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Rapid Responses to:
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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
What is the real use of Long-Acting ß-Agonists in aasthma ?
Effects of race and ICS use on outcomes
Author's response: Asthma-related death rate
Use of ICS with LABAs and CDC Statistics Regarding Asthma Mortality
Compliance with inhaled steroids for patients taking long-acting beta-agonists
Another Not So "SMART" Study
Should the African American Patient with Persistent Asthma be Treated Differently?
questions
What about anti-leukotrienes?
Dissapintment In Paper on Long Acting Bronchodilators
Lack of effectiveness of anticholinergics as controller medications in asthma
What about the severity of the disease and different types of long acting beta agonists?
Were all relevant trials included?
Untitled
Please check your statistics
Flawed analysis
Mortality related to LABA
Do inhaled steroids mitigate the deleterious effect of long acting beta agonists?
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DP VINCENT, MD,PhD CHU de Nîmes, Faculté de médecine de Montpellier-Nîmes, Place robert Debré, 30029 Nîmes cedex 9, France
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denis.vincent{at}chu-nimes.fr DP VINCENT, et al.
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I read with the greatest interest this article. It inspires me some comments. The rationale for Long-Acting ß-Agonists use in asthma is a sparing inhaled corticosteroid dose, because of the hypothesis of side effects. In a recent review of international bibliography (KOHLER-PARIS A, PEYRIERE H, VINCENT D. [Inhaled corticoids and systemic secondary effects: controversies] Allerg Immunol (Paris). 2002 Nov;34(9):333-6) we observed that almost every study, but one, trying to demonstrate inhaled corticosteroid side effect was mixing patients treated with inhaled corticosteroid and those treated with both systemic and inhaled corticosteroid. Since posologies are not on the same scale, differing for at least 1000 in terms of blood concentration, is this possible to compare these two classes of drugs ? We do not believe it. Demonstration of inhaled corticosteroid side effect is not done. Inhaled corticosteroids seem to be safe even with what is called high dose, up to 2000 microgramms of equivalent beclometasone. With this posology, are Long -Acting ß-Agonists still harmfull ? We certainly need some longitudinal study allowing us to follow patients treated only with high dose of inhaled corticosteroids in order to demonstrate the absence of side effects, but dysphonia (due to way of administration). This study should be performed with patients treated with high dose of inhaled corticosteroid in order to prevent exacerbations and then treatment with systemic corticosteroid. DP VINCENT, Md, PhD December 5, 2006 Conflict of Interest:None declared |
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Aaron B. Holley, MD Walter Reed Army Medical Center, Lisa K.Moores
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aaron.holley{at}NA.amedd.army.mil Aaron B. Holley, et al.
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The recently published SMART trial (1) raised important questions regarding long acting B-agonist (LABA) use for maintenance therapy in asthma patients. Sub-group analysis showed one of the primary outcomes, life-threatening experiences, was significantly increased in the African American population. Inhaled corticosteroid (ICS) use seemed to offer protection against any increase in mortality or adverse respiratory events. Drawing definitive conclusions from subgroup analysis is difficult, especially when sub-groups are not specifically pre-defined by the authors. Should physicians withhold B-agonist therapy from all patients or only from African Americans? Should this article change therapy at all for those who use B-agonist/ICS combination inhalers like Advair? The recent meta-analysis by Salpeter et al (2) published in the Annals of Internal Medicine concluded that LABA use is dangerous. The study was well done, but we feel the authors missed an important opportunity to address the issues of race and concomitant ICS use. Neither of these subgroups was defined a priori. The authors note in the results section that 15% of all patients were African American, but there is no race-specific analysis included. In the discussion the authors mention a sensitivity analysis conducted on trials in which > 75% of the participants used ICS (average 90%), with results showing a persistent, 2- fold increase in hospitalization rates. There is no listing of this data in the results section though, so readers are left wondering how many trials were contained in this analysis. LABAs have been shown to improve symptom control as determined by multiple different outcome measures (3), not just peak flows and FEV1 values as suggested in the conclusion of the meta-analysis and the accompanying editorial in the same issue of Annals. (4) A significant portion of the asthmatic population is young and active, and better control can have a profound impact on quality of life. If the increase in negative outcomes is specific to race, and if ICS is in fact protective, this information is important for asthma management. Before concluding that LABAs should be withdrawn from the market, could the authors expand on their data pertaining to race and ICS use, to include sensitivity analyses that assess for multiple outcomes with data expressed in tables and peto plots? This would help physicians at our institution make important treatment decisions. (1) Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129: 15-26. (2) Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting B-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144: 904-12. (3) Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, Pedersen PE, for the GOAL Investigators Group.Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med 2004; 170: 836–844. (4) Glassroth, J. The Role of Long-Acting B-Agonists in the Management of Asthma: Analysis, Meta-Analysis, and More Analysis. Ann Intern Med. 2006; 144: 9 Conflict of Interest:None declared |
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Shelley R Salpeter, MD Stanford University School of Medicine, Nicholas S. Buckley
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salpeter{at}stanford.edu Shelley R Salpeter, et al.
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Author's Response:
I have written a response to letters to the editor, which will be published in the Annals shortly. I will now comment on the figure showing asthma deaths in the United States, provided by Drs. Nelson and Dorinsky in their rapid response. It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonist (LABA). This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids (ICS) over time (1, 2). The figure below shows the yearly asthma death rate per 100,000 persons, along with the percentage of asthma patients prescribed short-acting beta-agonists (SABAs), LABAs, and ICS (3-6). In the recent past, ICS use has increased steadily while LABA use has begun to stabilize and SABA use has declined. The beta-agonist to ICS ratio is derived assuming that LABAs are associated with two times the mortality risk compared with SABAs. Using this estimate, we can imagine that if LABAs were withdrawn from the market while maintaining high ICS use, the death rate in the United States could be reduced significantly to less than one death per 100,000 persons, as was seen in New Zealand when the ratio of beta-agonist to ICS use was dramatically reduced (7).  References 1. Shelley M, Croft P, Chapman S, Pantin C. Is the quality of asthma prescribing, as measured by the general practice ratio of corticosteroid to bronchodilator, associated with asthma morbidity? J Clin Epidemiol. 2000;53(12):1217-21. 2. Sly RM. Changing asthma mortality and sales of inhaled bronchodilators and anti-asthmatic drugs. Ann Allergy. 1994;73(5):439-43. 3. Sly RM. Continuing decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol. 2004;92(3):313-8. 4. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma--United States, 1980-1999. MMWR Surveill Summ. 2002;51(1):1-13. 5. Stafford RS, Ma J, Finkelstein SN, Haver K, Cockburn I. National trends in asthma visits and asthma pharmacotherapy, 1978-2002. J Allergy Clin Immunol. 2003;111(4):729-35. 6. Hoyert DL, Heron MP, Murphy SL, Kung HC. Deaths: final data for 2003. Natl Vital Stat Rep. 2006;54(13):1-120. 7. Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol. 2001;107(6):937-44. Conflict of Interest:None declared |
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Harold S. Nelson, MD National Jewish Research and Medical Center, Paul Dorinsky MD
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nelsonh{at}njc.org Harold S. Nelson, et al.
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Dr. Salpeter and colleagues assert that concomitant use of inhaled corticosteroids (ICS) does not adequately protect against rare adverse events associated with long-acting beta2-agonist (LABA) use. However, this meta-analysis includes only studies for which patients were randomized to LABA or placebo and nearly 50% of patients were not receiving concomitant ICS. The authors attempt to control for this limitation by examining studies reporting concomitant ICS use in >75% of patients, but compliance with unblinded ICS use in those studies is unknown. In addition, in only one study were all patients reported to be using ICS in addition to study medications; therefore, this would be the only study that could potentially assess whether concomitant ICS impacted the outcomes. Had the authors wished to examine this fully, there are numerous studies in patients receiving ICS+LABA. In fact, a meta-analysis of 18 studies concluded that asthma-exacerbations were infrequent and similar comparing ICS+LABA with ICS alone (1). Furthermore, lower exacerbation rates have been reported in other meta-analyses (2,3,4) with ICS+LABA vs. double-dose ICS alone. A more recent, long-term study in >3,400 patients found that exacerbations and hospitalizations were significantly reduced in patients receiving ICS+LABA vs. ICS alone (5). These studies contributed to evidence-based guidelines supporting the use of ICS+LABA as the preferred treatment for patients symptomatic on low-dose ICS. The authors also assert that salmeterol may be responsible for 4,000 of the 5,000 asthma-related deaths that occur in the US annually. This ignores the fact that asthma deaths were greater than 5,000/yr when salmeterol was introduced in 1994. Since the peak of asthma deaths occurred in 1996, salmeterol sales have increased approximately 5-fold while overall asthma mortality has declined by approximately 25%, despite a continued increase in the total number of persons diagnosed with asthma. In fact, according to the most recent statistics of the National Center for Health Statistics (CDC), US asthma mortality peaked in 1996 at 5,667 deaths and has declined steadily since; the last available data, from 2004, indicates that there were 3,780 deaths. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts. Finally, we would like to provide additional information that may be of interest. SMART, which contributed nearly 80% of all patients in the Salpeter meta-analysis, per protocol did not specify collection of asthma- related hospitalizations as a primary or secondary outcome, nor are any additional data available to conduct such an analysis. However, all-cause hospitalizations were collected as a secondary outcome and there were no significant differences between salmeterol and placebo.
(1) Ni Chroinin M, Greenstone IR, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults. [Systematic Review] Cochrane Airways Group Cochrane Database of Systematic Reviews. August 2005; accessed June 16, 2006 (2) Matz J, Emmett A, Rickard K, et al. Addition of salmeterol to low- dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001;107(5 Suppl):783-789. (3) Shrewsbury SB, Pyke SD, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). Br Med J 2000;320:1368-1373. (4) Masoli M, Weatherall W, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 2005;60:730-34. (5) 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. Conflict of Interest: Harold S. Nelson, MD is a consultant for Altana, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, Schering-Plough and is a speaker for AstraZeneca, GlaxoSmithKline, Pfizer, Schering-Plough / Paul M. Dorinsky, MD is an employee of GlaxoSmithKline Conflict of Interest:Harold S. Nelson, MD is a consultant for Altana, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, Schering-Plough and is a speaker for AstraZeneca, GlaxoSmithKline, Pfizer, Schering-Plough / Paul M. Dorinsky, MD is an employee of GlaxoSmithKline |
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Donald D Peterson, M.D. Lankenau Hospital, Wynnewood, PA 19096, Lee W. Greenspon, M.D., Thomas J. Meyer, M.D., Susan A. Gregory, M.D., Catherine L. Kuntz, M.D.
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petersond{at}mlhs.org Donald D Peterson, et al.
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The recent meta-analysis by Salpeter et al1 concerning the possible relationship of long-acting beta-agonists to asthma exacerbations and asthma-related deaths heightens the concern of clinicians treating asthmatic patients that use of long-acting beta-agonists may be associated with a small, but significant, increase in sudden death, as well as an increase in severe exacerbations. Perhaps even more concerning is the contention that concomitant use of inhaled corticosteroids provided only partial protection. Unfortunately, the included trials did not rigorously evaluate compliance with inhaled corticosteroids, even in the slightly greater than 50% of patients prescribed inhaled corticosteroids. Non- compliance with inhaled corticosteroids is a well-documented problem in research studies, and is extremely familiar to the practicing clinician. Among the many factors are inconvenience and lack of perceived immediate effect. Therefore, the availability of fixed-dose combinations of fluticasone and salmeterol in a single inhaler was embraced by most clinicians as a partial solution to the general problem that patients frequently were non-compliant with inhaled corticosteroids. Also addressed is the specific concern that patients may increase their risk for sudden death and/or severe exacerbations by taking long-acting beta- agonists without the concurrently prescribed inhaled corticosteroids. Assessment of prescription refill records supports the contention of improved compliance with inhaled corticosteroids when using a fixed-dose combination with a long-acting beta-agonist2. Controlled trials of fixed combinations of long-acting beta-agonists and inhaled corticosteroids have shown uniformly favorable results in improving symptoms, pulmonary function, and decreasing severe exacerbations, without an apparent increase in deaths due to asthma. In fact, a recent study using budesonide/formoterol for both maintenance and for acute relief resulted in approximately 50% fewer severe exacerbations, as compared to patients treated with either budesonide or budesonide/formoterol for maintenance and terbutaline for acute relief, without an increase in side effects3. We believe that the apparent incomplete protection of inhaled corticosteroids against exacerbations of asthma associated with long- acting beta-agonists is simply due to medication non-compliance with inhaled corticosteroids. This hypothesis needs to be rigorously tested; if true, it would resolve the apparent conflict between the nearly uniformly favorable impression of clinicians and patients regarding fixed- dose combinations of salmeterol/fluticasone and the apparent finding of an increase in severe exacerbations and even deaths for patients taking long- acting beta-agonists. The suggestion by Salpeter et al1 that there should be a reassessment as to whether long-acting beta-agonists should be withdrawn from the market may be worth examining for the prescription of salmeterol or formoterol alone, since patient compliance with separate inhaled corticosteroid preparations cannot be assured. However, this suggestion is completely unwarranted and likely dangerous for fixed-dose combinations of long-acting beta-agonists/corticosteroids. Indeed, if salmeterol/fluticasone is withdrawn, we believe that, despite the best efforts on the part of clinicians, suboptimal compliance with inhaled corticosteroids is likely to result in a significant increase in asthma- related deaths. 1 Salpeter SR et al. Meta-analysis: Effect of long-acting beta- agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144:904-912. 2 Stempel DA et al. Adherence to asthma controller medication regimens. Respir Med. 2005;99:1263-1267. 3O’Byrne P et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Resp Crit Care Med 2005;171:129-136. Conflict of Interest:None declared |
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Peter Boggs, MD Clinical Professor Pediatrics and Medicine,, LSUHSC-Shreveport
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pboggs{at}ta2kg.org Peter Boggs
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1. This study is little more than a recitation of SMART, as the overwhelming majority of their data came from one study, the SMART study. It shares the same significant limitations. 2. Monotherapy with beta2-agonists for persistent asthma of any severity is not and has not been proper asthma treatment for decades. Salmeterol monotherapy (monotherapy with any LAB2-agonist) for asthma is not recommended by any guideline in the world nor is it considered acceptable therapy by any asthma organization for asthma. In the United States LAB2 agonist monotherapy regimens are not a part of the real-life daily management of asthma: they come to life only in clinical trials. Perhaps it is time to stop such high-risk studies. 3. Salmeterol monotherapy and the risks therein does not equate with the risks of treatment using a combination of salmeterol/fluticasone. Just cannot be said or implied. 4. The inappropriately named SMART study served no one well: patients with asthma or physicians who are trying to provide optimal care. The repercussions from the generalizations it invited are excessive and inappropriate. 5. The safety and efficacy of combined therapy using salmeterol and fluticasone (Advair) is well documented in the literature in adults and children. This fact has been lost in the reaction to the SMART study and within this study. 6. Restraint is needed in the execution of studies that have the potential to harm. Similar restraint is needed in the over-interpretation of the clinical meaning of such studies. That no responsible group recommends treating high-risk people with asthma the way the SMART study did does not seem to have been given its place in the sun. This fact should be respected and placed in proper context. It is one reason for the problems that resulted. 7. The black box warning regarding the use of LAB2 agonists extended to the combination product seems a gross overreaction to studies that do not mimic real life asthma care. I suggest that the actual data support that this warning belongs ONLY on studies or clinical circumstances in which salmeterol or formetorol are being considered as monotherapy. Generalizations to combined (LAB2/ICS)therapy are unwarranted. 8. A REVIEW article in the Annals should be held to a higher standard than was this article. Important information regarding the safety and efficacy of LAB2 agents when combined with inhaled corticosteroids was omitted or misinterpreted. The comment implying that 80% of the deaths from asthma might be due to salmeterol is unfounded and statistically improbable. Peter B. Boggs, M.D., FACP Clinical Professor Medicine & Pediatrics, LSUHSC-Shreveport The Asthma-Allergy Clinic and Research Center 850 Olive Shreveport, LA 71104 Conflict of Interest:None declared |
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Michael A. Lenoir, MD Chairperson, National Medical Associations, Asthma and Allergy Advisory Panel
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drlenoir{at}drlenoir.com Michael A. Lenoir
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The Asthma Advisory Panel of the National Medical Association, the oldest and largest organization of African American physicians, is concerned by the editorial written by Jeffrey Glassroth, MD, titled The Role of Long-Acting Beta-Agonist in the Management of Asthma: Analysis, Meta-analysis and More Analysis published in the Annals of Internal Medicine. The editorial was written as a response to the article in the same journal titled Meta-Analysis: Affect of Long-Acting Beta Agonist on Severe Asthma Exacerbations and Asthma Related Deaths authored by Shelley R. Saltpeter, MD. Dr. Glassroth suggested in his editorial that long-acting beta agonists alone or in combination with inhaled corticosteroids should be considered as a last resort in the treatment of African Americans with persistent asthma. Dr. Glassroth implies that African Americans should be considered differently from other patients when therapeutic decisions for the treatment of persistent asthma are considered by providers. While the data on polymorphisms at the beta receptor resulting in differing response to albuterol is important information, we believe that there has not been enough clinical or genetic research to justify unique therapeutic recommendations for the treatment of persistent asthma for African Americans. Presently, there is no definitive data on the affect of long-acting beta-agonist on phenotypes of the beta receptor in the African American patient or other ethnic groups. The recommendation that anticholinergic bronchodilators can be used as a substitute medication for albuterol in the treatment of persistent asthma has not been substantiated in the medical literature. Moreover, anticholinergic bronchodilators are not recommended for treatment of asthma in any ethnic group. Anticholinergic bronchodilators have not been studied in a representative sample of African Americans. UNFORTUNATELY NONE OF THE DRUGS USED TO TREAT PATIENTS WITH PERSISTENT ASTHMA HAS BEEN ADEQUATELY STUDIED IN AFRICAN AMERICANS. As the organization that represents African American physicians, we are acutely aware of the impact of asthma on the African American community. Decisions regarding the safety and effectiveness of medications for the treatment of persistent asthma must be guided by the best science available. In our view, therapeutic guidance for the treatment of African American patients with asthma based upon controversial data outside of established NHLBI Asthma Guidelines is unacceptable and could contribute to the already increased burden of asthma in the African-American community. Conflict of Interest:Speaker for GlaxoSmithKline |
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Mary Ann Petron, lpn vamc
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maryann.petron{at}med.va.gov Mary Ann Petron
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were subjects asked if they were smokers, previous or currently, live with smokers, or live in area with other factors present such as smog, etc.? Conflict of Interest:None declared |
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Graeme P Currie, MD Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, Scotland, UK
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graeme.currie{at}nhs.net Graeme P Currie
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Dear Editor, The meta-analysis by Salpeter et al raises concerns over the long term safety of long acting beta agonists in asthmatic patients.(1) However, the authors are incorrect in stating that "if long acting beta agonists were removed, the main treatment options for asthma would be inhaled cortisteroids and anti-cholinergic agents." Leukotriene receptor antagonists (LTRA) are advocated as suitable 2nd line controller therapy in persistent asthmatics already receiving inahled corticosteroids.(2, 3) Indeed, in terms of reducing exacerbation frequency, when compared to a long acting beta agonist, adding a LTRA has been shown to be as effective. Moreover, adding a LTRA would confer further beneficial effects upon attenuating inflammation and airway hyperresponsiveness.(4) Perhaps future guidelines may err on the side of caution and suggest that adding a LTRA is preferable over the addition of a long acting beta agonist in persistent asthmatics using inhaled corticosteroids. Yours sincerely, Graeme P Currie References 1) Salpeter et al. Effect of long acting beta-2 agonists on severe asthma exacerbations and asthma related deaths. Ann Intern Med 2006; 144: 904-912. 2) British guideline on the management of asthma. Thorax 2003;58 Suppl 1:i1-94. 3) GINA Workshop Report, Global Strategy for Asthma Management and Prevention - updated 2004. Scientific information and recommendations for asthma programs. NIH Publication No. 02-3659. 4) Currie GP, Lee DKC, Srivastava P. Long acting bronchodilator or leukotriene modifier as add-on therapy to inhaled corticosteroids in persistent asthma? Chest 2005 128: 2954-2962. Conflict of Interest:GPC has received funding from MSD and GSK for attending international conferences |
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David J Shulan, MD Certified Allergy and Asthma Consultants, David Shulan M.D.FACP , Michael Katlan M.D., Nancy Wade M.D. MPH, Scott Osur M.D, Mollie Shulan, M.D. FACP
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ragweed{at}msn.com David J Shulan, et al.
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We were disappointed by the recent article by Salpeter et al (1) on long acting bronchodilators (LAB).The paper provided us no new information regarding this pharmacologic class. There has been considerable data available suggesting that long acting bronchodilators used alone do not adequately treat asthma. The paper by Salpeter did not answer the more important question regarding the safety of long acting bronchodilators combined with inhaled corticosteroids steroids (ICS). The article questioned the validity of the reduction of exacerbation rates with when LABs and ICS are used in combination. There is, however, considerable data to support such a reduction in exacerbation rates when a variety of long acting bronchodilators are combined with differing inhaled steroids (2,3).
The purpose of a meta-analysis is that by combining the data from similar studies, one can determine associations with statistical validity that might otherwise not be possible. Although the Salpeter study combines data from 19 clinical studies, over three quarters of its data pool is gathered from one study (SMART), thereby reducing the value of the meta-analysis (4). Therefore the results of the meta-analysis essentially reiterate the conclusions of the previously published SMART article. The recommendation was made in the article by Salpeter to add anti-cholinergic agents in place of LABs in the treatment of asthma uncontrolled by an ICS alone. This strategy while useful in COPD and in acute asthma exacerbations, has been shown to be not as effective as LABs for chronic asthma (5,6).
Current data from the CDC (Center for Disease Control) actually has shown a decrease in asthma death rates for asthma since 1998 not an increase (7). This positive trend has occurred contemporaneously with the introduction of LABs in the United States. We fear following the author’s recommendations to delete LABs from our asthma armamentarium could result in increased asthma morbidity and mortality. We have seen patients in our own practice experience significant asthma exacerbations when they were taken off combination LABs and ICS because of fear of LAB associated adverse events. Certainly there are questions that remain to be fully answered regarding the safety of LABs and individual variability in response to such agents. Further study and judicious usage of LABs in clinical practice is warranted and these agents certainly should be reserved for moderate and severe asthma as recommended in the most recent NHLBI Guidelines 8. However, to remove LABs from clinical usage at this time would be unjustified and unwise.
David Shulan M.D.FACP , Michael Katlan M.D., Nancy Wade M.D. MPH, Scott Osur M.D, Mollie Shulan, M.D. FACP
References:
1. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of
long-acting Beta-agonists on severe asthma exacerbations and asthma-related deaths.
Ann Intern Med. 2006;144:904-12.
2. Bateman ED, et al Can Guideline –defined Asthma Control be Achieved? Am J Respir Crit care Med 2004, 170; 836-844.
3. Tatersfield AE et al. Exacerbations of Asthma: a descriptive study of 425 severe exacerbation. The FACET International Study Group. Am J Respir Crit care Med 1999 160; 594-9
4. Nelson HS et al The Salmeteral Multicenter Asthma Research Trial. Chest 2006; 129:15-26
5. Ullah MI, Newman GB, Saunders KB: Influence of age on response to ipratropium and salbutamol in asthma, Thorax 36:523-529, 1981
6. Rodrigo G, Rodrigo C, Burschtin O: A meta-analysis of the effects of ipratropium bromide in adults with acute asthma, Am J Med 107:363-370, 1999
7. CDC Data on Asthma mortality 1979-200
8. Updates The NEAPP Expert Panel Report 2 NIH Publications No. 97-4051 June 2002.
Conflict of Interest:I have been on Glaxo's Speaker bearuea in the past but I have not been in the last 5 years |
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Stuart W. Stoloff, MD University of Nevada School of Medicine
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drstoloff{at}sbcglobal.net Stuart W. Stoloff
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The citations listed by Salpeter to support her recommendations for use of anticholinergic agents in both acute asthma exacerbations and as an acceptable treatment for chronic asthma are,in fact,quoted inaccurately. The Rodrigo and Rodriguez meta-analysis in Thorax 2005 clearly state that " inhaled anticholinergic agents combined with B2-agoinsts lead to a reduction in admission rates of both children and adults of 30%." There are no published papers supporting anticholinergics as mono-therapy in acute asthma. In addition, only in patients with moderate to severe obstruction was there benefit in the addition of anticholinergics to B2- agoints. The Westby et al Cochrane Database Syst Rev 2004 did not identify any justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma was not well controlled on standard therapy. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with persistent asthma and there are no randomized controlled trials supporting this therapy. Taken together,these papers in fact do not support Dr. Salpeter's comments recommending the routine use of anticholinergics in either short-term therapy for acute exacerbations nor as add-on therapy in chronic asthma. Inhaled anticholinergic agents do have a bronchodilatory effect in patients with asthma but in both clinical and physiological terms this effect is small. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta- analysis. Thorax 2005;60:74-6. Westby M,Benson M, Gibson P. Anticholinergic agents for chronic asthm in adults. Cochrane Database Syst Rev. 2004. Conflict of Interest:None declared |
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Jeevan P Marasinghe Registrar in Obstetrics and Gynaecology,Teaching Hospital ,Peradeniya,Sri Lanka, Amarasinghe A.A.W. MD, Mcdonough, Georgia, USA
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jeevanmarasinghe{at}yahoo.com Jeevan P Marasinghe, et al.
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We are indebt to Shelley R et al(1) for such an excellent analysis of adverse effects of long acting beta agonists in treatment of asthma. The results are severe enough to curtail the widespread, unnecessary use of long acting beta agonists in treating asthmatics. But one of the drawbacks of the Meta analysis was that Shelley R and the colleges haven’t mentioned about the severity of asthmatics that had been recruited for the studies such as mild, moderate and severe persistent asthma. Patients with mild to moderate asthma may well do with a long acting agent such as salmeterol as compared to a severe persistent asthmatic who might have to adhere to inhaled or systemic corticosteroid in addition to beta agonist agents. This seems to be a major confounding factor and details about the process of randomization hasn’t been mentioned with regard to severity of the disease. The Meta analysis doesn’t provide substantial information about risks for hospitalization, life threatening asthma exacerbation and asthma related deaths in relation to the type of long acting beta agonist .But formeterol proves to be a better option than terbutaline(2) in asthmatics requiring moderate doses of relief medication despite inhaled corticosteroids. Addition of formeterol to inhaled corticosteroid regimen was found to be effective in improving symptoms and decreasing the use of rescue beta two agonists(3).But there found to no significant difference between salmeterol and formeterol in improving peak expiratory flow rates in patients with severe asthma. The effect seems to be different in different types of long acting beta agonists(4). An additional note on the severity of asthmatics in the study populations and the severity of harm caused each long acting beta agonist would have made the Meta analysis an exquisite product. References. 1. Shelley R.Meta analysis: effecet of long acting beta agonist on severe asthma exacerbations and asthma related deaths.Annal of internal medicine 20 June 2006; 144(12):904-12. 2. Tattersfield AE et al Comparison of formeterol and terbuteline for as needed treatment of asthma: a randomized trial. Lancet 2001 Jan 27; 357(9252):257-61. 3. Van Der Molen T Effects of long acting beta agonist formeterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian formeterol study investigators. Thorax 1997 Jun; 52(6):535-9. 4. Nightingale JA et al .Comparison of the effects of salmeterol and formeterol in patients with severe asthma. Chest 2002 May; 121(5):1401-6. Conflict of Interest:None declared |
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Mats Jacob Lindberg, MD, MHA Institute for Rational Pharmacotherapy, Copenhagen, Denmark
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mli{at}dadlnet.dk Mats Jacob Lindberg
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The metaanalysis by Salpeter et al. is interesting and important. My first concern is about the trial inclusion in the primary analysis. I have found two trials, that I think should have been included. The trials are: Pauwels RA et al. N Engl J Med 1997;337:1405-11. Woolcock A et al. Am J Respir Crit Care Med 1996;153:1481-8. Can Salpeter et al. explain why these trials were not included in the primary analysis? My second concern is the note in the discussion about separate evaluation of trials in which more than 75% of participants were receiving concomitant inhaled corticosteroids. This analysis should be published in detail, including a discussion of patient adherence to inhaled corticosteroid therapy in the included trials. Conflict of Interest:None declared |
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Matthew L Mintz, MD The George Washington University School of Medicine
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mmintz{at}mfa.gwu.edu Matthew L Mintz
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Dr. Salpeter's meta-analysis certainly contributes to the scientific debate on the safety of long-acting bronchodilators. However, in today's sensational media both authors and editors of medical journals must be extremely cautious regarding what is put into print. Dr. Salpeter's statements regarding asthma deaths in the discussion section is factually incorrect. Asthma deaths started increasing in the 1980's peaked in the mid 1990's has since declined. According to the CDC there were 5657 deaths from asthma in 1996 and 4261 in 2002. Since salmeterol was introduced in 1994, using the CDC data and evidence based guidelines which stat that LABA's in addition to inhaled corticosteroids are the preferred treatment for moderate to severe asthma, once could argue that LABA's may be responsible for the decline in asthma deaths. Though more evidence would be needed to support this statement, it certainly can not be true, as Dr. Salpeter claims, that LABA's are responsible for 4/5 asthma deaths. In addition, caution should be taken in extrapolation to combinations of inhaled corticosteroids (ICS) since no subgroup analysis was performed on patients taking both inhaled steroids and LABA's(perhaps because data was not available). The SMART study, which comprises the majority of patients and all of the mortality data in Sapeter's meta-analysis did have a subgroup which showed that there was no difference in death rates from LABA's for those patients taking ICS. This suggests that ICS may be protective of any harmful effects caused by LABA's and was not mentioned as part of Dr. Sapleter's discussion. Though the article provides some evidence that caution may be warranted, particularly when LABA's are used as monotherapy, the media quickly focused on the dangers of Advair (fluticasone propionate/salmeterol), since it is a commonly prescribed asthma drug. Marc Kaufman wrote in The Washington Post (Tuesday, June 6, 2006; Page A07) that, “Advair may be responsible for as many as 4,000 of the 5,000 asthma-related deaths each year in the United States.” Richard Knox's excerpt from the All Things Considered broadcast on June 9, 2006 from National Public Radio (NPR) stated that “Millions of people with asthma use inhalers, like Advair...studies suggest, however, that these drugs can sometimes make the underlying disease worse.” (http://www.npr.org/templates/story/story.php?storyId=5475125 retrieved 6/20/2006). Research and scientific discourse is to the benefit of our patients. However, in today's sensationalized media, authors must be careful in extrapolating data, as patients (and some physicians) may not be able to interpret that data on their own. Furthermore, reputable medical journals such as Annals have a responsibility to patients and physicians to ensure data that is printed is true, and that extrapolation of data is supported. Conflict of Interest:Speaker for GSK, Astra Zeneca, Pfizer |
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Sheldon L Spector, MD Clinical Professor, UCLA
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spector{at}calallergy.com Sheldon L Spector
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In the discussion section of the June 20, 2006 article by Salpeter PhD. et, al; there is a statement that “salmeterol may be responsible for approximately 4000 of the 5000 asthma related deaths that occur in the United States each year (91)”. Reference 91 refers to National Heart Lung Institute. I do not believe that this statistic is correct. It is my understanding that there are 4000-5000 asthma-related deaths per year. It is unlikely if not impossible for salmeterol to be responsible for all of them. Perhaps this is a typographical error. Conflict of Interest:None declared |
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Dermot Ryan, MB BCh BAO MRCGP University of Aberdeen
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dermotryan{at}doctors.org.uk Dermot Ryan
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The authors of this study appear to suggest that the cause for increased mortality from asthma is the use of long acting beta agonists (LABA). This class of medication became available in the UK in 1990 with the advent in salmeterol. Since that time asthma mortality has fallen from approximately 2000 deaths per annum to 1300 against a context of increased prevalence of asthma. It is of note that the advice in the UK is not to prescribe LABA without a concomitant prescription for inhaled corticosteroids, wheras in this metanalysis only 53% of patients in active or placebo treatment were recieving inhaled corticosteroids. Another contributing factor to explain increased mortality for asthma in the USA may well be structural. In the UK everyone has access to free health care wheras in the USA a large proportion of patients, largely from at risk groups do not. Inhaled corticosteroids are the mainstay of asthma control; the main reason for poor control is failure to take the medication ie poor compliance. For those patients who are compliant and who still have symptoms, both LABA and leukotriene receptor antagonists ( not mentioned by your authors) may provide improved symptom control. My fear is that this paper may persuade many physicians that the use of these excellent medications, when used in conjunction with appropriate doses of inhaled steroids, is dangerous, thus depriving those in need of a useful therapeutic option. Conflict of Interest:Ihave recieved sponsorship from, provided consultancy to and lectured on behalf of AstraZeneca, Altana, Boehringer,Pfizer, GSK,MSD,,Schering Plough,Novartis,Ivax,Trinity-Chiesi |
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Akin Ajayi, MD Orlando Ped Pulm & Sleep Assoc. PA
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sleep{at}oppsa.com Akin Ajayi
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The conclusions of your article are truly stunning. One that I do not understand fully is your assessment that about 4,000-5,000 deaths from asthma each year are very possibly related to long acting beta-agonist use. If that is the case then how many asthma deaths occur in people not on long acting beta-agonists?. From 1986-1999 the average number of reported asthma fatalities were between 3500 and 5000 per year (MMWR surveillance summaries, MARCH 29, 2002/51(SS01)PG1-13) and this was before combination ICS/LABA therapy became very popular. Am I then to conclude that it is your opinion that there would be almost no asthma fatalities in the United States if LABA were withdrawn from circulation? Since the basis of this artcle was not to evaluate efficacy or overall improvement in asthma management, lifestyle and morbidity I shall not delve into that topic. What do you assume would be the death rate from asthma if LABA did not exist? Have you taking old data and attempted to answer that question alongside your conclusions on the use of LABA? Conflict of Interest:Speaker bureau Sepracor Glaxo-smithkline |
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Jonathan Ilowite, MD Winthrop University Hospital
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jilowite{at}winthrop.org Jonathan Ilowite
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To the authors: I read with interest your study "Meta-Analysis: Effect of Long-Acting ß-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths". I have two concerns. The first concerns the comments on inhaled steroids in the discussion section of the paper, in which you note that the studies that investigated the use of inhaled steroids in addition to long acting beta agonists seemed to offer no additional protection over those that did not. There was no mention of this in the methods or results section of the paper. Was this an observation noted after the study was complete? If so, then it weakens the validity of the conclusion. Secondly, there was a recent, large, widely quoted study comparing fluticasone and the fluticasone/salmeterol combination product in achieving the goals of asthma therapy (Bateman ED et al. Am J Resp Crit Care Med 2004;170:836- 44). This study was apparently excluded from your analysis. I am curious as to the reason. Thank you for your attention. Conflict of Interest:Speaker Service and clinical research for Glaxo, Merck, Novartis, Genentech |
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