A Systematic Review of Long-Acting β2-Agonists Versus Higher Doses of Inhaled Corticosteroids in Asthma Jose A.
Castro-Rodriguez and Gustavo J. Rodrigo Pediatrics 2012;130;e650; originally published online August 27, 2012; DOI: 10.1542/peds.2012-0162
The online version of this article, along with updated information and services, is located on the World Wide Web at:
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Rodrigo.aappublications. adolescents. and interpretation of data. Piso. Chile.1542/peds. and bDepartamento de Emergencia. This trial has been registered with the International Prospective Register of Systematic Reviews (http://www. prospective. controlled trials published January 1996 to January 2012 with a minimum of 4 weeks of LABA +ICS versus higher doses of ICS were retrieved through Medline. Chile.ac. use of rescue medication.A Systematic Review of Long-Acting b2-Agonists Versus Higher Doses of Inhaled Corticosteroids in Asthma abstract
OBJECTIVE: To compare the efﬁcacy of inhaled corticosteroids (ICS) plus long-acting b2 agonist (LABA) versus higher doses of ICS in children/adolescents with uncontrolled persistent asthma.28–0. acquisition of data.2012-0162 Accepted for publication May 17. I2= 0). MD.crd. children. There were no other signiﬁcant differences in adverse events.82.22. 2012 Address correspondence to José A. and has provided ﬁnal approval of the version to be published. secondary outcomes were the pulmonary function test (PEF). Montevideo. I2 = 16%).org/cgi/doi/10. School of Medicine. and manufacturer’s databases. patients receiving LABA+ICS showed a decreased risk of asthma exacerbations compared with higher than twice ICS doses (odds ratio = 0.48–1. and adverse events. Lira 44. P = . RESULTS: Nine studies (n = 1641 patients) met criteria for inclusion (7 compared LABA+ICS versus double ICS doses and 2 LABA+ICS versus higher than double ICS doses).1542/peds. Pediatrics 2012. Santiago. MD.york.25. Pontiﬁcia Universidad Católica de Chile. Uruguay
KEY WORDS asthma. less use of rescue medication. efﬁcacy ABBREVIATIONS AEs—adverse events BDP—beclomethasone dipropionate CI—conﬁdence interval FDA—Food and Drug Administration FEV1—ﬂow expiratory volume in the ﬁrst second ICS—inhaled corticosteroids LABA—long-acting b2 agonist OR—odds ratio PEF—peak expiratory ﬂow RCT—randomized controlled trial RR—relative risk WMD—weighted mean differences Dr Castro-Rodriguez has made substantial contributions to the conception. 1er. Dr Rodrigo has made substantial contributions to the conception and design. design. 95% conﬁdence interval: 0. and higher short-term growth than those on higher ICS doses. Santiago. Departments of Family Medicine and Pediatrics.48.007. The primary outcome was asthma exacerbations requiring systemic corticosteroids. CONCLUSIONS: There were no statistically signiﬁcant group differences between ICS+LABA and double doses of ICS in reducing the incidence of asthma exacerbations but it did decrease the risk comparing to higher than double doses of ICS.2012-0162 doi:10. casilla 114-D. P = .uk/ PROSPERO/) (CRD42011001435). Castro-Rodriguez. METHODS: Randomized. Hospital Central de las Fuerzas Armadas. In the subgroup analysis. LABA.com. 95% conﬁdence interval: 0. Central. Embase.76. E-mail: jacastro17@hotmail. analysis and interpretation of data. (Continued on last page)
CASTRO-RODRíGUEZ and RODRIGO
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. withdrawals during the treatment period. has revised the article critically for important intellectual content.a and Gustavo J. has drafted the submitted article and revised it critically for important intellectual content. PhD.130:e650–e657
AUTHORS: Jose A. PhD. inhaled corticosteroids. days without symptoms. Children treated with LABA+ICS had signiﬁcantly higher PEF. Pontiﬁcia Universidad Católica de Chile. and has provided ﬁnal approval of the version to be published. There was no statistically significant difference in the number of patients with asthma exacerbations requiring systemic corticosteroids between children receiving LABA +ICS and those receiving higher doses of ICS (odds ratio = 0. School of Medicine.org at Indonesia:AAP Sponsored on December 3. MDb
aDepartments of Family Medicine and Pediatrics.pediatrics. Castro-Rodríguez.
In the case of multiple published or unpublished reports. The latter was assessed according to recommendations outlined in the Cochrane Handbook. 2012
.jsp. and keywords: long-acting b-2 agonists OR salmeterol OR formoterol OR indacaterol AND corticosteroids OR ﬂuticasone OR budesonide OR ciclesonide OR mometasone OR beclomethasone OR ﬂunisolide OR triamcinolone).1–3 A previous systematic review6 showed that in children. http://www. Data Analysis The present analysis was done by intention to treat with all participants. (2) the addition of LABA to ICS compared with a higher doses of ICS. Embase (search January 2012). however. adverse events (AEs).aappublications.novartisclinicaltrials. and the Cochrane Controlled Trials Register (CENTRAL) (search January 2012 databases using the following medical subject headings. and outcomes. study design. The authors were independently involved in all stages of study selection. to minimize bias owing to differences among groups.4 As well. LABA added to ICS had not signiﬁcantly reduced the risk of exacerbations requiring a short course of systemic corticosteroids (relative risk [RR] = 1.
Downloaded from pediatrics. full text. When effect estimates were signiﬁcantly different between groups. abstracts. The speciﬁc inclusion criteria were as follows: (1) children and adolescents aged 4 to 18 years with persistent asthma and having received ICS daily. (3) studies with at least 4 weeks’ duration. The primary outcome of the study was proportion of
subjects with asthma exacerbations requiring the use of systemic corticosteroids. and severe AEs. children could be almost 3 times more likely than adults to require oral steroids when they were treated with a LABA than with ICS. international guidelines recommend increasing the dose of ICS or adding leukotriene modiﬁers or long-acting b agonists (LABAs).REVIEW ARTICLE
According to the most commonly used international asthma guidelines.58–2. and 39% of the children had at least 1 asthma exacerbation that was treated with oral corticosteroids during a 48-week period. and citations were independently analyzed by all reviewers. some children included in the meta-analysis came from trials performed in mixed population (children and adults together). the reviewers independently assessed all studies for inclusion based on the criteria for population intervention. 95% conﬁdence interval [CI] 0. days without asthma symptoms. The objective of this systematic review was to assess the safety and efﬁcacy of the LABA/ICS combination compared with an increased dose of ICS (double or greater) in children and adolescents with uncontrolled persistent asthma. however.7 Data Abstraction and Assessment of Risk of Bias This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines.9 Disagreements were resolved by group consensus. A recent meta-analysis concludes that children receiving ICS showed a signiﬁcantly decreased risk of asthma exacerbation requiring systemic corticosteroids than children receiving montelukast.66) compared with the use of higher doses of ICS. In recent years. is life-threatening. more studies enrolling children exclusively have appeared in
PEDIATRICS Volume 130. (4) randomized (parallel group or crossover) controlled trials (RCTs) without language restriction. Therefore. pulmonary function tests (FEV1 or PEF). Trials published solely in abstract form were excluded because the methods and results could not be fully analyzed.com). From the full texts. data extraction. Secondary outcome measures were the following: withdrawals during treatment period. and http://www. As well. We calculated the Mantel-Haenszel odds ratios (ORs) and 95% CIs for binary outcomes. uncontrolled asthma occurred in more than 50% of the children. use of rescue medication. or results in persistent or signiﬁcant disability/ incapacity. requires inpatient hospitalization. including withdrawals. data from the most recent version were extracted. After obtaining full reports about potentially relevant trials.28. Number 3. it is important to know which option (increased doses of ICS or the addition of LABA) is better for step 3 of the guidelines for children when low doses of ICS do not control their asthma. Moreover. they assessed eligibility. children treated with ICS had signiﬁcantly higher pulmonary function and better clinical parameters compared with those receiving montelukast. we performed a search of relevant unpublished ﬁles from drug manufacturer databases (http://gsk-clinicalstudyregister. astrazenecaclinicaltrials. with leukotriene modiﬁers (eg. September 2012
the literature.4 Moreover.1–3 children with persistent asthma should be started on controller therapy with inhaled corticosteroids (ICS) as the preferred drug. The search was then limited with the terms children OR child OR pediatric OR adolescents OR infants OR preschoolers. the latest study comparing ICS and montelukast showed that ﬂuticasone (100 mg twice daily) was the most effective therapy.
Search and Selection Criteria We identiﬁed studies from Medline.org at Indonesia:AAP Sponsored on December 3. A serious AE was deﬁned as any untoward medical occurrence that sometimes results in death. and risk of bias assessment.com/ result_compounds.5 In cases where ICS is not sufﬁcient to control the disease in children. but not in adults.8 Titles.com. montelukast) as an alternative for patients who are unable or unwilling to use ICS.
21 The dose of ICS that the control group received was twice. 2011. This difference was compatible with a number needed
Downloaded from pediatrics.28–0.35. One trial was unpublished. 95% CI: –0. length of treatment (. 2012
Nine RCTs.82. plus additional doses as needed. The Cochrane Collaboration.aappublications. One study used the combination formoterol/ budesonide as maintenance.16–22 showed no statistically signiﬁcant differences in the number of patients with asthma exacerbations requiring systemic corticosteroids between children receiving LABA+ICS and those receiving higher doses of ICS (OR = 0. The remaining study recruited children with mild asthma.22 Rescue medications.16–20. Heterogeneity was measured by the I2 test (. age range (4–11 vs 11–17 years).76. low doses of ICS (200–500 µg/ d beclomethasone dipropionate [BDP] or equivalent).16–21 were funded by the pharmaceutical industry.13 A P .21. Continuous outcomes were pooled using weighted mean differences (WMDs) and 95% CIs.05 using a 2-tailed test was considered to indicate signiﬁcance. Eight trials14.14–22 involving a total of 1641 children and adolescents.15 Almost all studies tested the commonly recommended doses of LABAs (ie. or formoterol 9–12 mg twice daily).1.10 Because selected studies differed in the mixes of participants and interventions.007.74) or signiﬁcant heterogeneity among studies (I2 = 16%). Copenhagen.22.24 weeks versus $24 weeks). Six studies16–18.48. 95% CI: 0.20 All studies examined the combination LABA/ICS in 1 device (Table 1). Meta-analysis was performed with Review Manager 5. However. and the statistical model (ﬁxed versus random effects).12 Additional predeﬁned sensitivity analyses were done to explore the inﬂuence on effect size of risk of bias (low-risk trials versus high-risk trials). 95% CI: 0. the amount received by the LABA/ICS group.4 to 0. salmeterol 50 mg twice daily. type of LABA (salmeterol versus formoterol).
Process of study selection. and morning and evening PEF from baseline) Subgroups were compared by using the interaction test. a random-effects meta-analysis was performed to address this variation across studies in all outcomes.14–20 or more than twice. fulﬁlled the inclusion criteria (Fig 1). such as inhaled short-acting b2-agonists and systemic steroids.22 and 200 mg/d in 2 studies.20–22 were judged to have a low risk of bias
(successfully complied with at least 5 of the 6 domains of bias assessment) (Table 2). 0.25) (Fig 2).48–1. were permitted in all the trials. P = . Primary Outcome The analysis of 8 studies (n = l616 subjects)14.2 software (The Nordic Cochrane Centre.40% could be unimportant.21 Intervention groups received BDP equivalent doses of 400 mg/d in 7 studies14. . There was no evidence of publication bias (Egger’s test. and severity of airway obstruction (prebronchodilator FEV1.16–22 included subjects with inadequately controlled
e652 CASTRO-RODRíGUEZ and RODRIGO
asthma. with 59% being male. and 60% to 100% could be substantial). P = . Denmark).11 We used a priori subgroup analysis to explore the inﬂuence of the ICS dose (double versus more than double). combination therapy signiﬁcantly reduced the risk of exacerbations (OR = 0. 40% to 60% could be moderate. Publication bias of primary outcomes was evaluated by funnel plots.15.the number needed to treat to beneﬁt or to harm was obtained.org at Indonesia:AAP Sponsored on December 3. A low-risk bias was deﬁned as a minimum of 5 of 6 domains ﬁlled in an acceptable way. The mean age of participants was 9 years (range 4–17). I2 = 0%) (Fig 3B). Most of the studies14. among the subgroup studies that compared LABA+ICS versus higher than a double dose of ICS.
19. trials with low risk of bias16–18. as only 1 of the 2 independent studies had data on exacerbations. formoterol. the impact of the baseline severity of airway obstruction by lung function and type of LABA on size effect could not be examined.PG R. not reported.75. SALM. I2 = 0%) and evening PEF from baseline (WMD = 4. Sensitivity analysis based on the risk of bias showed different results.9).PG R. parallel group. In the same way.19 (OR = 0. n(% Male) 120 (63) 27 (52) 158 (58) MeanAge. Y.51 L/min.42– 1. they had an age range not mutually exclusive (4–11 and 6–17 years). SC. ﬂuticasone.15.20).20–22 were not associated with a signiﬁcantly low risk of exacerbation (OR = 0.DB.68. Number 3.05 L/min.38.PG R. 95% CI: 1.12–5.74. I2 = 8%) compared with trials with high risk of bias14. P = .53–1. twice daily. CO. Yes. 95% CI: 4. 2012
. the effect size obtained using random or ﬁxed effects models did not differ (OR = 0.PG R.5 88.3 (6–16) 8.PG
303 (64) 283 (68) 24 (50) 367 (69) 224 (69)
88 NR 75 75 NR
1. Secondary Outcomes The addition of LABA to ICS provided signiﬁcantly greater improvements in morning PEF from baseline (Fig 4A) (WMD = 8. P = .84.CO
BID. y (Range) 11. A sensitivity analysis comparing age range groups (4–11 vs 11–17 years) was not possible to do.REVIEW ARTICLE
TABLE 1 Characteristics of Included Studies
Study Verberne14 Heuck15 VaessenVerberne16 (SAM 101667) de Blic17 (SAM 104926) Gappa18 (VIAPAED 102318) Murray19 (SAM 40100) GSK SAM 4001220 Bisgaard21 (SD-039-0673) Lemanske22 Design R.DB.3 (4–11) 7.53.DB. 95% CI: 0.5 100 Selected Comparisons SALM/BDP 50/200 mg BID versus BDP 400 mg BID FORM/BUD 12/100 mg BID versus BUD 200 mg BID SALM/FLUT 50/100 mg BID versus FLUT 200 mg BID SALM/FLUT 50/100 mg BID versus FLUT 200 mg BID SALM/FLUT 50/100 mg BID versus FLUT 200 mg BID SALM/FLUT 50/100 mg BID versus FLUT 200 mg BID SALM/FLUT 50/100 mg BID versus FLUT 200 mg BID FORM/BUD 4.7 (4–11) 8 (4–11) 10.92. P = .77–7. cross over. Post hoc subgroup analysis showed that subjects in studies testing higher than twice ICS doses had a signiﬁcantly lower risk of asthma exacerbations than subjects in studies using a double ICS dose (OR = 0. compared with higher ICS doses. salmeterol. because the studies were not divided into these 2 age categories.1 (6–16) 9.DB.41.DB.40. FORM. The duration of interventions did not affect the magnitude of this improvement over
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TABLE 2 Risk of Bias of the Eligible Studies
Study Verberne 199814 Heuck 200015 Vaessen-Verberne 201016 DeBlic 200917 Gappa 200918 Murray 201019 GSK SAM4001220 Bisgaard 200621 Lemanske 201022
N. There was no
possibility of comparing trials sponsored by the pharmaceutical industry and independent studies.42–2. 95% CI: 0.7 liters 91 82 NR 76
R.DB.DB.PG R. No. BUD. FEV1= forced respiratory volume in the ﬁrst second.1 (4–11) 9. The duration of treatment ($24 weeks versus .aappublications.CO R.24 weeks) did not inﬂuence this effect size
PEDIATRICS Volume 130.10.95% CI: 0. budesonide. September 2012
(OR = 0.01). PG.9 (6–17) Atopy status (%) 89 NR 75 Mean Baseline FEV1 (% Predicted) 88.org at Indonesia:AAP Sponsored on December 3.5/80 mg BID plus additional doses as needed versus BUD 320 mg BID SALM/FLUT 50/100 mg BID versus FLUT 250 mg BID
R. Because the number of studies was low. 95% CI: 0. R. double-blind. I2 = 0%) at the end point (Fig 4B). Unknown. I2 = 42%). in contrast.DB. DB. 95% CI: 0. U.5 (4–16) 7. NR.6 (6–13) 9.PG Location and Duration Multicenter 54 wk SC 6 wk Multicenter 26 wk Multicenter 12 wk Multicenter 8 wk Multicenter 6 wk Multicenter 24 wk Multicenter 54 wk Multicenter 16 wk Patients. FLUT. single center.37– 0. randomized.84.DB.
Random Sequence Generation Y Y Y Y Y U Y Y Y
Allocation Concealment Y U Y Y Y U Y Y Y
Blinding of Participants & Personnel Y Y Y Y Y Y Y Y Y
Blinding of Outcome Assessment Y Y Y Y Y Y Y Y Y
Incomplete Outcome Data Addressed U U U Y Y U Y Y Y
Selective Reporting N N Y Y N N N N Y
to treat of 9 (95% CI: 5–45).87–12.
the combination of LABA+ICS is associated with signiﬁcantly lower. 95% CI: 0.1%). signiﬁcant effects were observed that favor the combination therapy in reducing the risk of asthma exacerbation (number needed to treat of 9).DISCUSSION
To our knowledge.16.1%). use of rescue medication (–0. In almost all of the variables. (2) withdrawals due to AEs (1.org at Indonesia:AAP Sponsored on December 3.34 L/s. Overall. the effect on asthma exacerbations was not observed when trials comparing LABA+ICS versus double doses of ICS were analyzed. and (6) severe AEs (2. In the Bisgaard et al study. but modest.11 puffs/d. this information came from only 3 studies.
Pooled ORs and 95% CIs for the number of patients with at least 1 asthma exacerbation (with 95% CI) requiring systemic corticosteroids comparing LABA+ICS versus double (A) or more than double dose of ICS (B).20 to –0.1% vs 1.4% vs 4.03%
[–10.01) (Table 3). data from 3 trials15. Curiously.21 showed that short-term growth was signiﬁcantly greater in children treated with combination therapy compared with children treated with higher ICS doses (WMD = 0. On the other hand. however.14.17 There were no signiﬁcant differences between the LABA+ICS and ICS groups in the following outcomes: (1) number of prematurely discontinued patients (4.
CASTRO-RODRíGUEZ and RODRIGO
Downloaded from pediatrics. comparing 2 trials by using LABA+ICS versus higher than double doses of ICS.93]). however. Finally.aappublications. (5) AEs (54.99 to 0.6%).46. Potential explanation could be attributable to the inclusion of 2 particular studies.3% vs 1.21 1 of the 2 groups with combination therapy used an adjustable
Pooled ORs and 95% CIs for the number of patients with at least 1 asthma exacerbation (with 95% CI) requiring systemic corticosteroids comparing LABA+ICS versus higher doses of ICS. (4) percentage of days free of asthma symptoms (WMD = –5. there were no statistically signiﬁcant group differences between ICS+LABA and double or higher doses of ICS in reducing the incidence of asthma exacerbations requiring systemic corticosteroids.25) (Table 3). P = . There were no statistically signiﬁcant group differences in prebronchodilator FEV1 between LABA+ICS versus higher ICS doses (WMD = 0.68). I2 = 74%.0% vs 2.66 cm/y [95% CI: 0. 2012
.16. The paradoxical effect is biologically difﬁcult to explain. (3) withdrawals because of asthma exacerbations (0.0%). this is the ﬁrst metaanalysis performed of trials exclusively about child and adolescent populations to explore the efﬁcacy of ICS+LABA compared with higher doses of ICS for uncontrolled persistent asthma.08–1. the degree of heterogeneity was unimportant or null.18–1.6% vs 55.
time.6%) (Table 3). 95% CI: –0.
and the highest asthma-related treatment cost for the
health care system and for the community in general. September 2012
meta-analysis.99 .11 (–0. 2012
TABLE 3 Effect of LABA plus ICS Versus Higher ICS Doses on Secondary Outcomes
Outcome Prematurely discontinued patients Withdrawals owing to adverse events Withdrawals owing to asthma exacerbations Percent of days without asthma symptoms Use of rescue medication.26 (0.21 14–16.16–21 14.01) OR = 0.
Studies 14–21 14–15.01 (0. It is important to consider that a crossover study is probably the best design to explore individual response to drugs.04 to 1. irreversible decrease in lung function. more than 50% of children still have uncontrolled asthma and 39% have had at least 1 asthma exacerbation that was treated with oral corticosteroids during a 48-week period.15 . 95% CI: 0.24.99 to 0.20–22 15–16. with 4 weeks for wash-out) given the possibility that the wash-out period used was not enough. A previous meta-analysis6 that included only 3 studies done in children showed a trend toward increased risk of rescue oral steroids (RR 1.64) associated with combination
Downloaded from pediatrics.23 Also. A control trial5 showed that in step 2 of asthma management (low ICS doses or leukotriene modiﬁers).66) and hospital admission (RR 2. and that trial22 showed the superiority of adding LABA to ICS versus higher doses of ICS in reducing asthma exacerbation requiring systemic corticosteroids.43 .20 to –0.99) OR = 0. and the burden imposed by these symptoms.66 (0. And in the Lemanske et al study. no statistically signiﬁcant group difference on asthma exacerbation was found between LABA+ICS versus higher doses of ICS. Asthma exacerbations are common events in asthmatic patients and represent the greatest risk.57 to 1.74– 6.02
46 0 0 0 0 25 0 0
rather than ﬁxed dose of LABA+ICS during exacerbations (and probably between exacerbations) or step-up therapy during exacerbation.21. the prevention of asthma exacerbations is an important component of establishing ideal asthma control. Number 3. and the risk of asthma exacerbations.25)
P .26 to 3.93) WMD = –0. versus those in the group of ICS who received ﬁxed ICS doses.2–25 Therefore.21 14.16–18.org at Indonesia:AAP Sponsored on December 3. 17.21 14. puffs/d AEs Serious AEs Linear growth rate.58–2. exacerbations are the most important cause of lost school days for asthmatic children.23 .39 to 1.74) OR = 1.98 .49) WMD = 0.REVIEW ARTICLE
Pooled WMD and 95% CIs for the mean change in morning (A) and evening (B) PEF (L/min) from baseline.25) OR = 0. cm/y
n. for that reason it is very important to prevent exacerbations.21
n 1543 713 665 1222 697 1495 1593 430
Measure (95% CI) OR = 1.24 Asthma control has 2 aspects: current control in response to day-to-day symptoms through the use of rescue medications.63) WMD = –5.17.76 (0. and side effects from asthma medications.0 (0. however.73 to 1. number of subjects.18–21 14–15. When we exclude these 2 studies in our
PEDIATRICS Volume 130.08 to 1. 95% CI: 0.95 (0. given the possibility that children in the latter group received a lower total ICS dose.10 .02 .18–19.22 the design was cross sectional (child received for 16 weeks LABA+ 200 mg/d of ﬂuticasone and for 16 weeks 500 mg/d of ﬂuticasone or vice versa.aappublications.
Update 2010. 95% CI: 0.org at Indonesia:AAP Sponsored on December 3. a recent study32 has summarized nearly 20 systemic reviews and databases on LABA safety and showed that there is no risk of serious asthma-related events when using LABA associated with ICS. However.63(suppl 4):iv1–121 4. As well. Evidence from RCTs. reduced use of rescue medication and showed less effect on short-term linear grow rate than children on higher doses of ICS.34 Conversely. 2008. More trials need to be done to deﬁnitively lay down the best treatment in children with persistent asthma.95(5):365–370 5.aappublications. The difference may be attributable to the number and type of studies included. such that increasing the dose does not necessarily improve the clinical response. indicate that the use of combination therapy (LABAs+ICS) in children and adults is associated with a decreased risk of serious asthmarelated events. Lung. the current study included 8 trials done exclusively in children showing a trend of decreased risk of asthma exacerbations requiring systemic corticosteroids in the group of LABA+ICS versus higher doses of ICS (OR = 0.32
This meta-analysis showed no statistically signiﬁcant group differences between ICS+LABA and double doses of ICS in reducing the incidence of asthma exacerbations requiring systemic corticosteroids but it did decrease the risk comparing to higher than double doses of ICS. Arch Dis Child. 2011 2. British Thoracic Society Scottish Intercollegiate Guidelines Network. et al. Available at: www.gov. and Blood Institute. and Blood Institute.nih. Lung. meta-analysis of RCTs. ICS treatment has a plateau.26 In the current study. no statistically signiﬁcant group differences in AEs and serious AEs were found between children on LABA+ICS versus higher doses of ICS.nhlbi.33 However. Bethesda. These ﬁndings could explain the higher performance of the combination of LABA+ICS versus higher doses of ICS. Another important direct effect of asthma exacerbations is the use of rescue medication and lung function deterioration. 2007. and observational studies. Mauger DT. P = . Global Initiative for Asthma. increases the nuclear translocation of the glucocorticoid receptor. it is important to consider the strong evidence of the ICS molecule-dependant effect on growth. and systemic effects can start. Castro-Rodriguez JA.ginasthma. 2012
. MD: National Institutes of Health. we found a statistically signiﬁcant but uncertain clinically signiﬁcant improvement in lung function (morning and evening PEF) among children/adolescents using LABA+ICS compared with those using higher doses of ICS. Thorax. if we found that short-term growth was signiﬁcantly greater in children with combination therapy (370 mg/d of BDP or equivalent) compared with children with higher ICS doses (770 mg/d of BDP or equivalent). Rodrigo GJ.27 In contrast. long-term growth studies need to conﬁrm this ﬁnding.66 cm/y could be important. 2010. Also. The role of inhaled corticosteroids and montelukast in children with mild-moderate asthma: results of a systematic review with metaanalysis. This is relevant because an international asthma guideline1 recommends increasing ICS doses ﬁrst instead of adding LABA in children older than 5 years. Accessed August 3.31. Sorkness CA. Available at: www. children on combination therapy had signiﬁcantly improved lung function (morning and evening PEF). the FDA called on manufactures of LABA to conduct large clinical trials to deﬁnitively determine whether the addition of LABAs to ICS increases the risk of serious asthma outcomes.30 Even though the studies included in the present meta-analysis have a wide range of duration (6 to 54 weeks).76. although limited by low statistical power. the synergistic effect of adding LABA to ICS has been reported.32 including 1 exclusively done in children by the FDA where those trials with LABA plus “assigned ICS
therapy” showed no presence of LABA risk. However. particularly when concomitant use of LABAs+ICS can be reasonably ensured (combined in a single inhaler).48–1.
1. Global Strategy for Asthma Management and Prevention. we found a signiﬁcant modest reduction in the use of rescue medication among children on LABA+ICS than those on higher doses of ICS. British guideline on the management of asthma. Childhood Asthma Research and Education Network of the National Heart. especially for children in their early years.28. along with its bronchodilator effect. Also.22.29 where LABA. it increases the expression of b2-receptors
by increasing gene transcription.25). this difference of 0.therapy versus higher ICS doses. com. These ﬁndings are in accordance with the latest Food and Drug Administration (FDA) recommendation. ICS is delivered in the same device and along with its anti-inﬂammatory effect. Lemanske RF Jr. Accessed August 3. National Heart. We were not able to perform a subanalysis of main outcome comparing age groups (4–11 vs 11–17 years) because trials included in the metaanalysis had overlap in age (4–11 and 6–17 years). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Moreover. Long-term comparison of 3 controller regimens for mild-moderate
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22. Progression of asthma in childhood.19(1):182–191 Sharek PJ. 2002.
33. Am J Respir Crit Care Med. Nurmagambetov TA. Cochrane handbook for systematic reviews of interventions. Greenstone I.
7.. et al.362(11):975–985 Barnett SB. and Dr Rodrigo has participated as a lecturer and speaker in scientiﬁc meetings and courses under the sponsorship of Admiral. Dymek A.
18.cochrane-handbook. Available at: http://gsk-clinicalstudyregister. Kamin W.326(7382):219 Egger M. 2005. Budesonide/ formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Dal Pan G. Pediatr Allergy Immunol. Hultquist C.
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28.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/ ucm200776. 2009. 1992. et al. 2011.
34. Available at: www.
31. 2010. et al. and Novartis. AstraZeneca. et al. Guyatt GH.
8. Thompson SG. Mosholder AD. graphical test. Zachgo W. 2010. Hedges LV. Altman DG. Ferrie PJ. 2012. Vermeulen JH. Levenson MS. 0031-4005.
29. 2003. Pediatr Pulmonol.127(1):145– 152 Juniper EF.org/ cgi/content/full/106/1/e8 FDA Drug Safety Communication. Ni Chroinin M. Copyright © 2012 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Castro-Rodriguez has participated as a lecturer and speaker in scientiﬁc meetings and courses under the sponsorship of AstraZeneca. Lowe LA. New safety requirements for long-acting inhaled asthma medications called LongActing Beta-Agonists (LABAs).
20.fda. 2011 Liberati A. Ltd.119(1):64–72 Ducharme FM. Le Roux P. Green S. No sponsorship from institutions or the pharmaceutical industry was provided to conduct this study. Minder C. Frost C. 362(13):1169–1171 McMahon AW. Dr Esteve SA. Scientiﬁc rationale for inhaled combination therapy with long-acting beta2agonists and corticosteroids. and Blood Institute. 2008. Ann Intern Med. Clinical safety data management: deﬁnitions and standards for expedited reporting. J Allergy Clin Immunol. Bland JM. Sorkness CA. Bergman DA.
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