|Year : 2006 | Volume
| Issue : 3 | Page : 97-99
Long-acting β2 -agonists: safety concerns and careful balance
Surender Kashyap1, Prasanta Raghab Mohapatra2
1 Principal cum Dean Professor and Head, Pulmonary Medicine, I.G. Medical College, Shimla - 171001., India
2 Senior Lecturer, Government Medical College and Hospital, Chandigarh., India
Principal cum Dean Professor and Head, Pulmonary Medicine, I.G. Medical College, Shimla - 171001.
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kashyap S, Mohapatra PR. Long-acting β2 -agonists: safety concerns and careful balance. Lung India 2006;23:97-9
Long-acting β2 -agonists (LABA) are commonly used as bronchodilators in the treatment of asthma and chronic obstructive pulmonary disease. These drugs which include salmeterol and formoterol have been shown to improve measures of lung function, disease control and quality of life in patients with asthma  . These longacting beta-agonists have been shown to be effective in improving symptom control and lung functions for 12 hours or more when added to inhaled corticosteroid therapy  .
More than a decade ago questions were raised about an excess of asthma-related events, including death, in a study of salmeterol  . Randomized trials were completed in recent years of either salmeterol or formoterol to resolve these safety concerns, but serious questions remained unanswered. Food and Drug Administration (FDA), USA has issued a stern public health advisory alerting "health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur"  . At a meeting held on July 13, 2005, the Pulmonary-Allergy Drugs Advisory Committee of the FDA considered "black box" labels for long-acting β -agonist drugs. The committee recognized that products containing salmeterol and formoterol are effective bronchodilators used for the treatment of patients with asthma and chronic obstructive pulmonary disease. The committee also was informed about adverse events associated with these drugs  . A "black box" warning is the highest level of 5 possible warning categories found in the package insert. The most severe warning is the "black box," followed in descending order of importance by "contraindications," "warnings," "precautions," and "adverse reactions." The FDA has never articulated the basis for "black box" warnings. They generally appear to be based on clinical data. Long-acting betaagonists (salmeterol and formoterol) received "black box" warnings because of reports of the occurrences of severe asthma exacerbations in some patients with asthma, with some associated deaths. 
Salmeterol Multicentre Asthma Research Trial (SMART), in which patients with asthma were randomly assigned to receive either salmeterol or placebo for 28 weeks in addition to their usual therapy. Strangely, SMART was not designed to test the hypothesis that salmeterol was safe to use as an adjunct to inhaled corticosteroids: subjects underwent randomization without consideration of their current corticosteroid therapy, and no records of such therapy were kept during the trial. An interim analysis, performed after approximately 26,000 patients had been enrolled, showed that asthma-related death was 4.4 times as likely in the salmeterol group as in the placebo group (95 percent confidence interval, 1.3 to 15.3; P=0.02). The study was eventually scheduled to enroll 60,000 patients, but was halted prematurely in 2003 after a total of about 30,000 patients had been enrolled. One death was attributable to salmeterol for every 700 patient-years of treatment, a result strikingly similar to that in the United Kingdom study  . The reason for the early termination was that an interim analysis of the data suggested that salmeterol might be associated with an increased risk of severe asthma exacerbations, including death. However, a post hoc analysis showed that black patients had much higher relative and absolute risks than non-black patients. The risk appeared to be much higher among black than among non-black patients for reasons that are not yet clear  .
Three available studies demonstrated the efficacy of both doses (24 µg and 12 µg) of formoterol, but because there was no remarkable increased benefit from the 24-µg dose compared with the 12-µg dose, only the 12-µg dose was approved for sale in the United States. In addition, the safety assessment noted that formoterol 24 µg every 12 hours was associated with more episodes of severe asthma exacerbations than the other 3 study arms  . After 3 small phase III studies of formoterol suggested that the risk of asthma exacerbations increased with higher drug doses, a 16-week phase IV study was conducted, enrolling 2307 patients above the age of 12. No deaths occurred in this trial. Although the absolute event rates were low, patients taking higher formoterol doses appeared to experience more serious asthma-related events than those given lower doses of the drug or placebos.
Responding to these findings, the manufacturers have argued that a case-control study recently performed in the United Kingdom showed no increased prescription of long-acting beta-agonists among patients who died with a diagnosis of asthma, as compared with control patients who were matched according to age and the date of an index hospitalization for asthma  . However, patients included in that study were considerably older than those enrolled in SMART; the ascertainment of the prescription of longacting beta-agonists was retrospective, and patients could have started or stopped their use without its being recorded; and the results could have been biased by the fact that 42 percent of the patients had a concomitant diagnosis of chronic obstructive pulmonary disease, a condition in which severe adverse reactions to these drugs do not seem to occur. The manufacturers have also argued that asthma-related mortality has not increased since longacting beta-agonists were first introduced: if anything, it has decreased  .
Should we prescribe the patients with asthma long-acting β-agonists products when we know-there is an increased risk of a severe asthma exacerbation and possibly death, while the frequency of this and the absolute proof of cause and effect await further study ? There is no correct answer to the management of drugs with "black box" warnings.
Since we do not know as yet whether long-acting betaagonists pose a risk when used appropriately in such patients, close medical monitoring is necessary. Only the lowest effective dose should be used. These risks should be communicated to patients. Patients prescribed LABAs should be made aware of the safety issues and told to seek prompt medical attention if their asthma deteriorates (e.g. requiring increased use of a short-acting bronchodilator). In patients with mild-to-moderate asthma, inhaled corticosteroids should be used in sufficient amounts to control chronic symptoms. If symptoms continue to persist, some of these patients may also benefit from the addition of leukotriene-receptor antagonists or low-dose theophylline therapy. Adequate doses of inhaled corticosteroids and other treatments, long-acting beta-agonists may not be usually needed.
Until the manufacturers of these drugs undertake the appropriate studies needed to clear the controversy, the safety of long-acting beta-agonists will remain uncertain.
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