The role of long-acting b-agonists (LABAs) in the treatment of asthma continues to be controversial. Growing evidence that LABAs may cause an increased risk of asthma exacerbations and asthma-related deaths prompted the U.S. Food and Drug Administration (FDA) to approve “black box” safety warning labels for Serevent Diskus (salmeterol xinafoate), Advair Diskus (fluticasone propionate; salmeterol xinafoate), and Foradil (formoterol fumarate). Concern about the safety of LABAs initially arose in the 1960s when a marked increase in asthma-related deaths occurred in countries where isoprenaline was available.1 Then a second epidemic of asthma-related deaths occurred in New Zealand after inhaled fenoterol, a non-selective LABA, was introduced in 1976. Rates of asthma death rapidly rose in proportion to fenoterol market sales. The asthma mortality rate in New Zealand in the age group 5-34 was the highest in the world, averaging 2.3 per 100,000 per year in the mid-1980s. In 1989, after safety warnings were issued in response to data from case-controlled studies implicating fenoterol, the death rate fell to 1.1 per 100,000 per year and further to less than 0.8 per 100,000 per year when the fenoterol was pulled from the market in 1990.2
In the early 1990s, highly selective, third generation LABAs, salmeterol and formoterol were introduced. A 16-week, randomized controlled trial, the Serevent Nationwide Surveillance (SNS) Study, with 25,180 patients in the United Kingdom was conducted, comparing twice daily salmeterol to albuterol four times daily.3 The frequency of asthma-related deaths was numerically but not significantly higher in the salmeterol group. This data prompted the large safety trial, the Salmeterol Multi-center Asthma Research Trial (SMART), a randomized, double-blind, placebo-controlled trial comparing salmeterol 42 mg bid via meter-dose inhaler (MDI) or placebo MDI with a primary outcome of combined respiratory-related deaths or respiratory-related life threatening experiences (defined as intubation and mechanical ventilation) over a 28-week study period.4 The study was initiated in 1996, and during interim analysis, the study was terminated early in January 2003 due to significantly higher rates of the secondary outcomes: respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences. Post hoc analysis showed that African-Americans were at much higher risk. In August 2003 in response to this data, the FDA issued “black-box” safety warning labels indicating a small increased risk of asthma-related death from salmeterol use. For the next few years, the FDA and GlaxoSmithKline, the manufacturer of Serevent and Advair (the fourth-best-selling drug worldwide with $5.6 billion in sales in 2005),5 would argue over how to describe the risks of these products. After much debate, in March 2006, tougher labeling changes to the black-box warnings on salmeterol products were released, including the recommendation that salmeterol should only be used if other asthma drugs, such as inhaled corticosteroids, proved insufficient. Subsequently, a meta-analysis of 19 randomized-controlled clinical trials involving over 33,800 asthma patients was performed to assess the risk of adverse outcomes of LABAs in the treatment of asthma.6 The meta-analysis found a significantly increased rate of hospitalizations for asthma exacerbations (OR 2.6; 95% CI, 1.6 to 4.3), life-threatening asthma attacks (OR 1.8; 95% CI, 1.1 to 2.9), and asthma-related deaths (OR 3.5; 95% CI 1.3 to 9.3). The absolute increase in asthma-related deaths was estimated to be 0.06% to 0.07% over 6 months, which is an excess of approximately 1 death per 1000 patient-years of use.
The proposed mechanism by which LABAs may worsen asthma control is the down-regulation of the b-adrenergic system as a result of the stimulation of b-receptors.7 Certain polymorphisms of the human b2-adrenergic receptor gene have also been implicated. Asthmatics who are homozygous for the variant with an arginine at the 16th amino-acid position of the b2-adrenergic receptor are at risk for decreased airflow and worsening asthma control when using b-agonists.8, 9 It is estimated that this genotype occurs in one sixth of the U.S. population and may be more prevalent in certain ethnic groups, such as African-Americans.
Many questions regarding the use of LABAs still remain. There are many limitations to the studies on LABAs. The mean length of follow-up is short, approximately six months. Furthermore, the relationship between LABAs and concurrent treatments, especially inhaled corticosteroids, remains unclear. Many argue that patients in these studies were not adequately treated with inhaled corticosteroids. Only 47% in both the treatment and control groups were using inhaled corticosteroids at baseline in the SMART study. There is also limited data on the correlation between the severity of disease and the adverse effects from LABAs. From the available data, it can be concluded that LABAs should not be used as initial treatment for patients with mild to moderate persistent asthma. Inhaled corticosteroids should be initiated as first line treatment to achieve asthma control with escalating doses as needed. We should all agree that there is substantial evidence that the regular use of inhaled steroids leads substantial decreases in exacerbations10 and mortality.11 The major take home message should be that we need to do a better job in making sure that our patients are on the recommended first-line medication.
It remains to be determined whether LABAs should be used at all in asthma patients. Some would advocate that only if asthma control is not attained on maximal doses of inhaled corticosteroids, then a LABA should be added, but with caution in African-American asthmatic patients.12 Others argue that a LABA should be added earlier, once the dose of inhaled corticosteroids is increased 2-fold or more, citing studies showing that the greatest benefit from inhaled corticosteroids occur at low doses and that higher doses of inhaled corticosteroid could be associated with higher risk of cataracts and fractures.13 Yet these are soft end-points compared to asthma-related death. Still others propose that LABAs should be removed from the market entirely, and perhaps the U.S. might witness a reduction in asthma mortality rates as was experienced in New Zealand with the restriction of fenoterol.6
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