Evidence Table 2Systematic Reviews

Study design:Number of patients:Aims of review:Studies included in analysis or review:Characteristics of included studies:Main results:Adverse Events:Quality rating:
Adams, N et al


Cochrane Database Systematic Review

NHS Research and Development UK and Garfield Weston Foundation UK
systematic review with meta-analysis1174 subjects (24 studies)To assess clinical outcomes in studies which have compared inhaled BDP and BUD in the treatment of chronic asthma.24 studies met the criteria for inclusion: Baran D. Brit J Diseases of the Chest 1987;81(2):170–5.; Bisgaard J All & Clin Immunol 1988;81(6):1088–95.; Bjorkander J, Euro J Resp Dis - Supplement 1982;122:108–17.; Boe J, Allergy: Euro J All & Clin Immunol 1989;44(5):349–55.; Brambilla C, Drug Investigation 1994;8(1): 49–56.; Dal Negro R, Euro Resp J. 1997:351S.; Ebden P, Thorax 1986;41(11):869–74.; Field HV, Arch Dis Childhood 1982;57(11): 864–6.; Greefhorst APM. Euro Resp J. 1992; Vol. 5, issue Suppl 15:360S.; Hamalainen KM, Euro Resp J 1998:61S.; Keelan P, Irish Medical Journal 1984;77(8): 244–7.; Micheletto C, Euro Resp J. 1997:351S.; Nicolaizik WH, Am J Respir & Crit Care Medicine 1994;150 (3):624–8.; Pedersen S, Euro Respir J 1988;1(5): 433–5.; Petrie GR, Drug Investigation 1990;2(2):129–31.; Rafferty P, Bri J Dis of the Chest 1985;79(3):244–50.; Selroos O, Allergy: Eu J All & Clin Immunol 1994;49(10):833–6.;

Springer C, Arch Dis in Childhood 1987;62(8):815–9.; Stiksa G, Euro J Respir Dis - Supplement 1982;122:266–7.; Stiksa G, Euro J Resp Dis - Supplement 1982;122:266–7.; Stiksa G, Annals of Allergy 1985;55(1):49–51.; Svendsen 1992: [[Svendsen UG, Ugeskrift for Laeger 1993;155(28):2197–202.; Svendsen UG, Allergy: European Journal of Aller and Clinical Immunology 1992;47(2 Pt 2):174–80.]]; Tjwa MK. Ann All, Asthma & Immunol 1995;75(2):107–11.; Willey RF, Eur J Respir Dis - Supplement 1982;122:138–42.
Five studies (Bisgaard 1988, Brambilla 1994, Dal Negro 1997, Micheletto 1997, Selroos 1994) were parallel group studies. Nineteen studies (79%) were of crossover design. The length of treatment period varied. Twelve studies (50%) had treatment periods of between two and four weeks, 10 studies (42%) had treatment periods of between six and 12 weeks. The longest study (Selroos 1994) had an effective treatment period of two years.

Methodological quality of included studies was variable. Only 10 studies (42%) were double blind. 19 studies (79%) provided adequate descriptions of numbers of patients withdrawn and the reasons for withdrawal. As assessed by the Jadad scoring method 15 studies (63%) achieved a score of 3 or 4; no studies achieved a maximum score of 5. In only four studies (17%) was allocation concealment clearly employed. In all other studies allocation concealment was unclear.
Symptoms: No difference
[symptom score (6 cross-over studies): SMD 0.06, 95% CI: −0.18 to 0.31, 6 studies; night-time breathlessness (three cross-over studies): SMD −0.09 (95% CI −0.43 to 0.25)]

Rescue medicine use: No difference
[qualitative summary, no meta-analysis]


Hypothalamo-pituitary adrenal axis (HPA) function

Three studies (118 subjects) reported morning plasma cortisol. Two studies (76 subjects) reported plasma cortisol following a short cosyntropin test. No significant differences between BDP and BUD treatment groups were evident. In a single crossover study (Pedersen 1988), conducted in children and of fair methodological quality (Jadad score 3) 24 hour urinary free cortisol excretion was assessed. In this study subjects treated with BDP 800–1200 mcg/d had significantly lower 24 hour urinary cortisol levels compared to BUD 800–1200 mcg/d: BDP 7.6 nmol cortisol/mmol creatinine/day v BUD 10.2 nmol cortisol/mmol creatinine/day p<0.01.

Local oral side effects

The incidence of local oral side effects was reported in a number of crossover studies (Baran 1987, Boe 1989, Ebden 1986, Petrie 1990, Svendsen 1992). However, interpretation of the results is extremely difficult. In each study, the incidence of side effects was reported by treatment (BDP or BUD), rather than by individual treatment period. It was not stated if, in the case of a patient experiencing an adverse event during the first period of the trial when receiving one ICS, this had resolved by the point of crossover.

Because none of the studies incorporated washout periods, this was especially unclear. In summary, the data regarding local oral side effects from the crossover studies comparing BDP to BUD are uninterpretable.


There were no significant differences between treatments with regard to the incidence of local oral side effects (hoarseness/sore throat or Candidiasis).


Outcomes reported included 24-hour urinary free cortisol excretion and plasma cortisol 30 min post 250 mcg i.v. tetracosactrin. No statistically significant difference between BDP and BUD were apparent for either outcome.



Adams, N et a., 2007

Cochrane Database Systematic Review

NHS Research and Development UK
systematic review with meta-analysis71 trials (14,602 participants),Fluticasone versus beclomethasone or budesonide for chronic asthma in adults and childrenFP vs. BDP (33 trials)

FP vs. BUD (37)

FP vs. BDP/BUD (2)

38 studies had FP:BDP/BUD dose ratio of 1:2; 22 had dose ratio 1:1; remainder had multiple dose ratio comparisons or ratio was unclear
RCTsDose ratio 1:2:
Symptoms: FP > BDP/BUD
[Change in symptom scores: SMD: −0.19 (95% CI −0.31 to −0.07) 6 studies, N = 1035.
Absolute percentage of symptom free days: MD 4.9% (95% CI −1 to 11), two studies, N = 699. Change in percentage of symptom free days: MD 6.43% (95% CI 0.47 to 12.39), two studies, N = 399.]
Nocturnal awakenings: No difference [Change in number of awakenings per night: MD: 0.01 (95% CI −0.04 to 0.06), two studies, N = 282]

Exacerbations: No difference
[Withdrawal due to asthma exacerbation: Peto OR 0.77 (95% CI 0.54 to 1.1), 11 studies N = 2824; Participants with an exacerbation: Peto OR 0.74 (95% CI 0.53 to 1.03), four studies N = 1213; Withdrawal due to lack of efficacy: Peto OR 0.6 (95% CI 0.33 to 1.07), seven studies, N = 1781]

Rescue med use: FP > BDP/BUD
[Change in percentage of rescue-free days: MD 6.89% (95% CI 0.32 to 13.46), two studies, N = 399; Change in rescue usage (puffs/day): MD −0.35 puffs (95% CI −0.63 to −0.07), four studies, N = 763; # of participants experiencing rescue-free days and nights: no significant differences were reported, 6 studies reported (data not pooled for several reasons)]
Dose ratio 1:1:
Symptoms: No difference
[proportion of symptom-free days: MD 5.54% (95% CI −0.68 to 11.76), two studies, N = 571; daytime symptoms: SMD: −0.10 (95%CI −0.34 to 0.13), two studies, N = 285.
Change from baseline in daytime symptoms: SMD −0.03 (95% CI −0.11 to 0.06), three studies, N = 534; change from baseline in nocturnal symptoms: SMD −0.03 (95% CI −0.15 to 0.09), three studies, N = 537]

Exacerbations: [Requirement for medication other than beta-agonist: Random Effects OR: 0.70 (95% CI 0.45, 1.09); One or more exacerbations: Peto OR 0.99 (95%CI 0.73 to 1.33), three studies, N = 1054; Withdrawal due to an exacerbation: Peto OR 0.72 (95% CI 0.38 to 1.35), five studies, N = 978]

Rescue med use:[Change from baseline, day use: −0.04 puffs/day (95% CI −0.12 to 0.04), two studies, N = 368; change from baseline, night use: −0.03 puffs/day (95% CI −0.13 to 0.08), two studies, N = 368]
Ducharme, F et al.


Cochrane Review

Canadian Cochrane Network CANADA and Fonds de la Santé du Québec CANADA
systematic review and meta-analysis5871 (27 studies)In patients who were symptomatic, despite use of maintenance ICS, to determine whether the addition of anti-leukotriene agents reduced the frequency and severity of exacerbations and improved chronic asthma control while maintaining a good safety profile. The addition of anti-leukotriene agents to inhaled corticosteroids was compared to either the use of the same or double dose of ICS. Also, in patients who were well controlled on their baseline dose of ICS, we wished to quantify the magnitude of dose reduction in inhaled glucocorticoids (glucocorticoid-sparing effect) that could be achieved with the addition of antileukotrienes.List of studies included in the review is available upon request.RCTs only; A total of 27 (2 paediatric and 25 adult) trials, 16 of which were published in full text at the time of this report (Kanniess 2002; Laviolette 1999;O’Sullivan 2003;Price 2003;Riccioni 2001;Riccioni 2002;Shingo 2002;Simons 2001; Tamaoki 1997; Tohda 2002;Tomari 2001;Tomita 1999;Vaquerizo 2003 ;Virchow 2000; Wada 1999), met the inclusion criteria for this review. We grouped these 27 trials according to one of three protocols defining their specific objective and design.

Randomised placebo controlled trials in adults and children in which anti-leukotriene agents were added to inhaled glucocorticoid were considered for inclusion. Sensitivity analyses were performed based on the reported quality of randomisation, concealment of allocation, blind assessment of outcomes, and description of withdrawals and dropouts.

Anti-leukotrienes + ICS versus SAME dose of inhaled corticosteroids (ICS):
Thirteen trials, including 10 full-text publications (Laviolette 1999; O’Sullivan 2003;Riccioni 2001;Riccioni 2002;Simons 2001;Tamaoki 1997;Tomita 1999;Vaquerizo 2003 ;Virchow 2000;Wada 1999) and two abstracts (Finn 2000;Nishimura 1999) and an unpublished report (Hultquist 2000) evaluated the degree of asthma control achieved by the addition of antileukotrienes to inhaled corticosteroids compared to the same dose of inhaled corticosteroids in the control group. All but three trials (Nishimura 1999;O’Sullivan 2003;Simons 2001) were parallel-group randomised controlled trials. Eight trials (Finn 2000;Hultquist 2000;Laviolette 1999;Nishimura 1999 ;Simons 2001;Vaquerizo 2003 ;Virchow 2000; Wada 1999) enrolled participants who were clearly symptomatic at baseline; two trials enrolled well controlled adults (Riccioni 2001;Riccioni 2002); twotrials (Tamaoki 1997; Tomita 1999) recruited well controlled participants in whom their usual dose of ICS required to maintain control was suddenly reduced by half on randomisation in an attempt to render them symptomatic; and the last trial (O’Sullivan 2003) enrolled well controlled mild asthmatics in a cross-sectional study to determine the impact on inflammatory markers and lung function of the addition of leukotriene receptor antagonists. Finn 2000 ’s trial randomised 479 children of whom only 98 received co-treatment with inhaled glucocorticoids which were analysed separately (although it is unclear if the randomisation was stratified on the presence/absence of co-treatment with inhaled glucocorticoids). Two trials (Tomita 1999;Wada 1999) were open label studies (no blinding) with no placebo use in the control group, while two other trials reported their study (Riccioni 2001; Riccioni 2001) as double-blind for the patients and assessor but with no use of placebo.

Anti-leukotrienes + ICS versus INCREASED dose of ICS: Seven trials, (Green RH 2002; Nayak 1998;Nsouli 2000;Price 2003;Ringdal 1999;Tomari 2001;Yildirim 2001), compared the addition of anti-leukotrienes to inhaled corticosteroids to increasing the dose of inhaled corticosteroids in symptomatic patients. All but one trial (Green RH 2002) were parallel-group, randomized trials, placebo-controlled. In two trials (Nayak 1998;Ringdal 1999), various doses of anti-leukotrienes were considered in a three-arm trial design (see below). Only two trials are currently full text publications (Price 2003; Tomari 2001), while data for two additional trials (Nayak 1998;Ringdal 1999) were derived from abstracts and unpublished reports kindly provided by Astra-Zeneca, the manufacturer of zafirlukast.

Anti-leukotrienes + ICS versus SAME dose of ICS (TAPERING ICS dose):
Seven trials included participants who were well controlled at baseline (Baba 1999;Bateman 1995;Kanniess 2002 ;Laitinen 1995; Lofdahl 1999; Shingo 2002;Tohda 2002), and assessed the magnitude of reduction in inhaled corticosteroids following the addition of anti-leukotrienes. At the time of publication, four trials (Kanniess 2002;Lofdahl 1999;Shingo 2002;Tohda 2002) were published in full-text; the data for Bateman 1995 and Laitinen 1995 were derived from abstracts and unpublished reports provided by Astra-Zeneca; the data provided in one abstract (Baba 1999) was insufficient to be used in this review. All but one trial (Kanniess 2002) were parallel-group trials;
Kanniess 2002 described a cross-over study where tapering (from 800 to 400 mcg/day of beclomethasone or equivalent) was initiated in the first period then, without a washout period, patients crossed-over to the alternate treatment strategy in the second period where the dose of inhaled steroids was tapered (from 400 to 200mcg/day of beclomethasone or equivalent). Because this unusual design did not allow merging of the two periods and because no significant change in asthma control occurred in the first period suggesting of over-treatment at baseline, the second period was chosen for analysis. Use of an identical placebo was described in all but one trial (Baba 1999).
LTRA+ICS vs. Same ICS:
Symptoms: No difference [change in symptom score (WMD = −0.10, 95% CI −0.24 to 0.03) or nocturnal awakenings (WMD −6.25, 95% CI −12.72 to 0.23) with licensed doses of LTRAs]

Exacerbations: LTRA+ICS >ICS trend [reduction in the risk of exacerbations requiring systemic steroids: RR 0.64, 95% CI 0.38 to 1.07]

Rescue medicine use: LTRA+ICS > ICS [change from baseline in beta-agonists use (SMD −0.15, 95% CI −0.24 to −0.05)]

QOL: No difference [(WMD 0.08, 95% CI −0.03 to 0.20)]

LTRA+ICS vs. Increased ICS :
Symptoms: No difference
[change from baseline in symptoms score (WMD 0.01, 95%CI −0.09 to 0.10)]

Exacerbations: No difference [risk of exacerbation requiring systemic steroids: RR 0.92, 95% CI 0.56 to 1.51; withdrawals due to poor asthma control: RR 0.49, 95% CI 0.15 to 1.63]

Rescue medicine use: No difference [change from baseline in use of rescue beta-agonists: WMD −0.03 95% CI −0.24 to 0.18]
Anti-leukotrienes + ICS vs. SAME dose of ICS:

No significant group differences were observed in the risk of overall withdrawals (3 trials, RR 0.97, 95% CI 0.69 to 1.37), withdrawal due to poor asthma control (3 trials, RR 0.46, 95% CI 0.16 to 1.31), withdrawals due to adverse effects (3 trials, RR 0.63, 95% CI 0.29 to 1.37), overall adverse effects (2 trials, RR 1.01, 95% CI 0.88 to 1.15), elevated liver enzymes (2 trials, RR 1.02, 95% CI 0.36 to 2.88), headache (3 trials, RR 1.15, 95% CI 0.89 to 1.49), and nausea (2 trials, RR 0.45, 95%CI 0.19 to 1.07),. There was no death.

For pooling of two trials that used higher than licensed odses of pranlukast or zafirlukast: There was no significant group difference in the risk of overall withdrawals (2 trials, RR 0. 74 95%CI 0.39 to 1.39), withdrawals due to adverse effects (RR 0.73, 95% CI: 0.28 to 1.88), overall adverse effects (RR 1.02, 95% CI: 0.81 to 1.27) and nausea (RR 1.48, 95% CI 0.45 to 4.87).

Anti-leukotrienes + ICS vs. INCREASED dose of ICS:
Safety measures also show no significant group difference for overall withdrawals (2 trials, RR 0.99, 95% CI 0.63 to 1.55), withdrawals due to side effects (2 trials, RR 1.14, 95% CI 0.55 to 2.37), overall adverse effects (2 trials, RR 0.95, 95% CI 0.84 to 1.06), elevated liver enzymes (2 trials, RR 0.8 95% CI 0.34 to 1.92), headache (2 trials, RR 1.07, 95% CI 0.76 to 1.52), and nausea (2 trials, RR 0.63 95% CI 0.25 to 1.60). There was no death.

When comparing the combination of two to four-fold the licensed doses of leukotriene receptor antagonists with 400–500 mcg/day of BDP or equivalent as opposed to doubling the dose of inhaled steroids, use of higher than licensed doses of leukotriene receptor antagonist was associated with a five-fold increased risk of liver enzyme elevation (3 trials, RR 4.97 95% CI 1.45 to 17), but has a marked protective effect on oralmoniliasis (3 trials, RR 0.29 95%CI 0.10 to 0.81).

Other safety measures show no significant group difference, namely for overall withdrawals (3 trials, RR 1.05 95% CI 0.73 to 1.50), withdrawals due to side effects (3 trials, RR 2.27 95% CI 0.95 to 5.45), overall adverse effects (3 trials, RR 0.98 95%CI 0.89 to 1.07), headache (3 trials, RR 1.14 95%CI 1.14 to 1.63), and nausea (3 trials, RR 1.77 95% CI 0.79 to 3.95). There was no death.

Anti-leukotrienes + ICS vs. SAME dose of ICS (TAPERING ICS dose):
Less withdrawals due to any cause were observed in the leukotriene receptor antagonists group (6 trials, RR 0.77, 95% CI: 0.60 to 0.98), probably influenced by the marked reduction in withdrawals due to poor asthma control in the anti-leukotriene group. With regard to side effects, there was no group difference in the number of withdrawals due to adverse effects (RR 0.88; 95% CI 0.52 to 1.51) overall adverse effects (RR 0.95; 95% CI 0.83 to 1.08, randomeffectmodel), elevated liver enzymes (RR1.67, 95% CI 0.86 to 3.21), headache (RR 0.79, 95% CI 0.58 to 1.08), nausea (RR 1.49, 95% CI 0.70 to 3.19). In contrast, there was a significant increased risk of serious adverse events defined in accordance to the U.S. Food and Drug Administration (FDA) criteria (Anonymous 2001), associated with zafirlukast (RR 2.47, 95% CI 1.53 to 3.97) (Bateman 1995; Laitinen 1995). Only one death, not related to asthma, was reported.
Ducharme, F et al.


Cochrane Review

Fonds de la Santé du Québec CANADA
systematic review and meta-analysis9100 (27 trials)The aim of this systematic review was (1) to compare the safety and efficacy of daily oral anti-leukotrienes with that of ICS in the management of children and adults with chronic asthma and (2) to determine the minimal required dose of maintenance ICS equivalent to the effect of anti-leukotriene agents. We also sought to determine whether the anti-leukotriene and inhaled steroid used, intervention duration, disease severity, patients’ age, methodological quality, publication status and sponsorship influenced the magnitude of effect attributable to antileukotrienes.List of studies included in the review is available upon request.RCTs conducted in adults and/or in children in which leukotriene antagonists were compared to ICS were included.Symptoms: ICS > LTRA [symptom scores: 6 trials, SMD=0.29, 95% CI: 0.21 to 0.37; symptom-free days: 3 trials, WMD= −12, 95%CI: −16 to −7; and nocturnal awakenings: 6 trials, SMD=0.21, 95% CI: 0.13 to 0.30].

Exacerbations: ICS > LTRA for some [65% increased risk of exacerbation requiring systemic steroids for any LTRA: relative risk 1.65 (1.36 – 2.00); No significant difference in exacerbations requiring hospitalization [relative risk 1.62 (0.64 – 4.15)]

Rescue medicine use: ICS > LTRA [daily use of B2-agonists: 6 trials, WMD= 0.28 puffs/day, 95% CI: 0.20 to 0.36; rescue-free days: 3 trials, WMD= −14%, 95% CI: −18 to −10]

Quality of Life: ICS > LTRA [quality of life: 2 trials: WMD= −0.3, 95% CI: −0.4 to −0.2].

Missed work or school: No difference [days off from school/work: 2 trials, WMD= 0.06 days, −0.03 to 0.15].

Anti-leukotriene therapy was associated with a 30% increased risk of overall withdrawals [N=19 trials, RR=1.3, 95% CI: 1.1 to 1.6, random effect model]. The withdrawals appeared to be attributable to a marked increased risk of withdrawals due to poor asthma control [N=17 trials, RR=2.6, 95% CI: 2.0 to 3.4, fixed effect model] and not due to adverse effects [N=14 trials, RR= 1.2, 95% CI: 0.9 to 1.6, fixed effect model]. If 29 patients are treated with anti-leukotrienes rather than inhaled corticosteroids there will be one extra withdrawal due to poor asthma control, NNH 29 (95% CI 20 to 48).


There was no significant group difference in the number of patients who experienced “any adverse effects,” [N=15 trials, RR= 0.99, 95% CI: 0.93 to 1.04, fixed effect model], which met our definition of equivalence. There was also no significant difference in elevation of liver enzymes, [N=6 trials, RR=1.3, 95% CI: 0.7 to 2.3], headaches [N=16 trials, RR=0.9, (95% CI: 0.8 to 1.1], nausea [N=12 trials, RR=1.0, 95% CI: 0.7 to 1.5)], oral candidiasis [N=2 trials, RR=0.15, 95% CI: 0.02 to, 1.18], or death which was reported in only 1 trial.
Ducharme, F.


Salary award of the Fonds de la Recherche en Santé du Québec. Ritz Kakuma was supported by the Canadian Cochrane Network.
systematic reivew and meta-analysis2967 (13 studies)Examined the safety and efficacy of oral antileukotrienes as add on therapy to inhaled glucocorticoids in children and adults with asthma to quantify the improvement in asthma control achieved over inhaled steroids alone (at the same or double the dose) and the glucocorticoid sparing effect when inhaled steroids are tapered.Lofdahl, C et al. BMJ 1999;319:87. Tamaoki, J et al. Am J Respir Crit Care Med 1997;155:1235. Virchow, J et al. Am J Respir Crit Care Med 1997;156:578. Laviolette, M et al. Am J Respir Crit Care Med 1999;160:1862. Simons, F et al. J Pediatr 2001;138:694. Wada, K et al. Allergol INt 2000;49:63. Ringdal, N et al. Am J Respir Crit Care Med 2000;159 (3 of part 2):639. (Abstract) Nayak, A et al. J Allergy Clin Immunol 1998;101 (1 of part 2): S233 (Abstract 965). Tomita, T et al. Arerugi 1999;48:459. Bateman, E et al. Allergy 1995;50 (suppl 26): 320. (Abstract P-0709). Laitinen, L et al. Allergy 1995; 50 (suppl 26): 320 (Abstract P-0710). Baba, K et al. Am Rev Resp Crit Care Med 1999;159:A626. Shingo, S et al. Theodore Reiss, personal communication, 2001.RCTs only. Documented measures of efficacy other than compliance.

For the SR/MA, the primary outcome measures were the number of exacerbations of asthma requiring rescue systemic glucocorticoids when the intervention was compared with the same or an increased dose of inhaled glucocorticoids and the change from the baseline dose of inhaled glucocorticoids required to maintain control when the intervention was aimed to establish the steroid sparing effect. Secondary outcomes were changes in pulmonary function tests, symptoms, use of rescue ß2 agonists, quality of life, exacerbations requiring hospital admission, adverse effects, and withdrawals.

data from 13 trials (one study in children and 12 in adults; six unpublished as of August 2001) were included in the review.
Antileukotrienes versus placebo as add-on therapy to inhaled glucocorticoids:

Although four of the six identified trials contributed data to the primary outcome, only two tested antileukotrienes (montelukast; Singulair, Merck Frosst) at licensed doses. With the addition of licensed doses of antileukotrienes to glucocorticoids, a nonsignificant reduction in the risk of exacerbations requiring systemic steroids was observed (relative risk 0.61, 95% confidence interval 0.36 to 1.05). The only paediatric trial did not show any significant group difference. When higher doses were examined, the addition of pranlukast (Ono, Japan), or zafirlukast (Accolate, Astra Zeneca) reduced the risk of exacerbations requiring systemic steroids by 66% (relative risk 0.34, 0.13 to 0.88) (fig 2). The number needed to treat was 20 (11 to 100). Within each stratum the results were homogeneous despite the different doses and antileukotrienes tested, age, baseline dose of inhaled glucocorticoids, and duration of antileukotriene use. No evidence was found of systematic bias identified by the measure of funnel plot asymmetry (intercept 0.17, −3.22 to 3.55).

Pooling of the two trials of higher than licensed doses of pranlukast or zafirlukast for six weeks showed a significant group difference favouring the addition of antileukotrienes to inhaled corticosteroids. This was shown in the magnitude of improvement from baseline use of rescue B2 agonists (−0.43, −0.22 to −0.63), and asthma symptoms (standard ised mean difference −0.46, −0.25 to −0.66).

Antileukotrienes as add on therapy to inhaled glucocorticoids versus double dose inhaled glucocorticoids:

The data from two unpublished trials, each testing two different doses of zafirlukast, were analysed. Pooling of data was only possible for zafirlukast at four times the licensed dose. No apparent group difference was found in the risk of an exacerbation requiring systemic steroids after 12 weeks of treatment with zafirlukast 80 mg twice daily (relative risk 1.08, 0.47 to 2.50); the width of this confidence interval exceeded our definition of equivalence (fig 3). The small number of trials prevented subgroup and sensitivity analyses. No group difference was found in secondary outcomes, including symptom score, use of short acting B2 agonists, withdrawal due to poor asthma control, or hospital admission.

Antileukotrienes versus placebo as add on therapy to tapered doses of inhaled glucocorticoids:

The data from four of the five identified trials testing licensed doses of antileukotrienes were provided in sufficient detail to be analysed. The assessment of the glucocorticoid sparing effect of antileukotrienes depends on showing adequate and comparable control of asthma between the intervention and control groups after tapering. After 12 weeks of treatment, two trials of zafirlukast reported no significant group difference in final mean symptom scores and use of ß2 agonists. Two trials testing montelukast failed to report sufficient data to confirm comparable asthma control after steroid tapering. Pooling of the four trials showed a noticeable reduction (relative risk 0.56, 0.35 to 0.89) in the rate of withdrawal owing to poor asthma control in the group treated with antileukotrienes, suggesting better asthma control with the combination therapy. After 12 to 20 weeks of treatment, no overall group difference was observed in change from the baseline dose of inhaled glucocorticoid required to maintain asthma control (three trials; weighted mean difference 1.87%, −3.52 to 7.27). When the lowest tolerated dose of inhaled glucocorticoids was considered, no meaningful group difference was observed either (−44.43 mcg/day, −147.87 to 59.02; random effect model). Heterogeneity was apparent among trials: the two trials of zafirlukast reported no group difference whereas the trial of montelukast reported a significant reduction of 200 mcg/day in favour of antileukotrienes. Based on the relative potency and distribution of inhaled steroids used in the montelukast trial, the 200 mcg/day would translate to an approximate corticosteroid sparing effect of 160 mcg/day of beclomethasone equivalent. The small number of trials and their design prevented the clear attribution of the source of heterogeneity; trials differed not only in the dose and antileukotriene used but also in the baseline dose and inhaled glucocorticoid used, dose optimisation period, weaning protocol, and intention to treat analysis. The rate of complete glucocorticoid weaning was similar between groups (three trials, relative risk 1.18, 0.95 to 1.47).
Antileukotrienes versus placebo as add on therapy to inhaled glucocorticoids:

No significant group difference was observed in the risk of overall withdrawals (relative risk 0.91, 0.54 to 1.53), withdrawals owing to adverse effects (0.65, 0.26 to 1.66), increased liver enzyme concentrations (1.02, 0.36 to 2.88), headache (1.16, 0.86 to 1.57), and nausea (0.45, 0.19 to 1.07). No death was reported.

Pooling of the two trials of higher than licensed doses: No group difference in overall adverse events or nausea was observed; insufficient number of trials prevented pooling of data for other adverse effects.

Antileukotrienes as add on therapy to inhaled glucocorticoids versus double dose inhaled glucocorticoids:

Zafirlukast (80 mg twice daily) was associated with an increased risk of increased liver enzyme concentrations (5.36, 1.40 to 20.44) and of withdrawal due to adverse events (2.77, 1.02 to 7.58)— that is, 1 in every 25 (95% confidence interval 14 to 100) patients and 1 in every 33 (16 to infinity) patients treated with high dose zafirlukast would have an increase in liver enzyme concentrations and withdrawals due to adverse events, respectively. In contrast, a double dose of beclomethasone was associated with a higher risk of oral moniliasis compared with antileukotrienes (7.1, 1.3 to 33; number needed to harm 33, 17 to 100).

Antileukotrienes versus placebo as add on therapy to tapered doses of inhaled glucocorticoids:

No group difference was found in the number of overall withdrawals, withdrawals owing to adverse effects (relative risk 1.07, 0.57 to 2.03), increased liver enzyme concentrations (2.13, 0.80 to 5.68), headache (0.90, 0.64 to 1.26), or nausea (1.14, 0.49 to 2.67). The similarity between groups in the number of overall adverse effects met the review's definition of equivalence (four trials; 0.98, 0.91 to 1.05). A significantly increased risk of serious adverse events as defined by the criteria of the Federal Drug Administration was associated with zafirlukast at licensed doses (2.47, 1.53 to 3.97).19 20 23 No death was reported.
Ducharme, FM et al.


Cochrane Review

Nederlands Astma Fonds NETHERLANDS, Francine M. Ducharme CANADA, NHS Research and Development UK
Systematic Review and Meta-analysis of randomised, parallel-group, trialsFifteen randomised controlled trials - 6476 participants (80 children participants) - 6,030 patients included to meta-anaylsisCompared the efficacy and safety profile of adding either daily LABA or LTRA in asthmatic patients who remained symptomatic on ICS.Nine full-text publications (Bjermer 2003; Ceylan 2004; Fish 2001; Grosclaude 2003; Ilowite 2004; Nelson 2000; Nelson 2001; Ringdal 2003; Storms 2004), two unpublished full-text reports (Hultquist 2000;McCarthy 2003) and four abstracts (Green (abs) 2002; Hendeles 2004; Nsouli 2001; Stelmach 2005). The abstracts did not provide data in sufficient detail to contribute to the meta-analyses. Therefore, the description hereafter pertained to eleven trials which contributed data from 6,030 patients to the meta-analysis.Only randomised controlled trials conducted in adults or children with recurrent asthma where a LABA (for example, salmeterol or formoterol) or LTRA (for example, montelukast, pranlukast, zafirlukast) was added to ICS for a minimum of 28 days were considered for inclusion. Inhaled short-acting ß2-agonists and short courses of oral steroids were permitted as rescue medications. Other dailyasthma treatments were permitted, providing the dose remained constant during the intervention period.

Twelve trials reported double-blinding while Ceylan 2004; Grosclaude 2003 and Nsouli 2001 were open-labelled. Nine double-blind trials reported the use of double-dummies to maintain allocation concealment; while three trial failed to clearly report means of blinding (Green (abs) 2002; Hendeles 2004; Stelmach 2005). Withdrawal rate was described in all but the two studies reported as abstracts (Green (abs) 2002; Nsouli 2001). Although total withdrawals were reported in Ceylan 2004, it was not clear how many participants from each group withdrew. Withdrawal rates varied from 8 to 17% in the LTRA group and 5 to 27% in the LABA group.
Symptoms: LABA + ICS > LTRA + ICS [% symptom free days: 6.75%; 95% CI 3.11 to 10.39, improvement in daytime symptom score: −0.18; 95% CI −0.25 to −0.12, decrease in nighttime awakenings: −0.12; 95% CI −0.19 to −0.06, increase in % awakening-free nights per week: 6.89%; 95% CI 2.87 to 10.91].

Exacerbations: LABA + ICS > LTRA + ICS [risk of exacerbation requiring systemic steroids: RR 0.83; 95% CI 0.71 to 0.97; regardless of LABA used, risk of exacerbation requiring hospital admission: RR 1.31; 95%CI: 0.58 to 2.98].

Rescue medicine use: LABA + ICS > LTRA + ICS [increase in % rescue free days: 8.96%; 95% CI 4.39 to 13.53, but there was significant heterogeneity in this pooled estimate with a significant difference between the two subgroups P < 0.05].

QOL: LABA + ICS > LTRA + ICS [increase (improvement) in Global Asthma Quality of Life score: 0.11; 95% CI 0.05 to 0.17].

Mortality: no difference (P = NR)
Withdrawals due to adverse effects: Ten studies with 6,225 patients reported withdrawals due to adverse effects (Bjermer 2003; Fish 2001; Grosclaude 2003; Hultquist 2000; Ilowite 2004; McCarthy 2003; Nelson 2000; Nelson 2001; Ringdal 2003; Storms 2004). The overall estimate comparing LABA+ICS with LTRA+ICS did not show a significant difference between the groups (RR 1.02; 95%CI 0.80 to 1.32).

There was also no significant difference in withdrawals due to adverse effects between subgroups when the studies were subgrouped according to type of LTRA.

Withdrawals due to poor asthma control/exacerbations: Seven studies with 5,276 patients reported this outcome measure (Bjermer 2003; Fish 2001; Grosclaude 2003;Hultquist 2000; Ilowite 2004; Nelson 2000; Nelson 2001). There were no significant differences in the overall estimate (RR 0.87; 95%CI 0.49 to 1.56) or between the subgroups. There was heterogeneity present (I2= 46.6%).

Patients with one or more exacerbations requiring hospital admission: Three studies with 3,747 patients reported this outcome (Bjermer 2003; Ilowite 2004; Ringdal 2003) comparing LABA+ICS to Montelukast+ICS. There was no significant difference between the two study groups (RR 1.31; 95%CI: 0.58 to 2.98).

Severe adverse events: Six studies with 5,592 patients reported this outcome (Bjermer 2003; Fish 2001; Ilowite 2004; Nelson 2000; Nelson 2001; Ringdal 2003). There was no significant difference in the overall result (RR 1.32: 95%CI: 0.98 to 1.79) nor between subgroup comparisons according to the type of LTRA. The overall confidence interval of severe adverse events is wide (95% CI 0.98, 1.79) and includes the possibility that LABA + ICS increases risk by more than the prespecified level of 10% (i.e. RR =1.1).

Deaths: Only one study reported deaths (Bjermer 2003) with no significant difference between the two study groups (only one death occurred).
Headache: Ten studies with 6,187 patients reported headache as an adverse event (Bjermer 2003; Ceylan 2004; Fish 2001; Grosclaude 2003; Hultquist 2000; Ilowite 2004; McCarthy 2003; Nelson 2000; Nelson 2001; Ringdal 2003). There was no significant difference in the overall result or when the two different types of LTRA were compared to LABA+ICS, (RR 1.07; 95% CI 0.9, 1.26).
Cardiovascular events: Five studies with 5,163 patients reported cardiovascular events (Bjermer 2003; Fish 2001; Ilowite 2004; Nelson 2000; Ringdal 2003). There was no significant difference when LABA+ICS was compared to Montelukast+ICS (RR 1.09; 95%CI: 0.77 to 1.52).

Oral moniliasis: Six studies with 5,203 patients reported number of patients with oral moniliasis (Bjermer 2003; Ceylan 2004; Fish 2001; Ilowite 2004;Nelson 2000; Ringdal 2003). The studies compared LABA+ ICS to Montelukast+ICS showing an overall significant rise in risk of oral moniliasis with LABA+ICS (RR 1.86; 95%CI 1 to 3.44). The occurrence rates were low and this represents an average risk of oral moniliasis of 1% for LABA and 0.5% for LTRA. The risk difference for this outcome was 0.01 (95% CI 0 to 0.01). Osteopenia/osteoporosis: Two studies reported this outcome (Bjermer 2003; Ilowite 2004) with no significant difference between the study groups (RR 0.56; 95%CI: 0.12 to 2.63).

Elevated liver enzymes: One study reported this outcome (Bjermer 2003) with no difference between the study groups. Overall adverse events: Eight studies (Bjermer 2003; Fish 2001; Ilowite 2004; McCarthy 2003; Nelson 2000; Nelson 2001; Ringdal 2003) with 5,911 patients reported adverse events which did not show a significant difference when LABA+ICS was compared to LTRA+ICS. The absence of group difference (RR 1.03; 95%CI 0.99 to 1.07) met our a priori definition of equivalence.


Systematic review and meta-analysis4528To determine the efficacy of adding LABA to maintenance ICS therapy in reducing the requirement for ICS while maintaining control of chronic asthma.19 citations (9 publications and 10 abstracts) describing 10 parallel designed RCTs - Baranuik 1999; Lalloo 2001; Bloom 2003; Dorinsky 2004; Kips 2000; Pauwels 1997; Busse 2003; Nielsen 1999; Self 1998; Lemanske 2001; )Randomised controlled trials of parallel design only were considered.

Double, single or unblinded studies were considered.
  1. Abrupt fixed reduced ICS + LABA versus fixed moderate or high dose of the same ICS
    Exacerbations requiring OCS: RR 1.0 (95% CI 0.76 to 1.32), comparison 1.01.
    Withdrawal due to worsening asthma: RR 0.82 (95% CI 0.50 to 1.35), comparison 1.02.
    Rescue medication use (puffs/day) change from baseline: WMD −0.11 (95%CI −0.25 to 0.03), comparison 1.07.
    Percent rescue free days change from baseline: WMD 9.21 (95%CI 1.36 to 17.05). Chi2 = 5.11, P = 0.08, I2 = 60.9%, comparison 1.08.
    Night Waking change from baseline: WMD 0.02 (95%CI −0.09 to 0.12), comparison 1.11.
    Percent symptom free days: WMD 5.76 (95%CI 0.81 to 10.7), comparison 4.09.
    Night Waking change from baseline: WMD 0.02 (95%CI −0.09 to 0.12), comparison 3.11.
    Overall Withdrawals: RR 0.97 (95%CI 0.74 to 1.28), comparison 1.13.
  2. Reduced or tapering ICS + LABA versus reduced or tapering dose of the same ICS according to asthma control [significantly greater proportion of participants in the LABA/ICS group attained a > 50% reduction in ICS dose with no significant difference in FEV1(L), morning or evening PEF between treatment groups when compared to their baseline sensitivity period.]
  3. Reduced ICS + LABA versus ICS alone in participants who demonstrate deteriorating asthma control when ICS are reduced
Rescue medication use (puffs/day) change from baseline: SMD −0.15 (95%CI −0.30 to 0.01). Chi 2=4.19, P= 0.24, I2 = 28.3%, comparison 3.07

Percent rescue free days:WMD 9.21 (95%CI 1.36 to 17.05). Chi2 = 5.11, P= 0.08, I2 = 60.9%, comparison 3.08.

Percent symptom free days change from baseline: WMD 6.0 (95%CI 1.86 to 10.15), comparison 3.09.

Overall Withdrawals: RR 01.03 (95%CI 0.65 to 1.61), comparison 3.13.

Authors’ conclusions

In adults with asthma, using moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. The addition of LABA permits more participants on minimum maintenance ICS to reduce ICS. The precise magnitude of the ICS dose reduction requires further study.

Abrupt fixed reduced ICS + LABA versus fixed moderate or high dose of the same ICS

Adverse Events: RR 0.92 (95%CI 0.79 to 1.07), comparison 1.12


Reduced ICS + LABA versus ICS alone in participants who demonstrate deteriorating asthma control when ICS are reduced

Adverse Events: RR 0.92 (95%CI 0.80 to 1.07), comparison 3.12.




Systematic review and meta-analysis9509To determine, in asthmatic patients, the effect of the combination of long-acting ß2 agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the incidence of asthma exacerbations, on pulmonary function and on other measures of asthma control and to look for characteristics associated with greater benefit for either treatment option.30 - three pediatric; 27 adult) (Fowler 2002, Pearlman 1999a, Heuck 2000, Baraniuk 1999, Bateman 2003, Bergmann 2004, Boulet 2003, Bouros 1999, Busse 2003, Johansson 2001, Lalloo 2003, Li 1999, Mitchell 2003, Ortega-Cisneros 1998, Van Noord 1999, Vermetten 1999, Wallin 2003, Condemi 1999, Greening 1994, Ind 2003, Jenkins 2000, Kalberg 1998, Kelsen 1999, Murray 1999, Woolcock 1996, Woolcock 1996, Kips 2000, O’Byrne 2001, Pauwels 1997, Verberne 1998a)RCTs - Trial duration was 24 weeks or less in all but four trials.The combination of LABA and ICS resulted in greater improvement from baseline in symptom-free days [N=8, WMD=11.90% (95% CI:7.37, 16.44), random effects model], and in the daytime use of rescue ß2 agonists than a higher dose of ICS [N=4, WMD= −0.99 puffs/day (95% CI: −1.41, −0.58), random effects

Patients with exacerbation requiring hospitalisation [N=11, RR= 0.73 (95% CI: 0.36, 1.49), fixed effects model]. However, the

Number of withdrawals due to poor asthma control [N=20, RR=0.69 (95%CI: 0.52, 0.93)].

Number of overall withdrawals (all reasons) [N=23, RR=0.92 (95%CI: 0.82, 1.03)].

Percentage of symptom-free days at endpoint [N=5, WMD= 5.22% (95% CI: −1.58, 12.02)], random effects model],

Percentage of % symptom-free nights at endpoint [N=2, WMD= −2.10%(95%CI: −7.98, 3.79)],

Change from baseline in nighttime awakenings [N=4, SMD= 0.01 (95% CI: −0.08, 0.10)].
There was no significant group difference in the rate of overall adverse events [N=15, RR=0.93 (95% CI: 0.84, 1.03), random effects model], or specific side effects, with the exception of a three-fold increase rate of tremor in the LABA group [N= 10, RR=2.96 (95%CI: 1.60, 5.45)]. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS [N=20, RR= 0.69 (95%CI: 0.52, 0.93)].Good
Halpern, T et al


United States

Meta-analysis5278 (6 studies)Compare the rate of hospitalization among patients with asthma treated with inhaled corticosteroids versus those treated with LTRA (for monotherapy) and to evaluate other resource use rates and costs for these patients.Oates, V and Gothard, L. PEER Study. 7/10/00. Available from GSK. Pathak, D et al. Pharmacotherapy 2002;22:166. Stanford, R et al. Chest 2001;120:225S. White, T et al. 11/27/00. Available from GSK. Stempel, D et al. J Allergy Clin Immunol 2001:107:94. Stempel, D et al. Respir Med 2001:95:227.

2 independent reviewers.
studies from 1991 to 2000, prospective and retrospective comparative design, of patients receiving ICS or LTRA monotherapy (no other controller medicine) were included. Had to have defined inclusion and exclusion criteria, defined number of patients in each arm, defined treatment protocol, and separate results for each medication. Only studies presenting primary research were included. Duration had to be at least 6 months on all participants included. Only US studies. 5 were retrospective cohort studies; only 1 study was identified as a prospective trial comparing ICS and LTRA and icluding results on resource use or medical care costs. All 6 were supported by GSK.Hospitalizations: patients taking ICS had a signifcantly lower annual rate of hospitalization than did patients taking LTRA (2.23% vs 4.3%, respectively; p<0.05) The absolute risk reduction was 2.07% (NNT = 48 for 1 year). The difference in annual hospitalizaiton visit rates for each study in the primary analysis found that 2 studies had statistically significant differences in hospitalizaiton rates, whereas the differences int he other 2 studies were not statistically significant (p<0.05). Combining studies with the use of a random effects model or a fixed effects model produced similar effects. No significant heterogeneity (p=0.43).

Annual visits to the ED due to asthma, ED costs, total drug costs, total asthma-related costs, and overall total costs:

Mean annual rates of visits to the ED and total annual drug costs were significantly higher for patients taking LTRA than for those taking ICS (p<0.005 for each). The higher rate and lower cost of ED visits for those taking LTRA suggest that medical resources were used less at each visit as compared with those for patients taking ICS.

Within-group analysis on before vs after treatment: Patients taking ICS had hospitalizaiton rates and ED visit rates significantly decrease after treatment initiation compared iwth the pre-initiation values (p<0.005 and p<0.05, respectively). The decreases for patients taking LTRA were smaller and not statistically significant.
See above. Otherwise none reported.fair


New Zealand

Funding NR; all authors report competing interests with prior grants from Astra Draco, GSK, and Novartis.
Meta-analysis4576To compare the clinical benefit of adding salmeterol to moderate doses of ICS (fluticasone propionate 200 mg/day or equivalent) with increasing the ICS dose by at least twofold in symptomatic adult patients with asthma not controlled on ICS.van Noord 1999, Kalberg 1998, Greening 1994, Kelsen 1999, Murray 1999, Condemi 1999, Vermetten 1999, Bloom 2003, Busse 2003, Baraniuk 1999, Johansson 2001double blind, randomised trial; direct comparison between; studies of at least 12 weeks duration; and data on measures of clinical efficacy.Salmeterol better for main outcomes: number of subjects withdrawn due to asthma (odds ratios 1.58; 95% CI 1.12 to 2.24) and with at least one moderate or severe exacerbation (OR 1.35, 95% CI 1.10 to 1.66) was higher in the high dose ICS group respectively.

Among the secondary variables, for daytime b agonist use there was significantly greater benefit in the salmeterol group.

Outcome measure is mean difference and represents the mean outcome measure for the group receiving added salmeterol minus the mean outcomes measure for the group receiving increased dose of ICS.
None reportedFair
Fixed effectsRandom effectsInconsistency measures
Night awakenings (no/week)−0.03 (0.00 to −0.07)−0.03 (0.01 to −0.07)20.5 (0.00 to 65.1)
Day time b agonist use (puffs/day)−0.58 (−0.44 to −0.72)−0.60 (−0.35 to −0.84)70.3 (30.5 to 87.3)
Night time b agonist use (puffs/night)−0.08 (−0.02 to −0.13)−0.08 (−0.00 to −0.16)58.0 (0.00 to 83.0)
Ni Chroinin



external support: Fonds de la Santé du Québec CANADA; Internal support: Canadian Cochrane Network - McGill University CANADA
Systematic review and meta-analysis1061 (18 trials met the inclusion criteria; 9 (totaling 1061 adults) contributed sufficient data to be analysed)To compare the efficacy of initiating anti-inflammatory therapy using the combination of inhaled corticosteroids and long-acting beta2- agonists (ICS+LABA) as compared to inhaled corticosteroids alone (ICS alone) in steroid-naive children and adults with persistent asthma.Creticos 1999, Nelson 2003; Di Franco 1999; Grutters 1997; O’Byrne 2001; Pearlman 1999; Weersink 1997; Chuchalin 2002RCTs in which the combination of inhaled corticosteroids and long-acting beta2-agonists (ICS+LABA) was compared to the same dose of inhaled corticosteroid (ICS alone). Controlled studies with or without placebo were considered.Symptoms: LABA + ICS > ICS [reduction in symptom score: SMD (95% CI) −0.31 (−0.48 to −0.13); N= 4 trials; improvement in % of symptom-free days: WMD (95% CI) 10.74% (1.86 to 19.62); N=3 trials]

Exacerbations: No difference [# of patients with ≥ 1 exacerbation requiring systemic oral corticosteroids: RR (95%CI)=1.19 (0.75, 1.88); data from 3 trials (N=514)]

Rescue medicine use: No difference [use of rescue short-acting beta-agonist [N=5 trials; WMD (95%CI): −0.39 puffs/day (−0.88, 0.11) puff/d]

Withdrawals: No difference [overall risk of withdrawals, RR (95%CI) 0.89 (0.64, 1.23); N=6 trials; withdrawals due to poor asthma control, RR (95%CI) 1.28 (0.48, 3.42); N=6 trials]
Any adverse effects (N=5 trials: RR 1.09; 95%CI 0.81 to 1.48),

Withdrawals due to AEs(N=3 trials: RR 1.71; 95% CI 0.68 to 4.27),

Oral candidiasis (N=2 trials: RR 0.43; 95% CI 0.07 to 2.84),

Headache (N=2 trials: RR 1.92; 95% CI 0.54 to 6.85),

Tremor (N=2 trials: RR=5.05; 95% CI 1.33 to 19.17).
Ni Chroinin, M et al. 2005
Cochrane Review External sources of support: Francine Ducharme was supported by a National Scientist Award from the Fonds de la Santé du Québec CANADA Internal sources of support: Canadian Cochrane Network, McGill University CANADA
Systematic review and meta-analysis26 trials involving 8147 asthmatic participantsTo quantify in asthmatic patients the safety and efficacy of the addition of long-acting B¬2-agonists to inhaled corticosteroids on the incidence of asthma exacerbations, pulmonary function and other measures of asthma control.A list of studies included in the review is available upon request.Only randomised controlled trials conducted in adults or children, or both, in whom long-acting ©¬2-agonists were added to inhaled corticosteroids were included. Of 594 identified citations, 49 trials met the inclusion criteria: 27 full-text publications, one unpublished full-text report and 21 abstracts. Twenty-three citations (21 abstracts and two full-text publications) provided data in insufficient detail, 26 trials contributed to this systematic review. Twenty-four trials had a parallel group design studies and two were cross-over studies (Norhaya ICS890; Simons BUD150) which failed to provide results stratified by period. All but three trials (Akpinarli ICS600; Molimard ICSNR; Wallin FP800) were of high quality (Jadad score 4 or greater). All trials were randomised though the method of randomisation was not described in 12 trials. Twenty-seven trials were double blind with an appropriate means of blinding in all but two trials, in which it was not reported (D¡¯Urzo ICSNR; Wallin FP800). The remaining one trial was open label (Molimard ICSNR).ISymptoms: [daytime symptoms [N=5, SMD (95%CI) −0.34 (−0.44, −0.23)], night-time symptoms [N=2, SMD (95%CI) −0.18 (−0.31, −0.05)], and overall 24-hour symptoms [(N=2, SMD (95%CI) −0.28 (−0.45, −0.11) while increasing % symptom-free days during the observation period [(N=4, SMD (95%CI) 0.32 (0.02, 0.62)], the change from baseline in % symptom-free day [N=6, WMD (95%CI) 17.21 (12.06, 22.36)], in symptom-free nights [N=4, SMD (95%CI) 0.51 (0.28, 0.74)], and the change in % asthma-control days [N=2, WMD (95%CI) 15.61 (8.51, 22.70)]
Nocturnal awakenings: [% nights with no awakening [N=2, WMD (95%CI) −1.37 (−2.75, 0.02)]; changes in % nights with no awakening [N=2, WMD (95%CI) 3.24 (−0.89, 7.38)]; night-time awakening [N=3, WMD (95%CI) −0.22 (−2.24, 1.81)]
Exacerbations: [patients experiencing ≥1 exacerbation requiring OCS, RRR 19% with LABA [RR 95%CI) 0.81 (0.73, 0.90); Risk of exacerbation decreased from 27% to 22% with the addition of LABA, with ARR (95%CI)=5% (3%, 8%), and NNT (95%CI) with LABA to prevent 1 exacerbation over 1yr is 18 (13, 33); overall withdrawals [N=26 comparisons, RR (95%CI) 0.87 (0.77, 0.97), RD (95%CI) −0.02, (−0.04, 0.00); withdrawals due to poor asthma control (N=22 comparisons, RR (95%CI) 0.50 (0.36, 0.70), RD (95%CI) −0.02 (−0.03, −0.01)]
Rescue med use: [daytime use at endpoint [N=2, WMD (95%CI) −0.73 (−1.24, −0.22)puffs/d] night-time use at endpoint [N=2, WMD (95%CI) −0.44 (−0.81, −0.07) puffs/night; change in overall 24-hour use (N = 8, WMD (95%CI) −0.81 (−1.17, −0.44) puffs/d], change in nighttime use [N=6, WMD (95%CI) −0.33 (−0.57,−0.1) puffs/night], change in daytime use [N=9, WMD (95%CI) −0.82 (−1.17, −0.44)], change in % rescue-free days [N=2, WMD (95%CI) 19.1 (12.19, 26.01)]
Quality of life:
[(N=2, WMD (95%CI) 0.33 (0.05, 0.6)].
There was no apparent group difference in the risk of overall adverse effects (N = 11, RR 0.98, 95% CI 0.92 to 1.05), meeting our a priori definition of equivalence. There was also no group difference in the risk of serious adverse events (N = 4 comparisons, RR 1.16, 95% CI 0.30 to 4.42) or in any of the reported specific side effects including headache (N = 12, RR 1.13, 95%CI 0.92 to 1.41); hoarseness (N = 3 comparisons, RR 0.71, 95% CI 0.16 to 3.18, random-effects model); oral thrush (N = 4, RR 1.04, 95% CI 0.35 to 3.06); tachycardia or palpitations (N = 5, RR 2.13, 95% CI 0.77 to 5.88);

cardiovascular adverse effects such as chest pain (N = 3, RR 0.90, 95%CI 0.32 to 2.54) or tremor (N = 7, RR 2.48, 95%CI 0.78 to 7.89, random-effectsmodel). However, the upper confidence interval for some adverse events was high (for example tachycardia, palpitations and tremor), ruling out total reassurance. The effect on growth, adrenal function and methacholine challenge could not be aggregated due to insufficient number of trials (fewer than 2) reporting these outcomes. Only one study reported deaths, with three deaths reported overall. The risk of withdrawals due to adverse effects was similar in the intervention and control groups (N = 19, RR 1.29, 95% CI 0.96 to 1.75).
Niebauer, K et al.
Funding: Genetech, Inc.
systematic review with meta-analysis2056To summarize asthma-related QOL outcomes associated with omalizumab therapy in moderate-to-severe allergic asthma.5 studies (multiple publcations, plus unpublished data from completed trials from Genetech): Busse 2001, Holgate 2004, Soler 2001, Vignola 2004, Finn 2003, Buhl 2002, Lemanske 2004, Milgrom 2001.double-blind RCTs, all parallel group, phase 3 trials with 4–6 week run-in, 16-week steroid stabilization phase, 12–16 wk steroid-reduction phase, and either an open-label or double-blind extension phase.All results favored OM. For improvement of > 0.5 for the 3 respective phases: 1.35 (1.11–1.64; P = 0.003), 1.69 (1.40–2.05; P < 0.001), and 1.50 (1.15–1.95; P = 0.001). test of homogeneity was NS (P = 0.06 to 0.94) suggesting consistency across trials. For improvement of 1 or more for the 3 phases: 1.61 (1.29–2.00; p < 0.001), 2.03 (1.66–2.47; P < 0.001), and 1.25 (0.9–1.59; P = 0.08). Test of homogeneity NS for first two phases (P = 0.69 and 0.51), but evidence of heterogeneity for extension phase (P = 0.01). For improving AQLQ overall scores by 1.5 or more for the 3 phases: OR 1.80 (1.36–2.38; P < 0.001), 2.11 (1.68–2.65; P < 0.001), and 1.59 (1.21–2.08; P < 0.001). Tests of homogeneity NS for first two phases (P = 0.97 and 0.84), but evidence of heterogeneity in effects for extension phase (P = 0.04).NRFair
Rahimi et al. 2006 NRSystematic review and meta-analysisNRTo collect all studies about the effects of ICs on obstetrical outcomes and determine whether ICS use is harmful or safe during pregnancy4 studies: Bracken et al., 2003; Schatz et al., 2004; Martel et al., 2005; Otsuka et al., 2005Studies that compared major malformation, preterm deliveryThe summary OR for major malformations in two studies was 0.96 with a 95% CI of 0.51 to 1.83 and a non-significant OR (P=0.9582). The summary OR for preterm delivery in three studies was 0.99 with a 95% CI of 0.8 to 1.22 and a non-significant OR (P=0.9687). The summary OR for low birth weight delivery in two studies was 0.89 with a 95% CI of 0.7 to 1.14 and a non-significant OR (P=0.4013). The summary OR for pregnancy-induced hypertension in three studies was 0.97 with a 95% CI of 0.84 to 1.2 and a non-significant OR (P=0.9932). The Breslow-Day tests for heterogeneity (P=0.9249, P=0.2521, P=0.6146 and P=0.0013 respectively) indicated that the studies for major malformation, preterm delivery and low birth weight were not significantly heterogeneous and could be combined. ICs do not increase the risk of major malformations, preterm delivery, low birth weight and pregnancy-induced hypertension; i.e., ICs did not increase the rates of any obstetrical outcomes.NRFair


salary support from Santa Clara Valley Medical Center for Drs. Salpeter and Ormiston.
Systematic review and meta-analysis33826To assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting B-agonists.19 studies- Bensch et al., 2001; Bensch et al., 2002; Busse et al., 2004

D’Urzo et al., 2001; Foradil 040 trial, 2001; Foradil 041 trial, 2001

Foradil 2307 trial, 2005; Lazarus et al., 2001

Levy et al., 2005 Lockey et al., 1999; Price et al., 2002 Rosenthal et al., 1999; Salmeterol SLD-390 trial, 2001; SMART, 2006; Serevent 3014 trial, 2001; Steffensen et al., 1995; Taylor et al., 1998; Von Berg et al., Weinstein et al., 1998
Randomized, placebo-controlled trials that lasted at least 3 months and evaluated long-acting B-agonist use in patients with asthma.OR for hospitalization was 2.6 (CI, 1.6 to 4.3) for LABAs vs. placebo

The risk difference for hospitalization attributed to LABAs was 0.7% (CI, 0.1% to 1.3%) over 6 months.

risk for hospitalization was increased in children (OR, 3.9 [CI, 1.7 to 8.8]) and in adults (OR, 2.0 [CI, 1.0 to 3.9]). The risk for hospitalization was also increased with salmeterol (OR, 1.7 [CI, 1.1 to 2.7]) and with formoterol (OR, 3.2 [CI, 1.7 to 6.0])

OR for life-threatening asthma attacks attributed to LABAs was 1.8 (CI, 1.1 to 2.9, with a risk difference of 0.12% (CI, 0.01% to 0.3%) over 6 months.

The risk for asthma-related deaths was increased (OR, 3.5 [CI, 1.3 to 9.3]), with a pooled risk difference of 0.07% (CI, 0.01% to 0.1%)
Sharek, PJ and DA Bergman



funding NR
systematic review with meta-analysis855To determine whether inhaled steroid therapy causes delayed linear growth in children with asthma.Doull et al 1995, Simons et al 1997, Tinkelman et al 1993, Verberne et al 1997, Allen et al 1998RCTs, subjects randomized to inhaled beclomethasone, budesonide, flunisolide, fluticasone, or triamcinolone versus a nonsteroidal inhaled control for a minimum of 3 months; and outcome convertible to linear growth velocity. English- and non–English-language trials were included.Results divided by ICS. Of the 5 studies included, 4 studies of BDP (450 subjects) showed a decrease in linear growth velocity of 1.51 cm/year (95% confidence interval: 1.15, 1.87). One study of FP (183 subjects) showed a decrease in linear growth velocity of 0.43 cm/year (95% confidence interval: .01,.85). Sensitivity analysis in the beclomethasone subgroup, which evaluated study quality, mode of medication delivery, control medication, and tatistical model, showed similar results.as aboveGood
Sharek, PJ et al 1999 Cochrane Database of Systematic Reviews Internal support from NHS Research and Development UKsystematic review with meta-analysis273 (3 studies)To determine whether inhaled beclomethasone causes significant delay in the linear growth of children with asthma.3 studies: Doull 1995, Verberne 1997, and Simons 1997.Inclusion criteria: Single or double-blind RCTs comparing beclomethasone delivered by nebulizer, MDI, diskhaler or rotahaler for a minimum of 3 months to placebo or nonsteroidal medication. Results: all were RCTs. Each was double blind (subject and provider) to treatment assignment. Quality ratings: Jadad scores (Jadad 1996), resulted in a grade of 5 for one study [Doull 1995], grade 4 for one study [Verberne 1997] and grade of 3 for the third [Simons 1997].All three of the included studies were consistent in their conclusions that beclomethasone decreased linear growth of children with asthma. Doull: treatment (4.12 cm/year with S.D. 1.41 cm/year) versus placebo group (5.94 cm/year with S.D. 1.15 cm/year). Verberne treatment (4.70 cm/year with S.D. 1.87 cm/year) versus control group (6.10 cm/year with S.D. 2.04 cm/year). Simons (3.96 cm/year with S.D. 2.04 cm/year) versus control group (5.04 cm/year with S.D. 2.04 cm/year). The average decrease, calculated through meta-analysis, was −1.54 cm per year (95% CI −1.15, −1.94). [meta-analysis shows a statistically significant decrease in linear growth velocity of children with mild to moderate asthma treated with moderate doses of beclomethasone.] There was no heterogeneity between studies; chi square was 2.71 with 2 degrees of freedom >.99. Authors’ conclusions In children with mild-moderate asthma, beclomethasone 200 mcg twice daily caused a decrease in linear growth of −1.54 cm per year. These studies lasted a maximum of 54 weeks, so it remains unclear whether the decrease in growth is sustained or whether it reverses with ’catch up’ after therapy is discontinued. We are unable to comment on growth effects of other inhaled steroids that have potentially less systemic effects. If inhaled steroids are required to control a child’s asthma, we recommend using theminimum dose that effectively controls the child’s asthma and closely following growth.See above.Good
Sharma et al.



meta-analysis635To determine the effect of ICSs on bone loss in patients with bronchial asthmaWong et al. 2000, Boulet et al. 1994, Israel et al. 2001, Wisniewski et al. 1997, Luengo et al. 1997, Packe et al. 1996Case control or prospective: published in peer reviewed journals; examined the effect of inhaled steroids on adult populations; median duration of at least 3 years; estimated lumbar spine BMD; lumbar spine BMD with actual numerical values reported; compared treatment group with controlsMean BMD of ICS-exposed group was decreased by 4.2% when compared to the non-exposed group (NS). Mean difference in BMD favoring controls 0.049 (CI 0.028 to 0.070 g/cm2 (P = 0.8))see main resultsFair
Uboweja et al.



funding NR
meta-analysis63,738 (approximately 20,000 cases and 50,000 controls)The objective of this study was to quantify the risk of cataract among users of inhaled corticosteroids (ICS).4 studies: Jick et al 2001, Cumming et al 1997, Garbe et al 1998, Smeeth et al 2003Evaluated the association between ICS and cataract in adult population. All were retrospective studies published in peer reviewed journals, data about dose and duration of therapy were not available for all of them.The pooled OR (95% CI) by the fixed effects Mantel–Haenszel method was 1.48 (1.39–1.57) and by the random effects DerSimonian–Laird method was 1.48 (1.30–1.68). The test for heterogeneity was not significant (data NR). A total number of nine negative studies would be required to make the results of our metaanalysis non-significant. Number needed to harm is 16 with 95% CI of 13–19.

Visual inspection of the funnel plot (figure 2) does not rule out publication bias.
see main resultsFair, no critical appraisal of studies.
UK, Cochrane Database of Systematic Reviews
No external support; Internal sources of support: NHS Research and Development UK, The Thriplow Charitable Trust UK, and Nederlands Asthma Fonds NETHERLANDS
systematic review with meta-analysis3143 (14 trials)To determine the efficacy of anti-IgE (Omalizumab) compared with placebo in patients with allergic asthma; to compare the clinical outcomes in studies that have compared anti-IgE monoclonal antibodies with placebo or other conventional therapy in the treatment of chronic asthma14 trials (more than 14 articles): Boulet 1997; Bruno 2005; Busse 2001 [Bousquet 2004; Busse 2001; Finn 2003; Kaiser J. 2003; Lanier 2001; Massanari 2005]; Djukanovic 2004 [Djukanovic 2003 and 2004]; Fahy 1997; Fahy 1999; Hanf 2005 [Hanf 2005; Noga 2005]; Holgate 2004 [Chung 2002; Holgate 2001; Holgate 2004]; Holgate 2004 [Chung 2002; Holgate 2001; Holgate 2004]; Humbert 2005 [Bleecker 2005; Humbert 2005; Korenblat 2005; Korenblat 2005; Korenblat 2004; Matz 2005; Novartis. Study number 2306.]; Milgrom 1999 [Metzger 1998; Milgrom 1999]; Milgrom 2001 [Berger 2003; Buhl 2001; Kaiser fda.gov 2003; Lemanske 2002; Milgrom 2001; Milgrom 2005; Nayak 2000]; Solèr 2001 [Bousquet 2004; Buhl 2002; Buhl 2002; Kaiser fda.gov 2003; Massanari 2005; Soler 2001; Solèr 2001; Solèr 2005]; van Rensen 2005; Vignola 2004 [Boulet 2003; Dahl 2004; Harnest 2004; Vignola 2004; Vignola 2003]All trials were double-blind RCTs of parallel group design; examining anti-IgE administered in any manner for any duration. Trials with co-interventions were included as long as they were the same in each armSymptoms:
End of treatment: Moderate/severe and severe participants receiving SQ OM had significantly lower asthma symptom scores during stable steroid phases (MD −0.46 (95% CI: −0.75, −0.29). There were no significant changes in asthma symptoms in the pediatric study (median nocturnal asthma scores were 0 in both groups throughout the study).

Change from baseline in symptom scores: significant reductions in symptom scores from baseline in favor of SQ OM in two trials (Vignola 2004 (−1.8, P =0.023); Humbert 2005 (P = 0.039, no mean scores presented).

Stable steroid phase: Significant reduction in the odds of a patient having an asthma exacerbation in favor of SQ OM (OR 0.55, 95% CI: 0.45, 0.69). Assuming a baseline risk of 25%, the NNT to prevent one exacerbation was 10 (95% CI: 8, 14)

Exacerbations per participant: When exacerbation rates were expressed as means, fewer asthma exacerbations per patient in favor of OM (−0.18 exacerbations (95% CI: −0.1, −0.25; seven studies, 2570 participants); moderate level of heterogeneity ; random effects modeling did not change the point estimate (95%CI: −0.08, −0.27)

Tapering phase: OM patients less likely to experience an exacerbation (OR 0.46 (95% CI: 0.36, 0.59); four trials). Assuming an overall control group event rate of 32%, 8 participants needed treatment with OM in order to prevent one exacerbation (NNT(b) = 8, 95% CI: 7, 11)

Rescue med use:
Stable phase: Moderate to severe adolescent and adult participants required significantly less rescue beta-2 agonist compared with placebo (−0.63 puffs/d (95% CI: −0.90, −0.36; six studies)).

Tapering phase: Change from baseline in rescue medication use: OM treatment enabled participants to use significantly less rescue medication than placebo [WMD −0.74, (95% CI: inus;1.05, −0.43; Busse 2001; Holgate 2004; Holgate 2004a; Solèr 2001).

Stable phase: Change from baseline in quality of life scores: significantly greater improvement in overall AQLQ in favour of OM of 0.32 (95%CI: 0.22, 0.43; five studies).
POOLED data from all the available [Omalizumab + steroid vs. placebo + steroid] studies regardless of whether they had conducted a steroid tapering phase. All between 28 and 32 weeks in duration. No difference in headache, urticaria, number of participants with any adverse events, and withdrawals due to adverse events. Omalizumab led to significantly greater injection site reactions compared with placebo [OR: 2 (95% CI 1.37 to 2.92), CER: 5.5%]; NNT(h)=21.Good
Walters, EH et al.


Cochrane Review

Commonwealth Department of Health and Aging AUSTRALIA
All randomised studies, both open and blinded, of at least four weeks duration, comparing a LABA given twice daily with a placebo, in chronic asthma. Selection criteria to this updated review have been altered to accommodate recently published Cochrane reviews on combination and addition of LABA to ICS therapy. Studies in which all individuals were uniformly taking ICS were excluded from this review.Sixty-seven studies (representing 68 experimental comparisons) randomising 42,333 participantsCompare the effects of regular inhaled LABA versus placebo in chronic asthma. The specific purpose of the review was to assess whether there are any beneficial or harmful effects from the regular use of inhaled LABA compared with placebo on the primary outcome of asthma control.Fifty-four studies were of parallel group design and 13 of cross over design. A list of studies included in the review is available upon request.Participants in one treatment arm used a LABA, either salmeterol or formoterol (also known as eformoterol), administered twice daily via any inhalation device. The second treatment arm consisted of regular doses of placebo, administered in the same way. The minimum period of treatment four weeks in this update.SYMPTOM SCORES: There were significantly fewer symptoms in the LABA group across the board on a variety of measures at the end of treatment. Scales used to measure asthma symptoms varied from 3 to 6 points and scores were generally derived as a composite based on a number of symptoms, e.g. cough, wheezing, shortness of breath and chest tightness assessed during the day and/or overnight and whether sleep was broken by asthma symptoms. All measures showed significant advantages in the LABA compared with placebo.

Daytime symptoms were significantly better in LABA treated participants (−0.34 95% CI −0.44 to −0.25; 14 studies, 1836 participants).
Nocturnal symptoms were also better in LABA treated participants: SMD −0.54 (95%CI −0.64 to −0.45 in eight studies with 1758 participants). There was no significant difference between the subgroups analysed on the basis of including background ICS use.

Subgroup analysis of symptom score data indicated that the effect of LABAs was consistent across the groups of trials based on the classifications of severity in the review. Symptoms fell from baseline by a greater amount during treatment with LABAs compared to placebo. The difference overall was −0.49 (95%CI −0.58 to −0.41) for day time symptoms in eleven studies with data reported on 2629 participants, and −0.54 (95%CI −0.87 to −0.22, random-effects modelling) for night time symptoms in three studies with 823 participants. The nocturnal symptom results showed significant heterogeneity that may be due to the variations in severity of asthma and different doses of preventer drugs being used. LABA treated participants had significantly fewer days affected by asthma (16%, 95% CI 14 to 19; nine studies, 2060 participants), and also fewer night symptoms expressed as both % nights without symptoms (10.79%, 95%CI 6.48 to 15.1; nine studies, 2093 participants), and the % nights without awakenings (15.81%, 95% CI 14.22 to 17.41; 13 studies, 3925 participants). The high level of statistical heterogeneity observed for % nights without symptoms may be partly explained by the difference between non-ICS users and participants where LABA was added to variable usual therapies (P = 0.047). Only one study in children was reported with the percentage of nights affected by asthma awakenings with LABA in 210 children being fewer with the MD being 6.40% (95%CI 2.11 to 10.69).

RESCUE BRONCHODILATOR USE: LABA treated participants used significantly less short-acting beta-2 agonist than the placebo group, expressed as absolute and change scores for 24-hour and also day and night periods. In spite of high levels of statistical heterogeneity in these outcomes the results were significant with both fixed-effect and random-effects modelling (difference in SABA usage for 24 hours: −0.9 puffs/d, 95%CI −1 to −0.7; eight studies, 1885 participants; mean change in SABA usage over 24 hours: −1.2 puffs/d, 95% CI −1.4 to −1; 12 studies, 2197 participants; SABA use (day): −1 puffs/d, (95% CI −1.3 to −0.8; three studies, 691 participants; change in SABA use (night): −0.54, 95% CI −0.7 to −0.4; two studies, 633 participants). There was significant heterogeneity found in the pooled analysis of rescue therapy use. A contributing factor in addition to variation in asthma severity and treatment may have been the different short acting beta-2 agonist agents used, the different doses and varying inhalational devices. Heterogeneity persisted in the subgroup analyses. Results of a similar magnitude and direction were seen for the change in rescue medication use both during the day time and at night time across the severity range.

EXACERBATIONS OF ASTHMA: MAJOR EXACERBATIONS: Twenty-three studies (5995 participants) reported data on exacerbations of asthma. There was a large reduction in the odds of experiencing at least one major exacerbation during the study in the LABA group compared with placebo, OR 0.73 (95%CI 0.64 to 0.84). In 10 studies with 2547 adult participants a major exacerbation of asthma was defined as worsening of asthma symptoms requiring treatment in addition to the study drug and usual rescue short acting inhaled beta-2 agonist agent. When the analysis was confined to these studies the OR was 0.64 (95% CI 0.52 to 0.79). In 10 studies with 2468 adult participants where a definition was not given or was less precise the result was similar, OR 0.59 (95%CI 0.46 to 0.76). 5 cross over studies (n=337) showed a similar but non-significant result, OR 0.80 (95%CI 0.42 to 1.54). Paradoxically, three studies on children reported data on exacerbations and the pooled analysis actually suggested an increased risk of exacerbation, OR 1.22 (95%CI 0.92 to 1.62) though the result was not statistically significant.

MINOR EXACERBATIONS OF ASTHMA: Taylor 1998 applied a somewhat onerous definition for a minor exacerbation based on fall in morning PEF, increasing symptoms and increasing use of rescue bronchodilator in a crossover study. The difference was significant (−0.68 exacerbations per patient per year, 95% CI (−0.95 to −0.41).
Asthma-related Death: Findings from SMART indicated that in participants using mixed co-interventions (including ICS) at baseline there was a significant increase in the odds of asthma-related death occurring in the LABA treated group (13 versus 3; RR 4.4, 1.25 to 15.3; N = 26355). This represents an absolute increase of one extra death over six months for every 1250 patients treated with LABA, but the confidence interval is wide (95% CI 700 to 10,000).

The size of this difference was consistent across all the mortality and life threatening experience outcomes measured in this study, and was statistically significant for asthma related death, respiratory related death and the combined outcome of asthma-related death and life threatening experiences, but not for all cause mortality (with or without life-threatening experiences or the combined endpoint of respiratory-related death or life-threatening experiences). In those not using ICS at baseline, the number of participants suffering asthma-related death was higher in LABA than placebo treated groups (9 versus 0, N = 14090). The published trial report did not provide an estimate of the risk ratio as the authors decided that Relative Risk should not be calculated when there were no event rates in the control group. However, we used RevMan 4.2 to calculate the Relative Risk of asthma-related death for both the subgroups with and without ICS at baseline (using the normal adjustment of adding 0.5 to each cell when there are no events in one cell); for those taking ICS at baseline the Relative Risk is 1.34 (95% CI 0.30 to 5.97), whilst for those not taking ICS at baseline the Relative Risk is 18.98 (95% CI 1.1 to 326).

The test for interaction between these subgroups does not reach signficance (P= 0.08). Caution should be exercised in the interpretation of subgroup differences as patients were not randomised to ICS in this study, and data on ICS use was collected at baseline only. A post-hoc within study subgroup analysis by ethnicity, indicated that African-Americans were more likely to experience a composite endpoint of respiratory -related death and life threatening adverse events (intubation and mechanical ventilation) than Caucasians, Relative Risk Increase 3.9 (95% CI 1.29 to 11.84). There was, however, no significant difference found in asthma-related deaths between African-Americans and Caucasians; results from life table analyses for African-Americans 7 versus 1; RR 7.26(95% CI 0.89 to 58.94: N = 4685), whilst for Caucasians 6 versus 1; RR 5.82 (95% CI 0.70 to 48.37; N=18,642).

When the endpoint was broadened to incorporate respiratory-related death there was a just significant difference in the Relative Risk of death between LABA and placebo for the total population of 2.18 (95% CI 1.07 to 4.05), N = 26355. There was no significant difference between the subgroups using ICS at baseline and those not using ICS at baseline (test for interaction P = 0.84). The increase in all-cause mortality yielded non-significant results (RR 1.33, 95% CI 0.76 to 2.35; three studies using the non-ICS subgroup from SMART, N = 14534 and RR 1.37, 95% CI 0.87 to 2.14 using all participants from SMART, N = 26799).

Serious adverse events: There was a significant increase in the odds of asthma-related serious adverse events on LABA treatment (OR 7.46, 95% CI 2.21 to 25.16; three studies, N = 895). However, the odds ratios of life-threatening adverse events from SMART for both mixed (i.e. total) and ICS - treated populations were not significantly different. LABA treatment led to a significant increase in the odds of serious adverse events where this was reported for ’total events’ in three paediatric studies (OR 2.11, 1.03 to 4.31; N = 973).

Total and drug-related adverse events: There was no significant difference between LABA and placebo in total adverse events, although the lower limit of the 95% CI only just crossed unity (OR 1.15, 95%CI 0.99 to 1.33; 18 studies, N=3447). There was a higher instance of drug-related adverse events occurring in LABA treated participants in mixed co-intervention groups (OR 1.37, 95%CI 1.01 to 1.87; seven studies, N = 2130), and “nervousness” (OR 5.11, 95%CI 1.72 to 15.22;, two studies, N = 546). There were also significant differences in favour of placebo in mixed co-intervention studies for tremor (OR 3.86, 95%CI 1.91 to 7.78; eight studies, 2257 participants), and across total populations for headache (OR 1.28, 95%CI 1.04 to 1.57; 23 studies with 5667 participants) and throat irritation (OR 1.68, 95% CI 1.10 to 2.56; eight studies, N = 1170). There was no significant different in the odds for pharyngitis, cough, cramps, myalgia/fatigue, insomnia, upper respiratory tract infection, of asthma, musculoskeletal pain or palpitations.

Withdrawals: All-cause study withdrawal was less likely on LABA than on placebo treatment (OR 0.91, 95% CI 0.86 to 0.96; 19 studies, N = 30599). There was no significant difference in the likelihood of withdrawal due to adverse events between placebo and LABA (OR 1.11, 95% CI 0.93 to 1.32; 21 studies, N = 30943). Withdrawals due to lack of efficacy were significantly less frequent on LABA than on placebo (OR 0.60, 95% CI 0.53 to 0.68; 14 studies, N = 29466). There was no significant difference in withdrawal due to exacerbations of asthma (OR 0.82, 95% CI 0.46 to 1.46; seven studies, N = 1658).

From: Original Report Evidence Tables A

Cover of Drug Class Review: Controller Medications for Asthma
Drug Class Review: Controller Medications for Asthma: Final Update 1 Report [Internet].
Jonas DE, Wines RCM, DelMonte M, et al.
Portland (OR): Oregon Health & Science University; 2011 Apr.
Copyright © 2011 by Oregon Health & Science University.

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