Long acting bronchodilators (LABAs) have long been accused of increasing the number of asthma related deaths. My 12/23/2005 posting gave a brief summary of events up to that time.
Concern about LABAs was exacerbated by two studies that lead the FDA to issue a black box warning in November 2004.
A 16 week study from Great Britain, the Salmeterol National Surveillance Study (SNS) of 25,180 patients, found 12 deaths in the salmeterol group versus 2 in the placebo group a finding that was obviously numerically greater but not statistically significant.
Of greater concern was the SMART trial. This was a 28 week trial with 26,350 patients which demonstrated a 4.3 fold increase in asthma related deaths,( 13 versus 3) in the salmeterol treated group.
At least one important piece of information was not available from SMART. In the FDA statement we find this statement:
"The data from the SMART trial was not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk."
We really need to know if inhaled steroids mitigate or eliminate the putative increased risk from LABAs.Current recommendations essentially depend on that as the recommendation is to not start a LABA for asthma treatment until the patient is receiving at least moderate doses of steroids.
A recent meta-analysis published in the Annals of Internal Medicine seems to provide that missing information. Dr. Shelley R. Salpeter et al pooled results from 19 trials with 33,826 patients and found that LABAs ( not just salmeterol) increased exacerbations requiring hospitalizations (O.R. 2.6) and asthma related deaths (O.R.3.5). When the authors looked at the trials in which more than 75% of the participants were taking inhaled corticosteroids, the O.R. for hospitalizations was still increased at 2.1 ( 1.3 - 3.4).
While this may not be a slam dunk to answer all we need to know or to settle the issue, it is bound to raise the level of concern to a higher notch. Unfortunately, the authors do not give us more information about that part of their analysis nor do they include it in their article summary.However, in their concluding paragraph they say : " Concomitant inhaled corticosteroids do not adequately protect against adverse effects "
The LABA controversy will not be settled by this meta-analysis. A recent article from Australia quotes a Cochrane systematic review of LABA use in asthma and concludes they are safe and effective. As the editorial in the Annals noted, Evidence Based Medicine exhorts us to use the best evidence. Determining what is best sometimes is no easy matter. The medical literature dealing with the long acting beta agonists is extensive and replete with contradictory data. Since deaths from asthma are relatively uncommon, many physicians who use Advair and other LABA containing medications have not seen serious complications in their patients and typically observe better control in those patients requiring LABAs. It is not surprising that-as noted in the Salpeter article-the Black Box warning has not altered physicians's prescribing habits. Whether those habits should be changed or not seems to still be an open question.