Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review
Introduction
For patients aged 5 years and older, long-acting beta agonists (LABA) remain the preferred add-on therapy to inhaled corticosteroids (ICS) for asthmatics whose disease is not adequately controlled with low doses of ICS [1], [2]. However, in the last years, the safety profile of LABA has been questioned, and there are concerns about the adverse effects of their regular use. Recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death. Thus, the results of Salmeterol Multicenter-Asthma Research Trial (SMART) [3] showed an increase in respiratory-related deaths and a fourfold increase in asthma-related deaths among patients receiving salmeterol as compared with placebo. Although no studies similar to SMART were performed for formoterol, data provided for the FDA advisory committee [4] showed an increased incidence of serious asthma-related events. Additionally, a systematic review by Salpeter and colleagues showed that LABA increased the risk for hospitalization for asthma exacerbations and life-threatening asthma attacks compared with placebo [5]. However, the results of this meta-analysis differs from those of three Cochrane reviews that examined the risk for asthma exacerbations (AE) in asthmatics receiving LABA as monotherapy as compared with placebo [6] or in addition to ICS as compared with ICS [7], [8]. Although these later reviews did not find differences between groups related with the risk of adverse effects, they did not report life-threatening asthma episodes. Recently, a new Cochrane review including 26 studies that compared regular use of salmeterol with placebo found an increased risk of serious adverse effects [9]. Finally, Bateman et al. [10] in a meta-analysis that summarizes 66 GlaxoSmithKline trials, showed that salmeterol combined with ICS decreases the risk of severe AE, does not seem to modify the risk for hospitalizations, and may not alter the risk for asthma-related deaths compared with ICS alone. Thus, in agreement with these different and limited messages regarding the security of LABA, we performed an independent systematic review (according to the QUOROM statements [11]) to evaluate the safety of regular use of LABA (compared with placebo or added to ICS) in patients with persistent asthma.
Section snippets
Data sources and search
We identified studies from MEDLINE (1966–September 2008), EMBASE (1980–September 2008) and Cochrane Controlled Trials Register (CENTRAL) (third quarter 2008) databases using the following MeSH, full text and keyword terms: long-acting beta2-adrenoceptor agonist OR salmeterol OR formoterol OR eformoterol AND inhaled corticosteroids OR beclomethasone OR triamcinolone OR fluticasone OR flunisolide OR budesonide AND asthma. Also, we performed a search of relevant files from AstraZeneca (//www.astrazenecaclinicaltrials.com
Results
A total of 92 randomized controlled trials (including more than 74,000 asthmatics) met the inclusion criteria and were selected for analysis (Fig. 1). Of them, 35 studies compared LABA vs. placebo [3], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], 52 compared LABA plus ICS vs. ICS [52], [53], [54], [55], [56], [57], [58], [59], [60], [61],
Discussion
The unique characteristics of this review were (1) This is an independent review not related to the pharma industry. (2) It included both LABA vs. placebo, and LABA/ICS vs. ICS comparisons; (3) it incorporated studies with formoterol and salmeterol; and (4) the influence on the results of different factors was explored through sensitivity analysis. Additionally, all the selected studies were randomized and double-blind, and combined with minimal evidence of clinical and statistical
Acknowledgment
The authors thank to Anthony Carlson by his aid with English writing of the manuscript.
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