Long-acting beta-agonists (or LABAs), the standard-bearer of treatment for childhood asthma, have been found to be not only useless as a 'chaser' drug, but also responsible for increasing the incidence of serious asthma attacks in children.
So weighty is the evidence against the drugs in this category-including Glaxo's Advair and Serevent, Astra-Zeneca's Symbicort and Novartis' Foradil-that the US Food and Drug Administration (FDA) had an advisory meeting in mid-December during which FDA staff members recom-mended withdrawing approval for all of these drugs for children, and for Serevent and Foradil for adults, too. The last two contain only LABAs, while Advair and Symbicort combine them with an inhaled steroid.
The FDA's move is a huge blow to drug makers, as LABAs with steroids have been the mainstay of asthma treatment for children with persistent or severe asthma that fails to respond to low- or medium-dose steroids. Indeed, some products such as Advair are fixed combinations of a LABA (salmeterol) and inhaled steroid (fluticasone). LABAs are also used against exercise-induced asthma and chronic obstructive pulmonary disease (COPD).
The FDA's sudden interest in this class of drugs represents a particular blow to Glaxo, for which Advair is its number-one bestseller.
LABAs are bronchodilators that relax the muscles around the airways in the lungs that, when tightened up, cause wheezing or bronchospasm. LABAs are said to relax constricted airways for 12 hours or longer, and so are often used for moderate-to-severe asthma and particularly to prevent nighttime episodes.
Nevertheless, regulatory bodies have begun to realize that, although LABAs reduce the frequency of asthmatic episodes, they also have a rebound effect in that, when episodes do occur, they are more severe.
A recent Cochrane Library over-view of seven reviews of LABAs as the primary or 'add-on' therapy-including four reviews of the therapy in children-found that inhaled ster-oids plus LABAs led to a significantly higher risk of adverse events vs steroids plus a placebo. Although the two-stage therapy improved the need for rescue medicine, nighttime awakenings and pulmonary function (as measured by the 'blow' test), the researchers concluded, "There is no clear benefit to LABA in preventing asthma exacerbations in children" (Evidence-Based Child Health, 2008: 3: 909-19; online: 10 December 2008).
The FDA's own meta-analysis of 110 trials, involving nearly 61,000 patients, found that, for every 1000 patients treated with LABAs, 2.8 had a more serious asthma attack. Those at greatest risk appeared to be children aged 4-11 years, with blacks and women also at higher risk than other users.
The FDA has been tracking beta-agonist problems since earlier this year, when the agency called for drug giants Glaxo, Novartis, AstraZeneca, Mylan and Sepracor to provide clinical-trial data demonstrating the safety of this class of drugs.
The agency was first alerted in 2007 during a routine yearly review of adverse/safety data for drugs approv-ed for children. For Serevent alone, the agency uncovered nine adverse-event reports in children and five deaths over a 13-month period.
The FDA had already set a black-box warning in 2006 for salmeterol and Advair on the basis of findings from the Salmeterol Multicenter Asthma Research Trial (SMART), which examined the safety of adding salmeterol to a patient's usual steroid-based asthma regime. Those taking the salmeterol suffered a significant increase in asthma-related death-four times that of those taking a placebo. This works out to one additional death for every thousand patients. However, the study did not include any patients under age 12.
In its advisory, the FDA warned that LABAs should not be used as a first-line treatment, or to relieve sudden wheezing or wheezing that is growing worse.
One reason why it took so long for problems with LABAs to surface is that conventional meta-analyses focus on single comparisons between drugs rather than on a number of analyses of different drug regimens to rank their effectiveness.
Indeed, a study using a networking meta-analytical technique attempted to do just that for the most commonly used inhaled drug regimens for reducing COPD attacks (BMC Med, 2009; 7: 2; doi:10.1186/1741-7015-7-2). It found that beta-agonists performed worse than all other regimes (long-acting anticholinergics, inhaled steroids and combination treatments) in patients with more serious forms of COPD, with the steroid/LABA combination only reducing exacerbations in those with milder disease.
Beware of these long-acting puffers
- Serevent Diskus, a disk-shaped inhaler that pumps out salmeterol
- Advair Diskus, which combines salmeterol with the inhaled steroid fluticasone, also delivered via a disk-shaped device
- Foradil Aerolizer, a puffer containing the LABA formoterol
- Symbicort, AstraZeneca's combo drug, mixes formoterol and the inhaled steroid budesonide.
To find alternatives to puffers that can help respiratory problems, consult The Asthma Manual, now available as an e-book (www.wddty.com).