Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA)

Abstract

Objective To examine the benefits of adding salmeterol compared with increasing dose of inhaled corticosteroids. Design Systematic review of randomised, double blind clinical trials. Independent data extraction and validation with summary data from study reports and manuscripts. Fixed and random effects analyses. Setting EMBASE, Medline, and GlaxoWellcome internal clinical study registers. Main outcome measures Efficacy and exacerbations.Results Among 2055 trials of treatment with salmeterol, there were nine parallel group trials of >12 weeks with 3685 symptomatic patients aged >12 years taking inhaled steroid in primary or secondary care. Compared with response to increased steroids, in patients receiving salmeterol morning peak expiratory flow was greater at three months (difference 22.4 (95% confidence interval 15.0 to 30.0) litre/min, P < 0.001) and six months (27.7 (19.0 to 36.4) litre/min, P < 0.001). Forced expiratory volume in one second (FEV 1 ) was also increased at three months (0.10 (0.04 to 0.16) litres, P < 0.001) and six months (0.08 (0.02 to 0.14) litres, P < 0.01), as were mean percentage of days and nights without symptoms (three months: days-12% (9% to 15%), nights-5% (3% to 7%); six months: days-15% (12% to 18%), nights-5% (3% to 7%); all P < 0.001) and mean percentage of days and nights without need for rescue treatment (three months: days-17% (14% to 20%), nights-9% (7% to 11%); six months: days-20% (17 to 23%), nights-8% (6% to 11%); all P < 0.001). Fewer patients experienced any exacerbation with salmeterol (difference 2.73% (0.43% to 5.04%), P = 0.02), and the proportion of patients with moderate or severe exacerbations was also lower (2.42% (0.24% to 4.60%), P = 0.03). Conclusions Addition of salmeterol in symptomatic patients aged 12 and over on low to moderate doses of inhaled steroid gives improved lung function and increased number of days and nights without symptoms or need for rescue treatment with no increase in exacerbations of any severity.

Long-Acting Beta-Agonists in Adult Asthma: Evidence that these Drugs are Safe

“…What was not anticipated was that the addition of formoterol to either dose of budesonide reduced the occurrence of asthma exacerbations -both minor exacerbations and those requiring prednisone treatment. A meta-analysis examining the addition of salmeterol to low dose inhaled corticosteroids as compared to at least doubling the dose of ICS confirmed the findings of FACET [14] -namely, that the addition of the LABA produced a greater reduction in exacerbations than the higher dose of ICS. Furthermore, two studies comparing the addition of salmeterol or the leukotriene antagonist montelukast to an inhaled corticosteroid found that there were significantly fewer exacerbations of asthma with the LABA plus ICS compared to the LTRA plus ICS [16,18].…”

“…From the standpoint of control of the typical parameters used to assess asthma control, the LABA-ICS combination is clearly the most effective. Meta-analyses have confirmed that adding a LABA to a dose of ICS which is failing to control asthma adequately produces a superior reduction of symptoms and use of rescue medication, and superior improvement in pulmonary function, when compared with doubling (or more than doubling) the dose of ICS [14]. A meta-analysis of nine randomized, controlled studies of salmeterol vs. theophylline, in which the majority were using inhaled corticosteroids, similarly showed salmeterol to be superior in terms C o p y r ig h t G e n e r a l P r a c t ic e A ir w a y s G r o u p R e p r o d u c t io n p r o h ib it e d of both symptoms and pulmonary function [15].…”

A Review on the Safety and Efficacy of Inhaled Corticosteroids in the Management of Asthma

“…A study by Greening et al [76] compared PEF as a primary variable between a group administered 400 lg/day BDP plus 100 lg/day salmeterol and a group administered 1000 lg/day BDP alone for 6 months in mild-to-moderate asthma. The add-on therapy with salmeterol resulted in significantly more favorable outcomes in terms of PEF change from baseline, the need for rescue medication, and the number of symptom-free days [76,77]. Recent multicenter, randomized, double-blind studies showed that treatment with budesonide/formoterol and fluticasone/salmeterol were associated with a lower risk of asthma exacerbations than budesonide alone and fluticasone alone groups respectively [78,79].…”

β2-Adrenoceptor Agonists, Like Glucocorticoids, Repress Eotaxin Gene Transcription by Selective Inhibition of Histone H4 Acetylation

“…Studies from our group and others in cell systems have described potential mechanisms that might account for this. We have recently reported that ␤ 2 -agonists, like glucocorticoids, partially inhibit TNF-␣-induced eotaxin production from human airway smooth muscle (HASM) 3 cells, and that their combined use results in greater inhibition (4). ␤ 2 -Agonists also inhibit GM-CSF and RANTES production and enhance the inhibition of TNF-␣-induced IL-8 production by glucocorticoids in the same cells (5,6).…”

“…␤ 2 -Adrenoceptor agonists (␤ 2 -agonists) are widely used as bronchodilators for asthma treatment. However, recent studies have suggested that long acting ␤ 2 -agonists potentiate the effect of glucocorticoids in reducing asthma exacerbations (2,3), suggesting that they may potentiate the anti-inflammatory effects of glucocorticoids. Studies from our group and others in cell systems have described potential mechanisms that might account for this.…”