The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations

Asthma affects 7% of the population in the United States. Asthma morbidity and mortality has increased over the past decade. Long-acting β-agonists (LABAs) combined with inhaled corticosteroids are the most rapidly growing form of asthma therapy in the USA. The only currently USA licensed pharmaceutical that combines a long-acting beta-agonist, salmeterol, and an inhaled corticosteroid is a product know as Advair®. It has become the most widely prescribed asthma controller medication in the United States. While studies have suggested that the combination of a LABA and an inhaled corticosteroid (LABA/ICS), on average, improves asthma control, other studies have suggested that a subpopulation of asthmatics may be at risk for severe exacerbations or death with the use of these agents. These latter studies have caused the FDA to place a "black box" warning on Advair®.

The primary site of therapeutic action of the β-agonists is the beta-adrenergic receptor (ADRB2). One of the common SNPs (allele frequency 0.4 in caucasians) in the coding region of ADRB2 codes for arginine instead of glycine at the 16th amino-acid position of the receptor. In a retrospective association study, we reported that homozygosity for the arginine polymorphism at the 16th amino-acid position (B16 Arg/Arg) as compared to homozygosity for glycine at that position (B16 Gly/Gly) was associated with adverse pulmonary function outcomes when patients used short-acting β-agonists regularly. This report was followed by a study from another group associating increased rates of exacerbations with regular use of short-acting β-agonist in B16 Arg/Arg patients. We subsequently organized and led the first non-oncologic prospective, controlled, double-blinded, genotype stratified trial. In this trial we randomized B16 Arg/Arg and B16 Gly/Gly patients with asthma to regular short-acting β-agonist therapy vs. as needed anti-cholinergic bronchodilator therapy. We showed that patients harboring B16 Arg/Arg, as compared with B16 Gly/Gly, benefited when their use of short-acting β-agonists was minimized by substituting an anti-cholinergic bronchodilator for the β-adrenergic bronchodilator.

Recently, we performed a genotype stratified analysis of patients who had participated in randomized trials using the LABA, salmeterol. We demonstrated that B16 Arg/Arg was associated with adverse outcomes even when the LABA was used with a concomitant inhaled corticosteroid. A recent cross-sectional analysis of pediatric patients using LABAs with ICS suggested that the OR was 3.4 for exacerbations over 6 months in Arg/Arg patients as compared with Gly/Gly patients. In this study, the OR for exacerbation in the presence of the B16 Arg allele in a codominant model was 1.8. Of interest, an industry-sponsored 12 week trial in press did not uncover such an association emphasizing the importance of prospectively confirming these finding[9].

In summary, substantial evidence suggests that asthmatic patients harboring B16 Arg/Arg are at increased risk for adverse outcomes when using a LABA and that they may benefit from the use of an anticholinergic.

A search of the RPDR across all Partners' sites in October 2006, revealed that 13,682 adults age 18-70 with a diagnosis of asthma are receiving a salmeterol containing preparation. At minimum 2.200 of these patients are Arg/Arg (likely more, since the frequency of B16 Arg/Arg is higher in Blacks and Asians). Multiple studies have suggested that patients requiring LABA/ICS therapy experience on average 0.3-0.6 exacerbations per year. The Palmer and Taylor studies suggest that the risk of exacerbations in Arg/Arg patients may be increased from 50-100% by exposure to regular β-agonist therapy. Based on these risks, alternative therapies could potentially reduce the rates of exacerbations by 1/3 to 1/2 in this subpopulation.

We therefore propose a prospective trial in which patients prescribed Advair®, or another combination of a LABA/ICS, are randomized, in a genotype stratified manner, to either continue on therapy with LABA/ICS preparations or to therapy with a long-acting anti-cholinergic/ICS. The primary outcome will be exacerbations as defined by events requiring oral corticosteroids, emergency room visits, or hospitalizations over the one year after randomization[1]. Secondary outcomes will include symptom-free days and quality of life (which we have assessed in prior studies utilizing validated instruments), days lost from work or school, lung function, and non-invasive measures of lung inflammation through collection of exhaled nitric oxide and exhaled breath condensate for assessment of oxidative stress through measures of pH. All techniques and procedures have been utilized by our team at BWH in the course of our prior asthma clinical studies and pharmacogenetic studies.

The primary objective of this study will be address the questions of whether the presence of the arginine polymorphism at the 16th amino-acid of ADRB2 increases the rate of exacerbations in patients with asthma treated with LABA/ICS and whether treatment with an anti-cholinergic/ICS in patients with asthma homozygous for the arginine polymorphism at the 16th amino-acid of ADRB2 reduce exacerbations as compared with treatment with LABA/ICS.