REVISITING THE SAFETY OF LABAS IN CHILDREN WITH SEVERE ASTHMA

FCAAIA Notes: Twenty years ago the SMART study suggested a risk of long-acting beta agonists (LABA) use, However, the rail was associated with the use of LABA alone and NOT with the concurrent use of inhaled corticosteroids (ICS). Study after study shows that when used in combination with ICS, LABAs do not increase risk of asthma morbidity or mortality. Of course, the patients who need LABAs along with their ICS have more severe asthma to start with, so their risk is greater than those who do not require LABAs.

An important point is that many patients who use ICS/LABA combinations have never tried and ICS alone.  Some of them would do fine on one medication rather than the combination of two medications.   Your allergist will try to “step down” your medical regimen to keep you as well as you can be with as little medication as it takes to do so.

For current guideline regrading appropriate step-care of asthma, see the Guidelines for the Diagnosis and Management of Asthma

(Source: http://www.medscape.com/viewarticle/871473?nlid=110789_3821&src=WNL_mdplsfeat_161122_mscpedit_aimm&uac=112079PK&spon=38&impID=1239786&faf=1 Nov.22, 2016.  For Medscape articles: User name: FCAAIA, Password: Allergies)

When the evidence suggested a higher risk for asthma-related death with single formulation (stand-alone) long-acting beta-agonists (LABAs) in the treatment of asthma, the US Food and Drug Administration (FDA) requested that drug manufacturers conduct clinical trials on the safety of LABAs in children, particularly when used in fixed-dose combinations with inhaled glucocorticoids. This randomized, double-blind, controlled 26 week trial was conducted by GlaxoSmithKline in 567 centers in 32 countries, enrolling children from 2011 to 2015. Because the risk for death associated with LABAs was highest in children aged 4-11 years, this age group was the focus of the study. The study excluded children with the most severe asthma, but sought to include those with true persistent asthma.

Children were randomly assigned in a 1:1 ratio to receive either inhaled fluticasone/salmeterol or fluticasone alone. The fluticasone dose varied according to the age and size of the patient, but the salmeterol dose was fixed at 50 µg, and all doses were administered twice daily as a dry powder inhaler. Patients also used rescue medications (albuterol) as needed and as prescribed by their providers.

The safety (and primary) outcome of interest was “serious asthma-related events,” a composite measure of death, endotracheal intubation, or hospitalization. The investigators also evaluated the efficacy of the drugs, measured as the time to the first asthma exacerbation (defined as the need for systemic glucocorticoids).

The study population included 6208 children. Approximately 61% of all children were boys; the mean age was 7.6 years; and the population was approximately 65% white, 17% black, and 18% other races.

The endpoints were almost identical between the two groups. From a safety standpoint, 0.9% of the fluticasone/salmeterol group compared with 0.7% of the fluticasone alone group experienced the composite safety outcome. No patient died or was intubated, so the findings were driven by hospitalizations. The hazard ratio (HR) for a serious asthma-related event was 1.28 when comparing fluticasone/salmeterol with fluticasone alone, with a 95% confidence interval (CI) of 0.73-2.27 (nonsignificant).

In each group, 1.1% of the children withdrew from study owing to asthma exacerbation, and almost identical percentages in each group experienced a serious adverse event. With respect to total exacerbations, 8.5% of the fluticasone/salmeterol group experienced exacerbations compared with 10% of the fluticasone-only group. The HR of 0.86 favored combination treatment (95% CI, 0.73-1.01 [nonsignificant]).

Most secondary analyses were similar among the two groups, including days that were free of rescue therapy (approximately 82% in each group).

The authors concluded that the use of salmeterol in fixed combination with an inhaled glucocorticoid produced a risk for serious asthma-related events in children that was similar to the risk associated with fluticasone alone.

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