).

Funding/Support: Dr Brozek holds a McMaster University Department of Medicine Internal Career Research Award. The American Academy of Allergy Asthma and Immunology and the American Thoracic Society provided staff support for conference calls and meetings.

Additional Contributions: We acknowledge the support and contributions of the American Academy of Allergy Asthma and Immunology and the American Thoracic Society.

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Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma.  Respir Med. 2007;101(6):1218-1228
PubMed   |  Link to Article
FitzGerald JM, Boulet L-P, Follows RMA. The CONCEPT trial: a 1-year, multicenter, randomized, double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.  Clin Ther. 2005;27(4):393-406
PubMed   |  Link to Article
FitzGerald JM, Sears MR, Boulet L-P,  et al; Canadian Investigators.  Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study.  Can Respir J. 2003;10(8):427-434
PubMed
Hagiwara M, Delea TE, Stanford RH, Stempel DA. Stepping down to fluticasone propionate or a lower dose of fluticasone propionate/salmeterol combination in asthma patients recently initiating combination therapy.  Allergy Asthma Proc. 2010;31(3):203-210
PubMed   |  Link to Article
Ind PW, Haughney J, Price D, Rosen JP, Kennelly J. Adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients: the ASSURE study.  Respir Med. 2004;98(5):464-475
PubMed   |  Link to Article
Kardos P, Brüggenjürgen B, Martin A,  et al.  Treatment of bronchial asthma using a new adjustable combination treatment plan: Asthma Control Plan (ATACO) [in German].  Pneumologie. 2001;55(5):253-257
PubMed   |  Link to Article
Korn S, Vogelmeier C, Buhl R. Budesonide/formoterol maintenance and reliever therapy: a new treatment approach for adult patients with asthma.  Med Klin (Munich). 2008;103(5):299-310
PubMed   |  Link to Article
Lee DKC, Jackson CM, Currie GP, Cockburn WJ, Lipworth BJ. Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma.  Br J Clin Pharmacol. 2003;56(5):494-500
PubMed   |  Link to Article
Leuppi JD, Salzberg M, Meyer L,  et al.  An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing.  Swiss Med Wkly. 2003;133(21-22):302-309
PubMed
Mathison DA, Koziol JA. Utility and efficacy of fluticasone propionate and salmeterol inhaled from a single inhaler for persistent asthma.  J Asthma. 2005;42(10):829-831
PubMed   |  Link to Article
Shamsul AI, Hadzri HM, Noradina AT,  et al.  Step-down approach in chronic stable asthma; a comparison of reducing dose inhaled formoterol/budesonide with maintaining inhaled budesonide [abstract].  Respirology. 2007;(suppl 4)  A141
Vogelmeier C, D’Urzo A, Pauwels R,  et al.  Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option?  Eur Respir J. 2005;26(5):819-828
PubMed   |  Link to Article
Welte T, Aalbers R, Naya I. Budesonide/formoterol adjustable maintenance dosing (B/F AMD) reduces the burden of asthma more effectively than fixed dosing (FD) with B/F or salmeterol/fluticasone (S/FL) [abstract].  Eur Respir J. 2004;(suppl 48)  508s
Zitt MJ, Rachelefsky GS. Reducing asthma treatment [letter].  N Engl J Med. 2007;357(5):504-505
PubMed   |  Link to Article
Higgins JPT, Altman DG, Sterne JAC.Cochrane Statistical Methods Group and the Cochrane Bias Methods Group.  Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
Balshem H, Helfand M, Schünemann HJ,  et al.  GRADE guidelines, 3: rating the quality of evidence.  J Clin Epidemiol. 2011;64(4):401-406
PubMed   |  Link to Article
Deeks JJ, Higgins JPT, Altman DG.Cochrane Statistical Methods Group.  Meta-analysis of counts and rates. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
 RevMan: Version 5.1.1. Copenhagen, Denmark: Nordic Cochrane Centre; 2011
Deeks JJ, Higgins JPT, Altman DG.Cochrane Statistical Methods Group.  Identifying and measuring heterogeneity. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
Berger WE, Bleecker ER, O’Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma.  Allergy Asthma Proc. 2010;31(1):49-59
PubMed   |  Link to Article
 A 12-week randomized, double-blind, double-dummy, placebo- and active-controlled study of Symbicort pMDI administered once daily in adults and adolescents with asthma. (SD-039-0726). AstraZeneca Clinical Trials. http://www.astrazenecaclinicaltrials.com/. Accessed March 20, 2011
Godard P, Greillier P, Pigearias B, Nachbaur G, Desfougeres J-L, Attali V. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study.  Respir Med. 2008;102(8):1124-1131
PubMed   |  Link to Article
 Maintenance of asthma control in adults: comparison of three therapeutic strategies in patients whose asthma is controlled by a medium dose of inhaled corticosteroid and a long-acting inhaled β2-agonist (SFCF4026/SAM40088). GlaxoSmithKline Clinical Trial Register. http://www.gsk-clinicalstudyregister.com/. Accessed September 25, 2011
Godard P, Attali V. Comparison of different treatment strategies in stepping down combination treatment: withdrawing the LABA versus reducing the ICS dose [abstract].  Pro Am Thorac Soc. 2006;3:A213
Koenig SM, Ostrom N, Pearlman D,  et al.  Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are “stepped-down.”  J Asthma. 2008;45(8):681-687
PubMed   |  Link to Article
 A multicenter, randomized, double-blind, double-dummy, parallel group, 16-week comparison of asthma control in adolescents and adults receiving either fluticasone propionate/salmeterol Diskus combination product 100/50 mcg BID, fluticasone propionate Diskus 100 mcg BID, salmeterol xinafoate Diskus 50 mcg BID, or oral montelukast 10mg QD (SAS40036). GlaxoSmithKline Clinical Study Register. http://www.gsk-clinicalstudyregister.com/. Accessed September 25, 2011
Koenig S, Waitkus-Edwards K, Yancey S, Prillaman B, Dorinsky P. Loss of asthma control when patients receiving fluticasone propionate/salmeterol 100/50μg Diskus are “stepped-down” to fluticasone propionate, salmeterol or montelukast alone.  J Allergy Clin Immunol. 2004;113:S94Link to Article
Link to Article
Dorinsky P, Stauffer J, Waitkus-Edwards K, Yancey S, Prillaman B, Sutton L. Stepping down from fluticasone propionate/salmeterol 100/50mcg Diskus results in loss of asthma control [abstract].  Eur Resp J. 2004;(suppl 48)  309s
Dorinsky P, Stauffer J, Waitkus-Edwards K, Yancey S, Prillaman B, Sutton L. “Stepping down” from fluticasone propionate/salmeterol 100/50mcg Diskus results in loss of asthma control regardless of baseline asthma severity. Poster presented at: American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, FL. Poster J95
Reddel HK, Gibson PG, Peters MJ,  et al.  Down-titration from high-dose combination therapy in asthma: removal of long-acting β2-agonist.  Respir Med. 2010;104(8):1110-1120
PubMed   |  Link to Article
Reddel HK, Peyters MJ, Wark PA, Sand IB, Jenkins CR. Comparison of the efficacy of Seretide and Flixotide when down-titrating the inhaled corticosteroid dose. Poster presented at: Thoracic Society of Australia and New Zealand Annual Scientific Meeting; March 25-28, 2007; Auckland, New Zealand. Abstract TP041
GlaxoSmithKline.  A 13 month, randomised, double-blind, parallel-group comparison of the efficacy of Seretide (fluticasone propionate/salmeterol combination Accuhaler) and Flixotide (fluticasone propionate Accuhaler) when down-titrating the inhaled corticosteroid dose in asthmatic adults who have previously received Seretide 500/50 mcg twice daily for at least 4 wk. GlaxoSmithKline Clinical Study Register. http://www.gsk-clinicalstudyregister.com/. Accessed March 20, 2011
Oppenheimer J, Stauffer J, Waitkus-Edwards K,  et al.  “Stepping down” from fluticasone propionate/salmeterol 100/50mcg Diskus results in loss of asthma control. Poster presented at: American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, FL. Poster J94
 Randomized, double-blind, double-dummy, parallel group, 16-week comparison of asthma control in adolescents and adults receiving either fluticasone propionate/salmeterol Diskus combination product 100/50 mcg BID, fluticasone propionate Diskus 100 mcg BID, salmeterol xinafoate Diskus 50 mcg BID, or oral montelukast 10 mg QD (SAS40037). GlaxoSmithKline Clinical Study Register. Updated June 21, 2005. http://www.gsk-clinicalstudyregister.com/. Accessed March 5, 2012
Castle W, Fuller R, Hall J, Palmer J. Serevent Nationwide Surveillance Study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.  BMJ. 1993;306(6884):1034-1037
PubMed   |  Link to Article
Lanes SF, Lanza LL, Wentworth CE III. Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol.  Am J Respir Crit Care Med. 1998;158(3):857-861
PubMed
Williams C, Crossland L, Finnerty J,  et al.  Case-control study of salmeterol and near-fatal attacks of asthma.  Thorax. 1998;53(1):7-13
PubMed   |  Link to Article
Anderson HR, Ayres JG, Sturdy PM,  et al.  Bronchodilator treatment and deaths from asthma: case-control study.  BMJ. 2005;330(7483):117
PubMed   |  Link to Article
Mann M, Chowdhury B, Sullivan E, Nicklas R, Anthracite R, Meyer RJ. Serious asthma exacerbations in asthmatics treated with high-dose formoterol.  Chest. 2003;124(1):70-74
PubMed   |  Link to Article
Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2008;(3):CD006363
PubMed
Cates CJ, Cates MJ, Lasserson TJ. Regular treatment with formoterol for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2008;(4):CD006923
PubMed
Cates CJ, Lasserson TJ. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2009;(4):CD007695
PubMed
Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2010;(1):CD007694
PubMed
Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2009;(3):CD006922
PubMed
Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events.  Cochrane Database Syst Rev. 2009;(2):CD006924
PubMed
Jaeschke R, O’Byrne PM, Nair P,  et al.  The safety of formoterol among patients with asthma using inhaled corticosteroids: systematic review and meta-analysis.  Pol Arch Med Wewn. 2008;118(11):627-635
PubMed
Jaeschke R, O’Byrne PM, Mejza F,  et al.  The safety of long-acting β-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis.  Am J Respir Crit Care Med. 2008;178(10):1009-1016
PubMed   |  Link to Article
Kemp J, Armstrong L, Wan Y, Alagappan VK, Ohlssen D, Pascoe S. Safety of formoterol in adults and children with asthma: a meta-analysis.  Ann Allergy Asthma Immunol. 2011;107(1):71-78
PubMed   |  Link to Article
Levenson M. Long-acting beta-agonists and adverse asthma events meta-analysis: statistical briefing package for joint meeting of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee on December 10-11, 2008. US Food and Drug Administration. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-01-FDA.pdf. Accessed July 23, 2010
Rodrigo GJ, Moral VP, Marcos LG, Castro-Rodriguez JA. Safety of regular use of long-acting β agonists as monotherapy or added to inhaled corticosteroids in asthma: a systematic review.  Pulm Pharmacol Ther. 2009;22(1):9-19
PubMed   |  Link to Article
Salpeter SR, Wall AJ, Buckley NS. Long-acting β-agonists with and without inhaled corticosteroids and catastrophic asthma events.  Am J Med. 2010;123(4):322-328
PubMed   |  Link to Article
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting β-agonists on severe asthma exacerbations and asthma-related deaths.  Ann Intern Med. 2006;144(12):904-912
PubMed

Figures

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Figure 1. Flow of information through the different stages of the systematic review (for details about the excluded studies, see eAppendix 2). CENTRAL indicates Cochrane Central Register of Controlled Trials.

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Figure 2. Forest plots of the effects of continuing long-acting β2-agonist (LABA) therapy vs stepping off with regard to any use of systemic corticosteroids, asthma control, and quality of life. ACQ indicates Asthma Control Questionnaire; RR, risk ratio. The size of the data marker corresponds to the relative weight assigned in the analysis. *Risk ratio. Mantel-Haenszel method; random effects analysis model. †Data obtained directly from the study sponsor. ‡Inverse variance method; random effects analysis model. §Asthma Quality of Life Questionnaire (AQLQ) (data obtained directly from the study sponsor); higher values indicate better quality of life. Sign of change score was changed to allow same direction of change in both studies. Results favored combination of inhaled corticosteroid plus LABA. ∥Marks AQLQ; higher values indicate better quality of life.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Forest plots of the effects of continuing long-acting β2-agonist (LABA) therapy vs stepping off with regard to deterioration of symptoms, night-waking due to asthma, and any serious adverse effect. OR indicates odds ratio; RR, risk ratio. The size of the data marker corresponds to the relative weight assigned in the analysis. *Inverse variance method; random effects analysis model. †Change from baseline. ‡Variability obtained directly from the study sponsor. §Final score. ∥Control group: breast cancer in situ, traffic accident, musculoskeletal chest pain; experimental group: tension headache; none was deemed related to study medication. ¶Control group: loss of consciousness, car crash, breast cancer, chest pain; experimental group: pulmonary embolism. #Control group: gallstones, severe respiratory tract infection; experimental group: bleeding hemorrhoids, esophageal narrowing, and a cerebral arteriovenous malformation thought to have been congenital. **Control group: cholecystitis; experimental group: herniated lumbar disc, breast cancer.

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Included Trials
Table Graphic Jump LocationTable 2. LABA Step-off vs Continued Use of LABAs in Patients With Asthma That Is Well Controlled With a Combination of ICS and LABA

References

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 A randomized, double-dummy, double-blind/open, parallel-group, phase-III, multicentre, 7-month study to assess the efficacy and safety of Symbicort Turbuhaler (budesonide/formoterol; 160/4.5 μg delivered dose) given either as standard therapy (2 inhal. b.i.d.) or with an adjustable dosing regimen (1, 2 or 4 inhal. b.i.d.) versus Seretide Diskus (salmeterol/fluticasone; 50/250 μg metered dose) given as standard therapy (1 inhal. b.i.d.) in adult and adolescent asthmatic patients (SD-039-0686). AstraZeneca Clinical Trials. http://www.astrazenecaclinicaltrials.com/. Accessed December 13, 2010
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Canonica GW, Castellani P, Cazzola M,  et al; CAST (Control of Asthma by Symbicort Turbuhaler) Study Group.  Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing.  Pulm Pharmacol Ther. 2004;17(4):239-247
PubMed   |  Link to Article
Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma.  Respir Med. 2007;101(6):1218-1228
PubMed   |  Link to Article
FitzGerald JM, Boulet L-P, Follows RMA. The CONCEPT trial: a 1-year, multicenter, randomized, double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.  Clin Ther. 2005;27(4):393-406
PubMed   |  Link to Article
FitzGerald JM, Sears MR, Boulet L-P,  et al; Canadian Investigators.  Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study.  Can Respir J. 2003;10(8):427-434
PubMed
Hagiwara M, Delea TE, Stanford RH, Stempel DA. Stepping down to fluticasone propionate or a lower dose of fluticasone propionate/salmeterol combination in asthma patients recently initiating combination therapy.  Allergy Asthma Proc. 2010;31(3):203-210
PubMed   |  Link to Article
Ind PW, Haughney J, Price D, Rosen JP, Kennelly J. Adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients: the ASSURE study.  Respir Med. 2004;98(5):464-475
PubMed   |  Link to Article
Kardos P, Brüggenjürgen B, Martin A,  et al.  Treatment of bronchial asthma using a new adjustable combination treatment plan: Asthma Control Plan (ATACO) [in German].  Pneumologie. 2001;55(5):253-257
PubMed   |  Link to Article
Korn S, Vogelmeier C, Buhl R. Budesonide/formoterol maintenance and reliever therapy: a new treatment approach for adult patients with asthma.  Med Klin (Munich). 2008;103(5):299-310
PubMed   |  Link to Article
Lee DKC, Jackson CM, Currie GP, Cockburn WJ, Lipworth BJ. Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma.  Br J Clin Pharmacol. 2003;56(5):494-500
PubMed   |  Link to Article
Leuppi JD, Salzberg M, Meyer L,  et al.  An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing.  Swiss Med Wkly. 2003;133(21-22):302-309
PubMed
Mathison DA, Koziol JA. Utility and efficacy of fluticasone propionate and salmeterol inhaled from a single inhaler for persistent asthma.  J Asthma. 2005;42(10):829-831
PubMed   |  Link to Article
Shamsul AI, Hadzri HM, Noradina AT,  et al.  Step-down approach in chronic stable asthma; a comparison of reducing dose inhaled formoterol/budesonide with maintaining inhaled budesonide [abstract].  Respirology. 2007;(suppl 4)  A141
Vogelmeier C, D’Urzo A, Pauwels R,  et al.  Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option?  Eur Respir J. 2005;26(5):819-828
PubMed   |  Link to Article
Welte T, Aalbers R, Naya I. Budesonide/formoterol adjustable maintenance dosing (B/F AMD) reduces the burden of asthma more effectively than fixed dosing (FD) with B/F or salmeterol/fluticasone (S/FL) [abstract].  Eur Respir J. 2004;(suppl 48)  508s
Zitt MJ, Rachelefsky GS. Reducing asthma treatment [letter].  N Engl J Med. 2007;357(5):504-505
PubMed   |  Link to Article
Higgins JPT, Altman DG, Sterne JAC.Cochrane Statistical Methods Group and the Cochrane Bias Methods Group.  Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
Balshem H, Helfand M, Schünemann HJ,  et al.  GRADE guidelines, 3: rating the quality of evidence.  J Clin Epidemiol. 2011;64(4):401-406
PubMed   |  Link to Article
Deeks JJ, Higgins JPT, Altman DG.Cochrane Statistical Methods Group.  Meta-analysis of counts and rates. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
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Deeks JJ, Higgins JPT, Altman DG.Cochrane Statistical Methods Group.  Identifying and measuring heterogeneity. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. Updated March 2011. http://www.cochrane-handbook.org. Accessed March 20, 2011
Berger WE, Bleecker ER, O’Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma.  Allergy Asthma Proc. 2010;31(1):49-59
PubMed   |  Link to Article
 A 12-week randomized, double-blind, double-dummy, placebo- and active-controlled study of Symbicort pMDI administered once daily in adults and adolescents with asthma. (SD-039-0726). AstraZeneca Clinical Trials. http://www.astrazenecaclinicaltrials.com/. Accessed March 20, 2011
Godard P, Greillier P, Pigearias B, Nachbaur G, Desfougeres J-L, Attali V. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study.  Respir Med. 2008;102(8):1124-1131
PubMed   |  Link to Article
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