Safety of Long-Acting Beta-Agonists
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The recommendation in the Perspective article by Martinez (Dec. 22 issue)1 of adding leukotriene modifiers or theophylline to therapy for asthma that is not controlled with the use of inhaled corticosteroids is completely opposite to that of the National Asthma Education and Prevention Program expert panel, which prefers the addition of long-acting beta-agonists.2 A Cochrane review showed that adding long-acting beta-agonists, instead of leukotriene modifiers, to the treatment of asthma not controlled by inhaled corticosteroids would prevent one exacerbation for every 38 patients treated.3 If only 25 percent (thought to be a large underestimate4) of the 19 million Americans with asthma5 have moderate-to-severe disease, then Martinez's recommendation would result in 125,000 excess exacerbations. No study has shown that the combination of inhaled corticosteroids and long-acting beta-agonists results in increased deaths from asthma, and the data from the Salmeterol Multicenter Asthma Research Trial (SMART) showed no increased risk of death from asthma with salmeterol, as compared with placebo, in patients taking inhaled corticosteroids.6 Overstating the risks of long-acting beta-agonists is irresponsible, because it may lead to the use by patients of suboptimal therapy, noncompliance with a regimen, or both. Reconciling the benefit with the potential harm of long-acting beta-agonists is simple: these drugs should not be used alone but, rather, should be added to therapy with inhaled corticosteroids for moderate-to-severe asthma, as recommended by current guidelines.
Matthew L. Mintz, M.D.
George Washington University School of Medicine
Washington, DC 20037
mmintz@mfa.gwu.edu
Dr. Mintz reports having served on advisory boards and speakers bureaus for AstraZeneca, GlaxoSmithKline, and Pfizer.
References
Martinez FD. Safety of long-acting beta-agonists -- an urgent need to clear the air. N Engl J Med 2005;353:2637-2639.
National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma — update on selected topics 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, June 2003. (NIH publication no. 02-5074.)
Ram FSF, Cates CJ, Ducharme FM. Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev 2005;1:CD003137-CD003137.
Fuhlbrigge AL, Adams RJ, Guilbert TW, et al. The burden of asthma in the United States: level and distribution are dependent on interpretation of the National Asthma Education and Prevention Program guidelines. Am J Respir Crit Care Med 2002;166:1044-1049.
National Center for Health Statistics. Current asthma population estimates, in thousands by age, United States: National Health Interview Survey, 2003. (Accessed February 23, 2006, at http://www.cdc.gov/asthma/NHIS/2003_table3-1.htm.)
Knobil K, Yancey S, Kral K, Rickard K. Salmeterol Multicenter Asthma Research Trial (SMART): results from an interim analysis. Chest 2003;124:335S-335S.
To the Editor: Martinez suggests that long-acting beta-agonists may contribute to deaths from asthma, but he fails to emphasize an important potential mechanism for this association. Long-acting beta-agonists cause patients with asthma to feel better. As a consequence, some patients may discontinue or reduce their use of inhaled corticosteroids, putting themselves at risk for increased airway inflammation and fatal asthma. The SMART study,1 an earlier salmeterol study,2 and the formoterol clinical trials3 cited by Martinez do not provide data to address this quite plausible behavioral effect of long-acting beta-agonists.
It is certainly possible that long-acting beta-agonists may adversely affect a subgroup of patients with asthma by direct pharmacologic mechanisms; however, it remains just as likely that an indirect behavioral mechanism underlies the observed association between the use of these agents and fatal asthma. Martinez's recommendation that asthma be treated with long-acting beta-agonists only when all other therapies fail does not appear to be justified at this time; however, it is prudent to limit the use of these agents in the treatment of asthma to combination products that include inhaled corticosteroids, whenever possible.
George T. O'Connor, M.D.
Boston University School of Medicine
Boston, MA 02118
goconnor@bu.edu
Dr. O'Connor reports having served as chairman of the data and safety monitoring board for the SMART study and having received consulting fees from GlaxoSmithKline, Astellas Pharma, and Wyeth.
References
GlaxoSmithKline. Safety of long-acting beta-agonist bronchodilators: Pulmonary-Allergy Drugs Advisory Committee Meeting, July 13, 2005. (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_01_01-GSK-Serevent.pdf.)
Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-1037.
Novartis. Drug regulatory affairs: Foradil Aerolizer (formoterol fumarate inhalation powder) 12 mcg. (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_02_01-Novartis-Foradil.pdf.)
Dr. Martinez replies: Dr. Mintz's arguments are based on a false premise: that the increased risk of severe side effects of long-acting beta-agonists does not occur in patients taking inhaled corticosteroids. A thorough analysis by the Food and Drug Administration concluded that the data from the SMART study do not allow any definitive conclusions with regard to this issue.1 What would be truly irresponsible would be to induce in physicians a false sense of security regarding the safety of long-acting beta-agonists when prescribed in combination with inhaled corticosteroids. Dr. Mintz also misquotes my recommendations, which are based on solid, recent evidence. In the Gaining Optimal Asthma Control (GOAL) study,2 40 to 50 percent of all patients with uncontrolled asthma achieved good control with moderate doses (500 μg per day) of fluticasone alone, with just 10 to 15 percent more patients achieving the same control with the addition of long-acting beta-agonists. Only among patients whose asthma was previously uncontrolled with high doses of inhaled corticosteroids was the continued use of these medicines alone predictably unsuccessful (20 percent had well-controlled asthma), and adding long-acting beta-agonists doubled the success rate.
Thus, when defining the severity of asthma, it seems reasonable to consider the degree of control achieved with the use of inhaled corticosteroids.3 In patients with mild-to-moderate asthma, as defined by good control (less-than-daily symptoms with the use of inhaled corticosteroids2), long-acting beta-agonists are unnecessary, and the addition of other medicines could be tried if further relief were needed. It is in patients who have more severe asthma (daily symptoms with the use of inhaled corticosteroids) that long-acting beta-agonists could be most beneficial and should be used. The GOAL study showed that patients whose asthma is not well controlled by high doses of inhaled corticosteroids are two to three times more likely to have exacerbations than those whose asthma is well controlled. This finding further justifies targeting such patients for the use of long-acting beta-agonists, as long as the patients are carefully monitored for the type of severe deterioration observed in the SMART study.
Dr. O'Connor's behavioral explanation is reasonable, but it is not supported by published evidence. Conversely, studies in animals4 and humans5 support the notion that genetically mediated, paradoxical bronchial obstruction or hyperresponsiveness may occur with long-term use of beta-agonists. Until the mechanisms for the uncommon but deleterious side effects of these agents have been elucidated or until the use of inhaled corticosteroids is convincingly shown to prevent these side effects, or both, long-acting beta-agonists should be used only in patients who really need them.
Fernando D. Martinez, M.D.
Arizona Respiratory Center
Tucson, AZ 85724
References
Salmeterol Postmarketing Study Review (SMART Study). (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_03_02-FDA-Smart-Study.pdf.)
Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-844.
British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guidelines on the management of asthma. Thorax 2003;58:Suppl 1:i1-i94.
McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox. J Clin Invest 2003;112:619-626.
Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505-1512.
Matthew L. Mintz, M.D.
George Washington University School of Medicine
Washington, DC 20037
mmintz@mfa.gwu.edu
Dr. Mintz reports having served on advisory boards and speakers bureaus for AstraZeneca, GlaxoSmithKline, and Pfizer.
References
Martinez FD. Safety of long-acting beta-agonists -- an urgent need to clear the air. N Engl J Med 2005;353:2637-2639.
National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma — update on selected topics 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, June 2003. (NIH publication no. 02-5074.)
Ram FSF, Cates CJ, Ducharme FM. Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev 2005;1:CD003137-CD003137.
Fuhlbrigge AL, Adams RJ, Guilbert TW, et al. The burden of asthma in the United States: level and distribution are dependent on interpretation of the National Asthma Education and Prevention Program guidelines. Am J Respir Crit Care Med 2002;166:1044-1049.
National Center for Health Statistics. Current asthma population estimates, in thousands by age, United States: National Health Interview Survey, 2003. (Accessed February 23, 2006, at http://www.cdc.gov/asthma/NHIS/2003_table3-1.htm.)
Knobil K, Yancey S, Kral K, Rickard K. Salmeterol Multicenter Asthma Research Trial (SMART): results from an interim analysis. Chest 2003;124:335S-335S.
To the Editor: Martinez suggests that long-acting beta-agonists may contribute to deaths from asthma, but he fails to emphasize an important potential mechanism for this association. Long-acting beta-agonists cause patients with asthma to feel better. As a consequence, some patients may discontinue or reduce their use of inhaled corticosteroids, putting themselves at risk for increased airway inflammation and fatal asthma. The SMART study,1 an earlier salmeterol study,2 and the formoterol clinical trials3 cited by Martinez do not provide data to address this quite plausible behavioral effect of long-acting beta-agonists.
It is certainly possible that long-acting beta-agonists may adversely affect a subgroup of patients with asthma by direct pharmacologic mechanisms; however, it remains just as likely that an indirect behavioral mechanism underlies the observed association between the use of these agents and fatal asthma. Martinez's recommendation that asthma be treated with long-acting beta-agonists only when all other therapies fail does not appear to be justified at this time; however, it is prudent to limit the use of these agents in the treatment of asthma to combination products that include inhaled corticosteroids, whenever possible.
George T. O'Connor, M.D.
Boston University School of Medicine
Boston, MA 02118
goconnor@bu.edu
Dr. O'Connor reports having served as chairman of the data and safety monitoring board for the SMART study and having received consulting fees from GlaxoSmithKline, Astellas Pharma, and Wyeth.
References
GlaxoSmithKline. Safety of long-acting beta-agonist bronchodilators: Pulmonary-Allergy Drugs Advisory Committee Meeting, July 13, 2005. (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_01_01-GSK-Serevent.pdf.)
Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-1037.
Novartis. Drug regulatory affairs: Foradil Aerolizer (formoterol fumarate inhalation powder) 12 mcg. (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_02_01-Novartis-Foradil.pdf.)
Dr. Martinez replies: Dr. Mintz's arguments are based on a false premise: that the increased risk of severe side effects of long-acting beta-agonists does not occur in patients taking inhaled corticosteroids. A thorough analysis by the Food and Drug Administration concluded that the data from the SMART study do not allow any definitive conclusions with regard to this issue.1 What would be truly irresponsible would be to induce in physicians a false sense of security regarding the safety of long-acting beta-agonists when prescribed in combination with inhaled corticosteroids. Dr. Mintz also misquotes my recommendations, which are based on solid, recent evidence. In the Gaining Optimal Asthma Control (GOAL) study,2 40 to 50 percent of all patients with uncontrolled asthma achieved good control with moderate doses (500 μg per day) of fluticasone alone, with just 10 to 15 percent more patients achieving the same control with the addition of long-acting beta-agonists. Only among patients whose asthma was previously uncontrolled with high doses of inhaled corticosteroids was the continued use of these medicines alone predictably unsuccessful (20 percent had well-controlled asthma), and adding long-acting beta-agonists doubled the success rate.
Thus, when defining the severity of asthma, it seems reasonable to consider the degree of control achieved with the use of inhaled corticosteroids.3 In patients with mild-to-moderate asthma, as defined by good control (less-than-daily symptoms with the use of inhaled corticosteroids2), long-acting beta-agonists are unnecessary, and the addition of other medicines could be tried if further relief were needed. It is in patients who have more severe asthma (daily symptoms with the use of inhaled corticosteroids) that long-acting beta-agonists could be most beneficial and should be used. The GOAL study showed that patients whose asthma is not well controlled by high doses of inhaled corticosteroids are two to three times more likely to have exacerbations than those whose asthma is well controlled. This finding further justifies targeting such patients for the use of long-acting beta-agonists, as long as the patients are carefully monitored for the type of severe deterioration observed in the SMART study.
Dr. O'Connor's behavioral explanation is reasonable, but it is not supported by published evidence. Conversely, studies in animals4 and humans5 support the notion that genetically mediated, paradoxical bronchial obstruction or hyperresponsiveness may occur with long-term use of beta-agonists. Until the mechanisms for the uncommon but deleterious side effects of these agents have been elucidated or until the use of inhaled corticosteroids is convincingly shown to prevent these side effects, or both, long-acting beta-agonists should be used only in patients who really need them.
Fernando D. Martinez, M.D.
Arizona Respiratory Center
Tucson, AZ 85724
References
Salmeterol Postmarketing Study Review (SMART Study). (Accessed February 23, 2006, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_03_02-FDA-Smart-Study.pdf.)
Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-844.
British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guidelines on the management of asthma. Thorax 2003;58:Suppl 1:i1-i94.
McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox. J Clin Invest 2003;112:619-626.
Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505-1512.