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A new meta-analysis of more than 23,000 asthma patients randomized either to formoterol-containing combination regimens or to treatment without a long-acting beta-adrenergic agent showed no asthma-related deaths.

The analysis looked at all 42 AstraZeneca-sponsored randomized, blinded, prospective clinical trials and found no evidence of increased risks of all-cause mortality, asthma-related deaths, or intubations in patients receiving combination therapy with the long-acting beta-agonist (LABA) formoterol.

The findings support those of an earlier meta-analysis (Ann. Intern. Med. 2008;149:33-42) involving all of the more than 28,000 participants in the 66 GlaxoSmithKline-sponsored randomized trials comparing outcomes with the LABA salmeterol plus an inhaled corticosteroid (ICS) versus an ICS alone, Dr. Harold S. Nelson said at a meeting on allergy and respiratory diseases.

Together, these two meta-analyses totaling more than 50,000 asthma patients paint a consistent and reassuring picture of the safety of LABAS when used in conjunction with an ICS. It's a picture at odds with the "rather frightening" conclusions about LABA safety drawn by the Food and Drug Administration's Office of Surveillance and Epidemiology in a Dec. 2008 meeting, said Dr. Nelson, professor of medicine at the University of Colorado/National Jewish Health, Denver.

It's noteworthy that the FDA analysis incorporated 1,270 of the 23,510 subjects included in the new meta-analysis. The regulators excluded data involving non-U.S.-approved drug dosages and age groups and thereby constructed for themselves a rather limited database, he said at the meeting, sponsored by the National Jewish Medical and Research Center.

FDA concerns regarding LABA safety arose in large part from the findings of the Salmeterol Multicenter Asthma Research Trial (SMART). The key findings of SMART, however, have not stood the test of time, he said.

One by one, the major SMART conclusions--that salmeterol is associated with increased risk of asthma-related mortality, that African Americans and children are subgroups uniquely vulnerable to asthma exacerbations while on LABAS, as are patients homozygous for arginine at codon position 16 on the beta-2-adrenergic receptor have subsequently been knocked down, said Dr. Nelson, who was the lead author of SMART (Chest 2006;129:15-26) and has been among those who've subsequently criticized the study.

One of the major problems with SMART, he said, was that compliance with ICS therapy wasn't monitored, and many patients assigned to salmeterol weren't taking the topical anti-inflammatory agent.

"There's no question that the outcomes with combination therapy in SMART were bad. The only question is was it because they weren't taking an inhaled corticosteroid," he said. Dr. Nelson stressed that the results of the two meta-analyses underscore the folly of recent much-publicized editorials calling for a new prospective trial of the safety of LABAs (Eur. Respir. J. 2009;33:3-5; N. Engl. J. Med. 2009;360:1671-2).

"We've got more than 50,000 patients in clinical trials without an asthma death. When you look at the data and see the lack of difference between patients who are treated with an inhaled corticosteroid and those who are treated with an inhaled corticosteroid and LABA, you can calculate that the number of patients required for this new study would be somewhere between 1 million and infinity," he said.

"There's no need to wipe out the black box warnings on salmeterol and formoterol as monotherapy; that's very appropriate. What's needed is to say that when you put them in a container with an inhaled corticosteroid those dangers have never been shown to exist," he said.

The new AstraZeneca-supported meta-analysis included 13,542 patients on formoterol-containing combination therapies and 9,968 on non-LABA regimens. All subjects were at least 4 years old.

Dr. Nelson disclosed having served as a consultant to AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, Genentech Inc., Novartis, Schering-Plough Corp., Sepracor Inc., Abbott Laboratories, and Array BioPharma Inc.

Outcomes, Formoterol vs. Non-LABA Therapies

Formoterol Non-LABA
combinations therapies

Patient-years of exposure 6.500 5.000

All-cause mortality 0.53 0.82
(per 1,000 patient-years
of exposure)

Asthma-related deaths 0 0

Asthma-related 12.05 16.4
hospitalizations
(per 1,000 patient-
years of exposure)

Study discontinuation 12.7% l5.4%
rate

Source: Dr. Nelson

Source Citation
Jancin, Bruce. "New meta-analysis shows safety of LABA combinations." Family Practice News 40.5 (2010): 40. Academic OneFile. Web. 13 Apr. 2010.
Document URL
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