Beta-2 adrenergic agonists: focus on safety and benefits versus risks

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The use of β2-adrenergic receptor agonists, or beta agonists, and their potential for an increased risk of asthma-related death were identified in the 1960's, and appears to have been related to the marketing of specific preparations of short-acting beta agonists (SABA) that are no longer in use today. Subsequent studies have reported a potential for life-threatening or fatal adverse events with the use of long-acting beta agonist (LABA) therapy, but this conclusion must be tempered by the suboptimal design of the studies which form the foundation for these conclusions. Multiple prospective clinical trials and meta-analyses have demonstrated that the combination of a LABA and an ICS confers proven clinical benefits which appear greater than the rare risk for serious or life-threatening adverse events, although all of these studies have inadequate power to be definitive.

Introduction

β2-Adrenergic receptor agonists, or beta agonists, are among the oldest and most commonly prescribed therapeutic agents for the management of asthma. The beta agonists exist as two drug classes: the long-acting beta agonists [LABA: salmeterol (Serevent®), formoterol (Foradil® and Perforomist®)] and the short-acting beta agonists [SABA: albuterol or salbutamol (Accuneb®, Proventil®, Proair®, and Ventolin®), pirbuterol (Maxair®), isoproterenol (Isuprel®), fenoterol, and terbutaline (Brethine®)]. LABA therapy is recommended as an adjunct to inhaled corticosteroids (ICS) therapy for the long-term management of asthma, while SABA therapy is recommended as a rescue inhaled therapy for the preventative or acute management of symptoms [1].

Before the 1990's, SABAs were the only inhaled beta agonists available. These agents have a short duration of action and were impractical for those requiring continuous symptom relief or for those with uncontrolled symptoms on inhaled corticosteroid therapy [2, 3, 4, 5]. In contrast, LABAs provide symptom control for at least 12 h and formoterol has an onset of action similar to that of albuterol [5]. Two LABAs, salmeterol and formoterol, are approved by the United States Food and Drug Administration (FDA) for the management of asthma. However, the results of a recent advisory panel on the safety of LABA therapy have questioned the safety of these agents in light of results from two large observational trials and a meta-analysis performed by the FDA.

The safety of LABA therapy came under scrutiny as these agents were introduced into the market in the United Kingdom, and subsequently in the United States. In 1993, the Serevent Nationwide Surveillance (SNS) Study demonstrated a statistically insignificant increase in asthma-related deaths associated with the use of salmeterol [6••]. This potential safety concern was subsequently demonstrated in another surveillance study performed in the United States and a meta-analysis [6••, 7]. These studies reported the potential for life-threatening adverse events with the use of LABA therapy but were limited by suboptimal study designs in order to assess the safety of these agents, particularly since asthma-related mortality is exceedingly rare. Furthermore, multiple prospective clinical trials and meta-analyses consistently demonstrate that LABA therapy is effective and safe when used in combination with ICS therapy, although these trials did not contain sufficient power to address these safety concerns definitively.

Section snippets

Beta-agonist exposure and asthma-related mortality: the beginning

The concern regarding beta-agonists and their potential for asthma-related death was a phenomenon identified in the 1960's and appears to have been related to the marketing of a SABA in an exceedingly high-dose regimen and, subsequently, to the marketing of another potent SABA. In the 1960's, marketing of a high-dose inhaled preparation of the nonspecific beta agonist, isoproterenol, in the United Kingdom was associated with an increase in asthma mortality that diminished as the inhaler was

Asthma-related mortality and the long-acting beta agonists: the saga continues

Salmeterol was the first LABA to be marketed for the management of asthma in the United Kingdom and the United States, and in both countries large surveillance studies were undertaken that have had a lasting impact. In the United Kingdom, the Serevent Nationwide Surveillance Study (SNS) was the first large-scale study performed in response to those studies showing a correlation between increased beta agonist use and asthma-related death [8, 9, 10, 11, 12, 13, 14, 16, 18]. The investigators

LABA therapy is efficacious and safe in the management of asthma: the retrospective and meta-analytic evidence

On the basis of the exceedingly rare frequency of asthma-related deaths, Anderson and colleagues performed a case–control retrospective analysis of asthma-related death from a registry in the United Kingdom and demonstrated no significant association between LABA use and the risk for asthma-related death when compared to the use of other asthma therapies. The median population age of 53 years increases the possibility of misconstruing a death from asthma that may have resulted from an alternate

The efficacy and safety of LABA therapy: the prospective trial evidence

The unresolved question is whether the combination of a LABA with an ICS augments the very rare risk of asthma-related deaths or severe exacerbation and, if so, does the therapeutic benefits exceed this risk. This question is best addressed by the multiple prospective clinical trials demonstrating the efficacy and safety of a LABA and an ICS for the management of asthma. Such studies suffer from small sample size and insufficient power to definitively address issues of safety, but are

The development of combination therapies for the management of asthma

LABA and ICS combination therapies are available as fixed-dose preparations allowing for the convenient and simultaneous administration of both a LABA and ICS therapy. Salmeterol and fluticasone are currently available as the fixed dose preparation Advair® while formoterol and budesonide are available as Symbicort®. An analysis of prescription refill rates from a managed care organization demonstrates that there is greater adherence with the fixed-dose combination preparation of salmeterol and

Conclusions: how do we proceed?

A recent FDA advisory panel has determined that the use of a LABA should be limited to those whose symptoms are poorly controlled on other asthma controller therapies and that LABA therapy should be discontinued in the shortest period of time possible to obtain optimal symptom control. Furthermore, the combination should be provided in the form of combination preparation in the pediatric population. These recent recommendations, as outlined by the FDA, imply that there remains a continuing

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • •• of outstanding interest

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