Long-acting beta agonists in asthma under scrutiny

The Washington Post reports on an FDA decision on long-acting beta agonists (LABAs) in asthma:

The risks of two widely used asthma drugs outweigh their benefits for both children and adults, a U.S. Food and Drug Administration advisory panel said Thursday.

The health panel targeted GlaxoSmithKline’s Serevent [salmeterol] and Foradil [formoterol], made jointly by Novartis AG and Schering-Plough, for restrictions, but it excluded Advair [salmeterol and fluticasone], Glaxo’s biggest-selling drug in the class of medications known as long-acting beta-agonists. It also left alone a fourth such drug, AstraZeneca’s Symbicort [formoterol and budesonide].

The health experts did not say that the use of Serevent and Foradil should be abandoned altogether. Instead, they said the medications’ labeling should be reworded to urge doctors to use the drugs along with an inhaled corticosteroid — as guidelines already recommend.

There was some talk that FDA staff wanted LABAs removed from the market for under 18 year olds. The briefing documents the FDA advisory panel considered are freely available on the FDA site:

Overall, the meta-analysis showed that LABAs were associated with an increased risk of asthma-related events relative to non-LABA treatment as measured by the asthma composite endpoint consisting of asthma-related death, asthma-related intubation, and asthma-related hospitalization. Non-LABA treatment included ICSs [inhaled corticosteroids], short-acting betaagonists, other non-LABA treatments, placebo, or a combination of treatments. The risk difference estimate for the asthma composite endpoint of the LABA rate minus the non-LABA rate was 2.80 (95% CI: 1.11, 4.49) per 1000 subjects. This overall finding for the asthma composite endpoint was supported by both the asthma-related hospitalization and the asthma-related death components. However, findings for individual drugs and subgroups were driven by the asthma-related hospitalization component.

Three of the four drugs (Foradil, Serevent, Symbicort) had positive risk difference estimates for the asthma composite endpoint; however, only Serevent had a statistically significant estimate. The risk difference estimates for the asthma composite endpoint were positive both when (1) LABA without assigned ICS was compared to non-LABA treatment and (2) LABA with assigned ICS was compared to assigned ICS treatment. However, only comparison (1) was statistically significant [3.63 (95% CI: 1.51 – 5.75) per 1000 subjects], and comparison (2) had a small risk difference estimate [0.25 (95% CI: -1.69 – 2.18) per 1000 subjects].

So, the increased risk of asthma events is related to the use of LABAs when used without inhaled corticosteroids. When concern about LABAs came up a year ago, the NPC posted a useful blog post advising on the evidence and action to take:

Healthcare professionals should follow current CHM advice and national guidance on management of asthma. LABAs should be initiated (at step 3) only if inhaled corticosteroids at moderate doses are failing to control asthma symptoms adequately. Before initiating a new drug therapy practitioners should recheck compliance, inhaler technique and eliminate trigger factors. If LABAs are introduced this should be in context of a therapeutic trial.

Professionals should take particular note that LABAs should not be initiated in patients with rapidly deteriorating asthma: they are for “stable but poorly controlled” asthma. Practitioners should consider stepping down LABA use when good long term asthma control has been achieved.

It will be interesting to see if any of these views are revised in the light of the FDA data and the Advisory Panel descisions, but it is arguable that the above advice still stands and that the focus should be on inappropriate prescribing rather than the drugs themselves.