Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review

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Abstract

Background

Safety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death.

Objective

To evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma.

Methods

Randomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths.

Results

We identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR] = 0.80; 95% CI, 0.73–0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk = 3.83; 95% CI, 1.21–12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment >12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR = 0.73; 95% CI, 0.67–0.79), and hospitalizations (RR = 0.58, 95% CI, 0.45–0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively.

Conclusions

This review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.

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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