β₂ Déjà Vu

Inhaled β₂-agonists have been used for > 40 years in the treatment of asthma. Until fairly recently, their regular use had been advocated as the first-line therapy for asthma treatment. This is because inhaled β₂-agonists provide rapid bronchodilation as a result of their action as airway smooth muscle relaxants, and, thus, provide rapid improvement of symptoms. Also, inhaled β₂-agonists protect against stimuli, such as exercise, allergen, or pollutants, that cause bronchoconstriction in asthmatic patients. For these reasons, inhaled β₂-agonists are the most widely prescribed and used drug in the treatment of asthma in many (possibly most) countries, and their regular use is still regarded by many physicians as a first-line treatment option.

The regular use of inhaled β₂-agonists by asthmatic patients has been beset by controversy for almost 30 years. This began in 1968 with the identification of an association between the use of a more potent formulation of isoproterenol and increases in asthma mortality in the United Kingdom, Australia, and New Zealand.¹ The increases in asthma mortality did not occur in those countries (such as the United States) in which this formulation was not available.² This controversy was rekindled by a second dramatic increase in asthma mortality in New Zealand in the late 1970s, with a less dramatic increase in many other countries. In New Zealand, the increase was temporally associated with the introduction of a β₂-agonist, fenoterol, in a metered-dose inhaler, which delivered twice the amount of the drug compared to albuterol, even though their potencies were similar.³ A subsequent analysis of the association between use and asthma mortality came from a Canadian study,⁴ which showed a markedly increased odds ratio for the risk of dying from severe asthma with the overuse of fenoterol and, to a lesser extent, of albuterol.

The concerns about the risks of asthma-related mortality associated with these “short-acting” inhaled β₂-agonists has been extended to the regular use of the long-acting inhaled β₂-agonist (LABA) salmeterol in a study by Nelson et al⁵ published in this issue of CHEST (see page 15). In the somewhat inaptly named SMART study, which was a surveillance study mandated after salmeterol was approved for use in the United States, an increased risk of respiratory-related mortality or life-threatening experiences was identified with the use of salmeterol, when compared to placebo, in a group of very poorly controlled asthmatic patients, and these differences were significant for the African-American subset of patients in the study. The study is consistent with the results of studies (largely retrospective) of the regular use of short-acting inhaled β₂-agonists and with those of the postmarketing surveillance study conducted in the United Kingdom,⁶ in which there was a numerically higher number of asthma-related deaths associated with the regular use of salmeterol, which was not quite statistically significant.

A number of important considerations arise from this study. The first is that asthma continues to be very poorly controlled. The fact that the study population entered the trial with persistent symptoms (nocturnal symptoms, > 60% of patients; visit to an emergency department in the previous month, > 25% of patients) and airflow obstruction, yet < 50% of these patients reported being treated with inhaled corticosteroids (ICSs), continues to be a very depressing statistic. Second, the number of patients who were actually using their ICSs as prescribed was never documented. This leads to the third consideration, which is whether the combination of ICSs and LABAs carries the same risk to patients as using LABAs as monotherapy (ie, the majority of patients in the SMART study). The great weight of evidence suggests that this is not the case. All studies (mostly large, prospective, placebo-controlled, and randomized) that have evaluated the effects of therapy with either of the two currently available combinations of ICSs and LABAs (ie, salmeterol/fluticasone or formoterol/budesonide)⁷⁸⁹¹⁰ have demonstrated a reduction, often as much as 50%, in severe asthma exacerbations or severe asthma-related events. Thus, it is highly improbable that combination therapy carries the same risks to patients as that of monotherapy with LABAs. Fourth, the African-American population had more severe asthma than the population as a whole, with lower lung function, with 67% of the patients having experienced nocturnal symptoms, 41% having visited an emergency department in the previous month, and with fewer patients prescribed ICSs. Thus, it is unclear whether the increased risks that this population experienced was because of this increased disease severity or because of other factors, possibly genetic, such as an increased prevalence of the Arg-Arg polymorphism at position 16 of the β₂-receptor. These issues require further consideration. A final issue is whether the concerns raised by the SMART study are applicable to all LABAs. Another study published in this issue of CHEST (see page 27) by Wolfe et al¹¹ suggests that this may not be the case for inhaled formoterol, which has a somewhat different pharmacologic profile when compared to that of salmeterol.¹² This randomized placebo-controlled study compared higher dose formoterol (24 μg twice daily) to lower dose formoterol (12 μg twice daily), with or without up to 12 μg twice daily used as rescue therapy, to placebo in > 2,000 patients for 4 months of therapy. The study confirmed the efficacy of formoterol as a bronchodilator but did not demonstrate any increase in severe asthma-related events or asthma deaths with formoterol treatment.

There are, however, a number of important differences between the two studies that need to be considered when coming to a conclusion about the relative safety of the two LABAs. First, the study with formoterol by Wolfe et al¹¹ was much smaller and of shorter duration than that with salmeterol; however, the study was adequately powered to find a clinically important difference between the lower dose and higher dose treatment groups in serious asthma exacerbations that were life-threatening or required hospitalization. Second, the patient population had, on average, less severe disease than that in the SMART study, and a higher percentage of patients (about 65%) reported taking ICSs through the study. This may be very relevant, as in the SMART study the Africa-American population had (as a group) had the most severe asthma, the lowest use of ICSs, and the highest risk of asthma mortality associated with salmeterol use. Finally, the number of African Americans in each of the study populations was small (59 to 75 patients in the four treatment arms), and if racial background confers an inherent increased risk, the study is greatly underpowered to identify this.

Despite all of the concerns raised by the SMART study, inhaled β₂-agonists remain the most effective bronchodilators available for the immediate relief of asthma symptoms and, as such, remain an important component of asthma management. In addition, LABAs in combination with ICSs remain the most effective asthma treatment currently available for the management of asthma. The SMART study reinforces the view that LABAs should not be used as monotherapy for the treatment of asthma, but rather as additional therapy added to ICSs, when ICSs alone are not providing optimal asthma control, as recommended by the current guidelines.¹³