CRD summary

The authors concluded that the evidence supported the continued use of long-acting beta (β₂) agonists to maintain control of asthma symptoms, but discontinuation could be safe in a subset of patients. This was a generally well conducted review, but the limitations and paucity of the evidence suggest the findings may not be reliable.

Authors' objectives

To assess the effects of discontinuing long-acting beta (β₂) agonists in patients with asthma who have achieved control of symptoms with combined therapy with inhaled corticosteroids and long-acting β₂ agonists.

Searching

MEDLINE, EMBASE and The Cochrane Library were searched up to August 2010. The search strategy was presented. In addition, relevant clinical trials registries and references of relevant articles and reviews were manually searched. Experts in the field and relevant drug manufacturers were also contacted.

Study selection

Eligible for inclusion were randomised controlled trials (RCTs) of children aged at least four years and adults with asthma treated with inhaled corticosteroids and long-acting β₂ agonists (salmeterol or formoterol fumarate dihydrate) twice daily and well controlled for at least three months. Eligible trials compared the effects of discontinuing long-acting β₂ agonist therapy with unchanged inhaled corticosteroids dosing (long-acting β₂ agonist step-off) versus continued use of unchanged dosage of long-acting β₂ agonists and inhaled corticosteroids (no change in treatment). Outcomes of primary interest included use of systemic corticosteroids, hospitalisation, emergency department visit or unscheduled consultation for asthma, intensive care unit admission or intubation or non-invasive mechanical ventilation and death. Other outcomes were stated.

Included trials were multicentre and conducted in the USA, France or Australia. Participants were aged at least 15 years (mean age range 38 to 47 years). Where reported, the mean duration of asthma ranged from 19 to 22 years. Most patients were female and, where reported, some patients had a history of smoking. Patients in the long-acting β₂ agonists step-off group received fluticasone 100 to 500μg twice daily or budesonide 320μg once daily. Patients in the no change groups received the same dose of fluticasone plus salmeterol 50μg twice daily using the same inhaler, or budesonide 160μg twice daily plus formoterol 9μg twice daily from the same inhaler. Treatment duration was 12 or 16 weeks.

Two reviewers independently screened studies for inclusion. Discrepancies were resolved by discussion or consultation with a third reviewer.

Assessment of study quality

The quality of trials was assessed using the Cochrane risk of bias tool, which included criteria on sequence generation, allocation concealment, blinding, intention-to-treat analysis, loss to follow-up, selective outcome reporting, and other threats to validity. Each criterion was rated as (probably) low, (probably) high or unclear risk of bias.

The authors did not explicitly state how many reviewers performed the quality assessment.

Data extraction

One reviewer extracted outcome data measured at 12 weeks, or the closest duration of follow-up, on an intention-to-treat basis. For dichotomous outcomes, the numbers of events were extracted to calculate risk ratios and 95% confidence intervals. For other outcomes, the change from baseline or final values and measures of variability were extracted to calculate mean differences and 95% confidence intervals.

Study sponsors were contacted for missing data. A second reviewer checked the data extraction and any discrepancies were resolved by discussion.

Methods of synthesis

It appeared that a random-effects model was used to combine risk ratios (RRs), mean differences (MDs) and their 95% confidence intervals (CIs).

Statistical heterogeneity was assessed by visual inspection of forest plots and using the Ι² statistic (50% or greater indicated substantial heterogeneity). A priori subgroup analyses were intended to explore heterogeneity, but were not undertaken.

Funnel plots were not used to detect publication bias due to the small number of included studies.

Results of the review

Five RCTs (approximately 1,352 patients) were included in the review. All trials were at high risk of bias for loss to follow-up (12% to 38% patients discontinued treatment). For individual outcomes, the quality was very low to moderate.

No patients died, were admitted to hospital or required intubation or mechanical ventilation during the treatment period. There were no statistically significant differences between treatment groups for the following outcomes: emergency department visit or unscheduled consultation for asthma; use of systemic corticosteroids for asthma; loss of asthma control; deterioration of symptom score; or rescue medication free days.

Long-acting β₂ agonist step-off did however reduce patient quality of life according to the Asthma Quality of Life Questionnaire (MD -0.36 points, 95% CI -0.57 to -0.15; two RCTs; Ι²=0%). There was a slight discrepancy in the figures reported in the text and forest plot and we have used the figures from the forest plot. Long-acting β2 agonist step-off also reduced patient quality of life according to the Asthma Control Questionnaire (MD 0.24 points higher, 95% CI 0.13 to 0.35; three RCTs; Ι²=0%). Long-acting β₂ agonist step-off also reduced the proportion of symptom-free days (MD -9.15%, 95% CI -16.69% to -1.62%; four RCTs; Ι²=80%) and increased the risk of withdrawing from treatment due to lack of efficacy or loss of asthma control (RR 3.27, 95% CI 2.16 to 4.96; four RCTs; Ι²=0%).

There were no statistically significant differences between treatment groups in the frequency of adverse or serious adverse events. Other outcomes were reported.

Authors' conclusions

The evidence suggested that discontinuing long-acting β₂ agonists increased the risk of loss of asthma control in adults, which supported the continued use of long-acting β₂ agonists to maintain symptom control. Long-acting β₂ agonist step-off could be safe in a subset of patients.

CRD commentary

The review question and inclusion criteria were clearly stated. A satisfactory search was undertaken to identify both published and unpublished data, but the authors acknowledged potential for publication bias. Study selection and data extraction were performed in duplicate, but it was unclear whether this was the same for quality assessment, which meant that reviewer error and bias could not be ruled out. The authors acknowledged issues with the quality of the included trials.

Appropriate methods appeared to have been undertaken to combine study data, but there was evidence of statistical heterogeneity for some outcomes. The authors acknowledged limitations of the evidence, including uncertainties regarding whether combined treatment with inhaled corticosteroids and long-acting β₂ agonists were required to control symptoms in patients at study enrolment in four of the trials, short study duration and paucity of evidence.

This was a generally well conducted review, but the limitations and paucity of the evidence suggest the findings may not be reliable and the authors' conclusions should be treated with caution.

Implications of the review for practice and research

Practice: The authors stated that health professionals should evaluate the risk-benefit ratio of long-acting β₂ agonists for individual patients.

Research: The authors stated that further RCTs were needed to assess long-acting β₂ agonist step-off in patients with differing severities of asthma. Individual patient data could hep to identify the subset of patients in whom long-acting β₂ agonist step-off may be safe.

Funding

McMaster University Department of Medicine Internal Career Research Award.

Bibliographic details

Brozek JL, Kraft M, Krishnan JA, Cloutier MM, Lazarus SC, Li JT, Santesso N, Strunk RC, Casale TB. Long-acting beta2-agonist step-off in patients with controlled asthma: systematic review with meta-analysis. Archives of Internal Medicine 2012; 172: 1-11. [PubMed: 22928176]

Original Paper URL

http://dx.doi.org/10.1001/archinternmed.2012.3250

Indexing Status

Subject indexing assigned by NLM

MeSH

Administration, Inhalation; Adrenal Cortex Hormones /administration & dosage /therapeutic use; Adrenergic beta-2 Receptor Agonists /administration & dosage /therapeutic use; Anti-Asthmatic Agents /administration & dosage /therapeutic use; Asthma /drug therapy; Drug Therapy, Combination; Humans; Questionnaires; Treatment Outcome

AccessionNumber

12012039181

Database entry date

31/08/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.