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Internal Medicine Specialty Resident, Virginia Commonwealth University Health System, Medical College of Virginia Hospitals, Richmond, VA
Director, Drug Information Services, Virginia Commonwealth University Health System, Medical College of Virginia Hospitals; Assistant Clinical Professor, School of Pharmacy, Virginia Commonwealth University
Clinical Specialist, Internal Medicine, Virginia Commonwealth University Health System, Medical College of Virginia Hospitals; Assistant Clinical Professor, School of Pharmacy, Virginia Commonwealth University
Reprints: Dr. Kockler, School of Pharmacy, Virginia Commonwealth University, 401 N. 12th St., PO Box 980042, Richmond, VA 23298, fax 804/628-3919, dkockler{at}mcvh-vcu.edu
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CASE SUMMARY: A 49-year-old black female presented to the emergency department with acute shortness of breath with subsequent intubation. After extubation, she reported multiple hospitalizations for asthma with one prior intubation, adherence to asthma medications, and very frequent use of her short-acting β2-agonist (SABA). Because of her asthma history, self-reported adherence, and race, she was tested for β2-adrenoreceptor genotype, which revealed Arg/Arg. Based on these findings, β2-agonists were discontinued and tiotropium (maintenance) and ipratropium (primary rescue) were initiated as part of her asthma regimen. Application of the Naranjo probability scale revealed probable causality between uncontrolled asthma in our patient and SABA use. The patient is followed in our outpatient pulmonary clinic and, at time of writing, had not been admitted to our hospital for asthma-related events.
DISCUSSION: Approximately 15% of Americans with asthma are Arg/Arg, with an increased prevalence in black and Asian populations. It is hypothesized that changes in the degree of sensitivity or desensitization to the bronchodilator effect of β2-agonists may occur in these individuals. Data exist, although they are conflicting, suggesting that inhaled β2-agonists may worsen clinical outcomes. Trials have reported declines in peak expiratory flow rates plus increases in asthma symptoms and exacerbations when SABAs have been used regularly in patients with Arg/Arg. Studies evaluating long-acting β2-agonists (LABAs) have inconsistent results. Preliminary data suggest that anticholinergics may serve as a beneficial primary rescue medication instead of β2-agonists in patients with Arg/Arg.
CONCLUSIONS: Clinicians should be aware of factors (eg, race and polymorphisms) that may predict unfavorable outcomes with regular SABA and possibly LABA use. Patients with poor asthma control despite adherence to asthma therapy may benefit from β2-adrenoreceptor genotyping and, possibly, from anticholinergics.
Key Words: anticholinergic, asthma, β-agonist, polymorphism
Published Online, April 22, 2008. www.theannals.com, DOI 10.1345/aph.1K682
Approximately 15% of Americans with asthma have the Arg/Arg genotype, with an increased prevalence in black and Asian populations.3,10,11 It has been hypothesized that a change in the degree of sensitivity or desensitization to the bronchodilator effect of β2-agonists may occur in these individuals.6,12 Results of clinical trials have reported declines in peak expiratory flow rates (PEFRs), along with increased asthma symptoms and exacerbations, when SABAs have been used regularly in patients with Arg/Arg.3-5 However, outcomes with LABAs are conflicting. Data exist showing poorer outcomes when LABAs are used in patients with Arg/Arg,7 although other trials have concluded that therapeutic response is not impaired.13,14 We report a case of confirmed Arg/Arg polymorphism in a patient with uncontrolled asthma.
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In the emergency department (day 1), she complained of shortness of breath, cough, chills, chest tightness, left lower extremity swelling, and lightheadedness. A respiratory examination revealed distress, prolonged expiration, accessory muscle use, decreased air movement, and wheezing. Her chest roentgenogram showed shallow inspiration and no definite focal area of consolidation. Spiral computed tomography (for detection of pulmonary embolism) and ultrasound (for detection of deep vein thrombosis) were not performed since the woman was receiving anticoagulation therapy (international normalized ratio 2.5) and had a significant asthma history. Physical examination revealed blood pressure 133/92 mm Hg, pulse 137 beats/min, and respiratory rate 24 breaths/min with 81% oxygen saturation on room air. Arterial blood gas findings were significant for pCO2 70 mm Hg (reference range 35–45), pO2 78 mm Hg (80–110), and 96% oxygen saturation. Her basic metabolic profile was notable for hyperglycemia (blood glucose 234 mg/dL, reference range 65–100), hypocalcemia (calcium 8.2 mg/dL, 8.4–10.2 mg/dL), and hypophosphatemia (phosphate 2.2 mg/dL, 2.5–4.6 mg/dL). Cardiac enzyme levels were normal.
Pharmacologic intervention in the emergency department consisted of continuous nebulized albuterol 5 mg/h, nebulized ipratropium 0.5 mg every 6 hours, one dose of prednisone 60 mg, and one dose of intravenous magnesium sulfate 2000 mg. No improvement in the patient's respiratory status was noted. She was admitted to the medical intensive care unit and intubated. Respiratory treatment included continuous nebulized albuterol 10 mg/h, nebulized ipratropium 0.5 mg every 6 hours, and intravenous methylprednisolone 125 mg every 6 hours. Home medications continued upon admission included a proton pump inhibitor and warfarin. Her respiratory status stabilized (day 3); therefore, continuous albuterol was changed to intermittent administration (2.5 mg every 4 h). Ipratropium and methylprednisolone were continued, and she was extubated.
On day 4, the patient was transferred to an internal medicine floor. After transfer, she complained of shortness of breath. A chest roentgenogram revealed increased hydrostatic edema and poor aeration of the right lung base. Oral levofloxacin 500 mg daily was initiated for community-acquired pneumonia and cystitis (>100,000 Escherichia coli identified on urine culture). At this time, her asthma regimen included nebulized albuterol 2.5 mg every 4 hours, nebulized ipratropium 0.5 mg every 6 hours, intravenous methylprednisolone 60 mg every 6 hours, montelukast 10 mg daily, and fluticasone metered-dose inhaler 220 µg every 12 hours.
After medical stabilization, the patient revealed that she had multiple previous hospitalizations for asthma exacerbations, with one prior intubation. She stated that she was adherent to her home drug therapy and regular outpatient pulmonary care, as well as very frequent use of her SABA. Due to her asthma history, self-reported adherence, and race, testing for β2-adrenoreceptor genotype was performed and revealed Arg/Arg (day 8). Based on these findings, albuterol was discontinued and fluticasone/salmeterol was not reinitiated. Tiotropium 18 µg daily (maintenance) and ipratropium 0.5 mg as needed (primary rescue) were initiated as part of her asthma regimen. Moreover, she was continued on inhaled corticosteroids (fluticasone changed to budesonide), systemic corticosteroids (methylprednisolone changed to prednisone), and montelukast. Albuterol was recommended only if an asthma exacerbation was unresponsive to ipratropium. The patient's respiratory status continued to improve throughout her hospitalization, with mild expiratory wheezes and 98% oxygen saturation on room air. On day 9, she was discharged. Her asthma medications included tiotropium 18 µg daily, budesonide metered-dose inhaler 400 µg twice daily, montelukast 10 mg every evening, nebulized ipratropium 0.5 mg every 6 hours as needed, oral prednisone (taper), and nebulized albuterol 2.5 mg every 2 hours if needed for ipratropium failure. At the time of writing, approximately 12 months since her discharge, the patient had not been admitted to our hospital for asthma-related events.
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Studies evaluating the efficacy and safety of β2-agonists in patients with Arg/Arg have shown conflicting results.3-5,7,13,14 Several trials have revealed that differences in inhaled β2-agonist responses exist and that poorer asthma outcomes may occur in this population,3-5,7 although others report no difference in therapeutic outcomes.13,14 These studies are summarized below and described in Table 1.
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The initial large trial that reported an association between increased risk of adverse effects with SABAs and polymorphisms evaluated the effects of regular versus intermittent use of albuterol in 2 cohorts of patients (n = 255) with mild asthma.3 No significant differences were reported for morning PEFR (PEFRAM), although some patients did experience a reduction in PEFR during the study. Due to this reduction, patients were contacted for genotyping. Seventy-five percent (190/255) of the patients were genotyped, with 68% (173/255) of the patients having a confirmed genotype. PEFRAM and PEFRPM reductions (30.5 ± 12.1 L/min; p = 0.012 and 31.1 ± 13.0 L/min; p = 0.0167, respectively) were reported in patients with Arg/Arg who used regularly scheduled albuterol when compared with intermittent albuterol. The authors concluded that patients with Arg/Arg respond differently to β2-agonists and may benefit from avoidance of scheduled β2-agonists.
These authors then conducted a trial to confirm their earlier findings.5 Eligible patients had mild asthma, intermittent β2-agonist use, and were Arg/Arg or β16-Gly/Gly (Gly/Gly). Forced expiratory volume at 1 minute (FEV1) was used to match Arg/Arg with Gly/Gly patients. After a 6-week placebo run-in period, patients were randomized to receive scheduled albuterol or placebo for 16 weeks and then crossed over. As-needed albuterol use was avoided. Instead, ipratropium was the primary rescue medication. If an exacerbation was unresponsive to ipratropium, patients were allowed to use albuterol. Once albuterol was discontinued, patients with Arg/Arg had improved PEFRAM compared with patients with Gly/Gly (–37 vs –12 L/min, respectively). Since an improvement in PEFRAM was noted in patients with Arg/Arg during the run-in period (albuterol switched to ipratropium for primary rescue), a secondary analysis was performed and revealed a 23-L/min increase in PEFRAM from baseline for these patients at week 6. However, only a 2-L/min improvement in PEFRAM was reported in those who were Gly/Gly. It was concluded that patients with Arg/Arg may have better asthma responses if SABAs are avoided and that other therapies (anticholinergics) should be evaluated in this population.
Taylor et al.4 conducted a retrospective analysis to determine a relationship between β2-agonist responses and polymorphisms. Patients who completed a 3-way crossover trial that evaluated their asthma exacerbations during treatment with albuterol (SABA), salmeterol (LABA), or placebo were genotyped. Patients with Arg/Arg had more frequent major exacerbations per year when receiving albuterol (95% CI 1.07 to 3.12) compared with placebo (95% CI 0.28 to 1.66). No significant differences between genotypes were reported for other treatments. The authors concluded that asthma exacerbations increase in patients with Arg/Arg during chronic SABA therapy.
SMART (Salmeterol Multicenter Asthma Research Trial) is the largest randomized trial published to date that questions LABA safety.9 Patients with asthma without prior LABA use were maintained on their current asthma regimen and then randomized to receive salmeterol or placebo twice daily. The study was terminated early. A scheduled interim analysis revealed that, although there was no significant difference in the primary endpoint for the total population, a difference in an increased frequency of respiratory-related deaths or life-threatening experiences, as well as combined asthma-related deaths or life-threatening experiences, existed in blacks who were treated with salmeterol compared with those who received placebo (20 vs 5, RR 4.10, 95% CI 1.54 to 10.90; 19 vs 4, RR 4.92, 95% CI 1.68 to 14.45, respectively). It was hypothesized that differences in the black subgroup may be due to variations in β2-adrenoreceptor genotypes, decreased use of inhaled corticosteroids, or more severe asthma at baseline.
Emerging data for adverse outcomes in patients with Arg/Arg and use of SABAs, and possibly LABAs, prompted Wechsler et al.7 to examine the results of the SOCS (Salmeterol or Corticosteroid) and SLIC (Salmeterol ± Inhaled Corticosteroid) trials. Patients enrolled in these trials were stratified by polymorphism (Arg/Arg, n = 25; Gly/Gly,n = 48). Both trials reported worse asthma outcomes for salmeterol in the Arg/Arg compared with the Gly/Gly subjects. In the SOCS trial, when patients had milder asthma, their inhaled corticosteroids were withdrawn and replaced by salmeterol or placebo. During the treatment period, a significant decline in PEFRAM was detected when salmeterol was used alone in patients with Arg/Arg versus those with Gly/Gly. In the SLIC trial, salmeterol was added to inhaled corticosteroid therapy. Initially, patients with Arg/Arg appeared to benefit from the addition of salmeterol; however, by week 18, they had declines in PEFRAM when compared with patients with Gly/Gly. Likewise, patients with Arg/Arg had lower FEV1 (0.42 L; p = 0.003), greater symptom scores (0.2 units; p = 0.034), and increased use of albuterol rescue (0.95 puffs/day; p = 0.004). These results suggested that patients with Arg/Arg may have decreased therapeutic responses when LABAs replace or are used with an inhaled corticosteroid.
A cross-sectional survey tested the hypothesis that Arg/Arg polymorphism increases the likelihood of asthma exacerbations.8 Patients were children and young adults with asthma (age 10.2 ± 3.8 y, mean ± SD) who received salmeterol (LABA). The primary endpoint was asthma exacerbations 6 months prior to study entry. When patients with Arg/Arg were compared with those with Gly/Gly, increased asthma exacerbations across all asthma treatment steps (British Thoracic Society Asthma Guidelines) were reported (95% CI 1.19 to 3.53), with an increased hazard in patients receiving salmeterol (95% CI 1.19 to 9.40). It was concluded that Arg/Arg may predispose children and young adults to asthma exacerbations, primarily those receiving salmeterol.
Bleecker et al.13,14 published 2 reports on previously conducted trials that disputed the summarized LABA data. The first report included patients with persistent asthma who were receiving SABAs.13 The primary hypothesis was that no difference in clinical response existed for salmeterol with an inhaled corticosteroid in patients with Arg/Arg compared with other genotypes. Treatment with salmeterol/fluticasone provided significant improvement in all measures of asthma control regardless of patient genotype. Only 2 patients (1 Arg/Arg, 1 Arg/Gly) experienced asthma exacerbations requiring medications outside of the protocol. The authors concluded that clinical response to a LABA with concomitant inhaled corticosteroids is not affected by β2-adrenoreceptor genotype.
The second report included data from 2 studies that assessed the impact of LABAs on the frequency of severe asthma exacerbations and asthma control when patients were stratified by β2-adrenoreceptor genotype.14 The first study included asthmatics (n = 2250) who were at least 12 years of age and on prior inhaled corticosteroid therapy. Patients were excluded if they used more than 10 inhalations of a rescue inhaler daily or had experienced an asthma exacerbation during the 14-day run-in period. Patients were randomized to budesonide plus formoterol twice daily (budesonide plus formoterol for rescue), budesonide plus formoterol twice daily (tertbutaline for rescue), or fluticasone plus salmeterol twice daily (terbutaline for rescue). The primary endpoint was time to first severe asthma exacerbation. No significant difference was detected for the primary endpoint when patients with Gly/Gly were compared with those with Arg/Arg (p = 0.28). The second study included 405 patients with asthma who were managed with moderate dose inhaled corticosteroid or inhaled corticosteroid plus a LABA. Patients were randomized to adjustable dose budesonide plus formoterol twice daily, fixed-dose budesonide plus formoterol twice daily, or fixed-dose fluticasone plus salmeterol twice daily. All treatment groups used albuterol for primary rescue. The primary endpoint was asthma control. Similar asthma control was reported between genotypes; however, asthma exacerbations were reported in less than 10% of the study population. The authors concluded that pharmacogenetic effects do not impact therapeutic responses to LABAs when used with an inhaled corticosteroid.
Reasons for conflicting outcomes in the LABA studies exist. It has been reported that inhaled corticosteroids may affect the inflammatory mediators on the β2-adrenoreceptor and somehow minimize adverse effects.16,17 Also, β-agonist dosing was different. LABA exposure has been limited by dose and patient exclusion; therefore, it is not known how patients may respond to increased exposure to β-agonists.
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