Four years after it first appeared on the scene, the debate over conflicting evidence on asthma treatment rages on. On one side are the current treatment guidelines recently issued by the National Asthma Education and Prevention Program (NAEPP). They recommend a short-acting bronchodilator for intermittent asthma, with the addition of a low-dose inhaled corticosteroid for mild persistent asthma and the further addition of a long-acting beta agonist (LABA) as the first-line treatment for moderate persistent asthma.1
On the other side is the Salmeterol Multicenter Research Trial (SMART). In August 2003, following early termination of SMART for safety concerns, the FDA added a black-box warning to U.S. products containing the LABAs salmeterol and formoterol. The FDA cited a small but significant increased risk of “life-threatening asthma attacks or asthma-related deaths” for African-American participants in this trial.
Adding to the mix, the Cochrane Database concluded that “the addition of [a] LABA is superior to a leukotriene receptor antagonist (LTRA) for preventing exacerbations requiring systemic steroids and for improving lung function, symptoms, and the use of rescue beta agonists.”2
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So how do you ferret out clear direction on the best way to manage patients with moderate-to-severe persistent asthma? Read on.
Analyzing SMART
This large, 28-week, double-blind, randomized, placebo-controlled observational study enrolled 26,355 asthma patients at 6,163 sites throughout the United States. Study participants were treated with their usual care plus placebo or salmeterol.3 The primary end point was combined respiratory-related death or life-threatening experiences. Secondary end points were all-cause death, all-cause hospitalization, respiratory-related death, asthma-related death, and two combined end points.
While no significant difference in primary or secondary end points was observed in the overall population, a subset interim analysis noted a statistically significant difference in the primary end point and two secondary end points within the African-American study population (18% of the total study population). In comparing salmeterol vs. placebo use in black patients, researchers observed more respiratory-related deaths or life-threatening experiences (20 vs. 5) and more combined asthma-related deaths or life-threatening experiences (19 vs. 4). These events were numerically small and have been difficult to interpret. Based on the limitations of post hoc subset analysis, most experts agree there isn’t enough evidence to make a race-based decision on the use of LABAs at this point.
It is unclear if the observed racial differences in the study represented a genetic predisposition to disease, differences in health-care access, other as yet unidentified causes, or some combination of factors.
The beta2 receptor—a possible explanation?
DNA polymorphisms in the beta2-adrenergic receptor (ADRB2) have been associated with increased bronchial and vascular hyperreactivity in response to continuous receptor stimulation.4 The polymorphism most associated with bronchial reactivity and severe asthma is an arginine-arginine homozygosity at position 16 (Arg/Arg16) on ADRB2. This polymorphism leads to the down-regulation of the beta receptor in response to both LABA and continuous short-acting beta-agonist use. As a result, patients can experience a decline in beta-agonist responsiveness.5,6 This may worsen the severity of exacerbations and blunt the effectiveness of any beta agonist.
A racial difference in the prevalence of the Arg/Arg16 polymorphism could explain the racial disparities in the SMART trial. ADRB2 polymorphisms have been studied in black, white, and Chinese populations, and a large variance in the prevalence of these polymorphisms has been observed. However, a significant increase in the prevalence of Arg/Arg16 in American blacks compared with American whites has not been clearly demonstrated.7,8
Health-care access differences are another possible explanation. Black patients are less likely to have structured outpatient asthma care. It is possible that the increase in asthma-related events in blacks in the SMART trial represents a sicker patient population, rather than an ethnic or genetic predisposition. The SMART trial was not designed to explore these differences.
Recommendations for the clinician
Based on the available literature, the study results, and FDA Public Health Advisory concerns, we offer seven recommendations for LABA use in asthma.
- Paramount in the management of asthma is the development of a partnership (an asthma action plan) between the patient and clinician.
- Low- to medium-dose inhaled corticosteroids should re-main first-line for the management of persistent asthma in all adults. All other medications should be viewed as additive and used only when low- to medium-dose inhaled cortico-steroids are not controlling asthma signs and symptoms.1
- When incorporating the results of the SMART trial, you should still consider LABAs the primary additive therapy for asthma management. The addition of LABAs to inhaled corticosteroids has been shown to provide better asthma control than increasing the inhaled corticosteroids dose or adding an LTRA.2,3 Based on the SMART trial results, it appears prudent at this time not to initiate LABAs as first-line monotherapy in black patients.
- Prescribe LTRAs to provide additional asthma control for patients having symptoms not controlled by inhaled corticosteroids and a LABA. In patients with prominent sinus symptoms, LTRAs should be considered early or a second-line therapy in place of LABAs.9
- Patients having success with LABAs should not discontinue this medication. LABAs are commonly prescribed medications that have been shown to be safe. The combined event rate in the SMART trial occurred in <1% of patients. The increase in asthma-related death and life-threatening experiences was seen in subgroup analysis, but the study population as a whole did not show a difference.3
- If wheezing worsens with LABA use, reassess the need for this medication. Why? ADRB2 polymorphisms have been associated with increased bronchospasm and a lack of beta-agonist response in patients receiving continuous stimulation, either by LABA or scheduled short-acting beta-agonist use.4-6
- At this time, don’t avoid prescribing LABAs as add-on therapy for black patients. There is currently not enough evidence to support such avoidance, nor is there a clear mechanism to explain the observed increase in events from the SMART trial. Increasing use of rescue medication or significant fall in peak expiratory flow rates should trigger an urgent reassessment of asthma control in these patients.
Dr. Stollenwerk is a clinical fellow in pulmonary and critical care medicine, University of California Davis Medical Center, in Sacramento, where Dr. Tharratt is professor of medicine and anesthesiology and vice chief, Division of Pulmonary Medicine.
References
1. National Asthma Education and Prevention Program. Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, Md.: National Institutes of Health; July 2007. Publication No. 08-4051. Available at: www.nhlbi.nih.gov/guidelines/asthma. Accessed September 7, 2007.
2. Ducharme FM, Lasserson CJ, Cates TJ. Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2006;(4):CD003137.
3. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial (SMART): a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26.
4. Dishy V, Sofowora GG, Xie HG, et al. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med. 2001;345:1030-1035.
5. Palmer CN, Lipworth BJ, Lee S, et al. Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax. 2006;61:940-944.
6. Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term beta-agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax. 2000;55:762-767.
7. Xie HG, Stein CM, Kim RB, et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian, and Chinese individuals. Pharmacogenetics. 1999;9:511-516.
8. Maxwell TJ, Ameyaw MM, Pritchard S, et al. Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. Int J Mol Med. 2005;16:573-580.
9. Currie GP, Lee DK, Srivastava P. Long-acting bronchodilator or leukotriene modifier as add-on therapy to inhaled corticosteroids in persistent asthma? Chest. 2005;128:2954-2962.
