Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Errata
- Rod C Hall (21 March 2003)
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Outcome selection for meta-analysis
- Cathy M Jackson, Prof Brian J Lipworth (24 March 2003)
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Why glucocorticoids are better than leukotriene receptor antagonists
- G.N. Malavige (25 March 2003)
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Reply to Electronic Responses
- Francine M. Ducharme, 2300 Tupper Street, Montreal, Quebec, Canada, H3H 1P3 (15 April 2003)
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FURTHER ASSESSMENT OF THE EQUIVALENCE OF ANTI-LEUKOTRIENES AND ICS
- Peter G. Polos, S. Balachandra Dass, and Arlene S. Swern (30 May 2003)
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Reply to “Further assessment of the equivalency of anti-leukotrienes and ICS”
- Francine M. Ducharme (11 June 2003)
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Rod C Hall, Director Strategic Support AstraZeneca R&D Charnwood,LE11 5RH
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I note that all the doses quoted for the trials in this paper refer to mg. This surely should be microgram or a clarification that mg is the abbreviation for microgram Competing interests: Employee of AstraZeneca |
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Cathy M Jackson, Lecturer in primary care medicine Tayside centre for general practice,University of Dundee,DD1 9SY, Prof Brian J Lipworth
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The meta-analysis of Ducharme should be interpreted with caution, due to the selection of the main outcome of exacerbations requiring systemic steroids, since none of the individual trials was powered on this outcome. Moreover no distinction was made between asthma of mild or moderate severity. A previous meta analysis has shown montelukast as monotherapy to be superior to placebo on a variety of outcomes in mild persistent asthma (1). In a trial comparing montelukast 10mg and beclomethasone 400ug, there was 98% overlap in the distribution of asthma control days, with no difference in the number of asthma attacks and corticosteroid rescue (2). Thus, patients who do not respond to one agent should be tried on the other .To make recommendations about superiority with one agent over another on the basis of mean response, does not take into account the considerable interindividual variability in response to both agents, which is important in real life clinical decision making. For patients who are steroid phobic, or where compliance with twice daily therapy or inhaler technique is a potential problem, a once daily tablet is an attractive option, and should not be dismissed. Another relevant factor in choosing first line preventer therapy for atopic patients is that montelukast is effective and licensed (in the USA) for allergic rhinitis (3) ,which may be relevant ,since there is common co-morbidity with asthma. Pointedly no assessment was made of any inflammatory related outcomes. For example in a randomised double blind crossover study of mild persistent asthmatics, montelukast 10mg versus HFA-Triamcinolone 450ug daily via spacer were equally effective over 4 weeks in improving airway hyperresponiveness to adenosine and methacholine, the primary outcome variable (4). Thus, for patients with mild persistent asthma, especially those with concomitant allergic rhinitis, with poor inhaler technique and compliance, once daily montelukast may be a suitable option to inhaled corticosteroids. For moderate to severe asthma, inhaled corticosteroids are more appropriate first line therapy. References: [1] Barnes N,Wei LX,Reiss TF,et al .Analysis of montelukast in mild persistent asthmatic patients with near normal lung function. Respir Med 2001;95:379-86 [2] Israel E, Chervinsky P,Friedman B, et al .Effects of montleukast and beclomethasone on airway function and asthma control.J Allergy Clin Immunol 2002;110:847-54 [3] Van Adelsberg J, Philip G, Laforce C, et al . Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis.Annals Allergy Asthma Immunol 2003;90:214-212 [4] Dempsey OJ, Kennedy G, Lipworth BJ. Comparative efficacy and anti- inflammatory profile of once daily therapy with leukotriene antagonist or low dose inhaled corticosteroid in patients with mild persistent asthma .J Allergy Clin Immunol 2002; 109: 68-74. Competing interests: CMJ has stock holdings in GSK. BJL has received financial support for equipment,clinical trials,attending postgraduate meetings,giving educational posgraduate lectures ,from MSD,GSK,AstraZeneca,Schering Plough,3M Health Care,Innovata Biomed,UCB,Novartis. |
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G.N. Malavige, Lecturer in Microbiology Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayawardenapura,Sri Lanka
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Although leukotrienes play a substantial role in causing airway narrowing in asthma, there are many more immune mechanisms involved. For instance, there is considerable evidence to support a role for T cells in asthma, particularly the involvement of T(H)2 cells both in atopic allergic asthma and in nonatopic and occupational asthma 1. Several T(H)2 cytokines have the potential to modulate airway inflammation, particularly IL-13, which induces airway hyperresponsiveness independently of IgE and eosinophilia in animal models 1. Following allergic sensitization, T cells from atopic patients tend to produce elevated levels of Th2-type cytokines, especially interleukin (IL)-4, IL-13, IL-5 and IL-6, which induce and regulate IgE production and eosinophil airway infiltration 2. Controlled clinical trials have documented the efficacy of leukotriene receptor antagonists (LRA) in asthma treatment, but reservations about their use for asthma therapy center on two main issues: the heterogeneity of patient responses and their reduced potency relative to other asthma medications such as glucocorticoids 3. LRA have been shown to be less efficacious than inhaled corticosteroids for several end points, including symptom relief, reduced markers of inflammation, and improved pulmonary function 3. The difference could be attributed to the wide range in the clinical effects of the two groups of drugs. While the LRAs only counteract the effects of leucotrienes in asthma the glucocorticoids have a more wide range of action on eosinophils, T cells and other inflammatory cells. Therefore, the difference in the efficacy is to be expected. Reference: 1. Larche M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003 Mar;111(3):450-63 2. Hamelmann E, Gelfand EW. IL-5-induced airway eosinophilia--the key to asthma? Immunol Rev 2001 Feb;179:182-91 3. Peters SP. Leukotriene receptor antagonists in asthma therapy. J Allergy Clin Immunol 2003 Jan;111(1 Suppl):S62-70 Competing interests: None declared |
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Francine M. Ducharme, William Dawson Professor, Mcgill University Montreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, Canada, H3H 1P3
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Dear Dr Hall, Indeed, the doses of inhaled steroids were incorrectly referred to as milligram (mg) rather than microgram (mcg). Fortunately, the doses of anti-leukotrienes were correctly reported in milligram (mcg). Thank you for bringing it to my attention as well as that of the readers. Dear Dr. Jackson and Professor Lipworth, Thank you for taking the time to express your concerns. You expressed scepticism about the findings of this meta-analysis, primarily because of the following issues, which I will address point-by-point: (1)The selection of exacerbations requiring systemic steroids as main outcome when individual RCTs were not powered on this outcome. We chose the exacerbations requiring systemic steroids as our main outcome because it is clinically important to the patient, to the physician, and to the policy maker, as it usually requires an unscheduled contact with a health care provider. This outcome has a much greater impact than a given group difference in the forced expiratory volume in 1 second (FEV1). Proving equivalency between drugs requires thousands of patients because it entails ruling out a small but clinically important group difference. Published trials with a few hundred patients gave the clinicians a false perception of equivalency for this very reason. In fact, these trials were frequently insufficiently powered to detect a small, but clinically important, group difference in lung function, symptomatic days and nights, use of rescue beta2-agonists and exacerbations. By merging similar trials combining over 5000 patients, the meta-analysis gave the required power not only for exacerbations but also for other outcomes selected as primary outcomes in most trials. More specifically, the meta-analysis clearly shows that low doses of inhaled steroids were not only more effective than anti-leukotrienes for preventing exacerbations by 60%, but also for improving lung function by an additional 130 mL, reducing symptomatic days by an additional 9%, use of rescue-beta2-agonists, etc. (2)The distinction between mild and moderate asthma As detailed under the heading "source of heterogeneity", we explored the possibility of results being influenced by several factors, including asthma severity, the leukotriene receptor antagonist used, and the inhaled glucocorticoids preparation used. Although, the number of trials is relatively small, none of these factors appeared as important determinants of the magnitude of effect. (3)The demonstrated superiority of montelukast over placebo in a previous meta-analysis. There is no argument about montelukast or any other leukotriene receptor antagonists being superior then placebo… only that they are not superior or equivalent to low doses of inhaled steroids. (4)The considerable inter-individual variability in response to both agents Clinicians would love to accurately predict who will or will not respond to a particular treatment. There may, or may not, be inter- individual variability in the response to inhaled steroids and/or to leukotriene receptor antagonists. I explored this possibility, looking for gender, age, atopy, co-morbidity with allergic rhinitis, smoking status, etc, as possible important characteristics. Unfortunately, none of the publications and none of the contacted authors/pharmaceutical companies were able to provide me with subgroup analyses. Until these data become available, it remains impossible to confirm or infirm that any baseline characteristics can predict the magnitude of response to either drug. At this time however, one can comfortably say that, as a group, patients treated with low doses inhaled steroids would be better controlled than those treated with leukotriene receptor antagonists. (5) The beneficial effect of montelukast for treating patients with allergic rhinitis. With the concept of "the united airways", this possibility is indeed interesting. However, as displayed in Table 1, the proportion of atopic patients constituted the majority of patients enrolled in the trials; in 10 of the 13 trials, the proportion of atopic patients varied between 54% and 90%, while only two trials reporting atopy in less than half their patients (45% Bleecker and al: 32% in Busse et al) – unreported % in the last trial. Despite the high proportion of atopic patients, inhaled steroids remained more effective than anti-leukotrienes. Thank you for your challenging comments. Dear Dr.Malavige, Thank you for your thoughtful comments about the proposed rationale why anti-leukotrienes are less effective than inhaled steroids for asthma. Such insight is always welcome. Sincerely, Francine M. Ducharme Competing interests: The author has received travel support, research funds, and fees for speaking from AstraZeneca, Merck Frosst, and GlaxoSmithKline. |
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Peter G. Polos, Director, Clinical Development Merck & Co., Inc., Whitehouse Station, NJ 08889., S. Balachandra Dass, and Arlene S. Swern
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Physicians treating asthma are often confronted with inter-individual variability in patient response to therapy, relatively poor compliance to inhaled corticosteroids (ICS), and concerns over the pediatric safety of ICS. Studies using compounds that block leukotrienes (receptor antagonists and 5-lipooxygenase inhibitors) have demonstrated improvement in asthma control in pediatric and adult patients. However, not all anti-leukotriene agents approved for asthma are similar in their potency, tolerability and efficacy. Hence they should not be treated the same, as this review(1) does. Furthermore, the Laviolette study differed in its design from the other montelukast studies described in the review and hence may not be appropriate for inclusion in the analysis by Dr. Ducharme. Patients in this study were chronic ICS users and had been on ICS for 6 weeks or more before enrollment (in effect, pre-selecting/favoring ICS responders). This baseline condition does not allow for meaningful comparisons between monotherapy anti-inflammatory agents. During run-in, patients were on 400 microgram beclomethasone. Following randomization, the ICS arm continued to receive beclomethasone, while the montelukast arm was created by adding montelukast and removing (by 4 weeks) beclomethasone. This destabilization in the montelukast arm made both arms methodologically non -comparable and precluded comparison with other studies. Our reanalysis without Laviolette results in a relative risk of 1.27 (95% CI 0.98, 1.65) and an absolute risk difference of 0.02 (-0.0014, 0.04) for asthma exacerbation, reflecting a statistically insignificant difference in treatment effect between montelukast and ICS. Sensitivity analyses including tests for heterogeneity confirmed that the Laviolette study was a statistical outlier (and the only outlier) among the montelukast data analyzed. (1)Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence. BMJ 2003, 326:621. Competing interests: Authors are employees of Merck & Co., Inc. |
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Francine M. Ducharme, Associate Professor McGill University Health Centre, Montreal, Quebec, Canada, H3H 1P3
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Dear Dr Polos, You expressed concerns about several interesting issues. First, you mentioned the inter-individual variability in therapeutic response, adherence to treatment, and anti-leukotriene agents used. Unfortunately, trials reported pooled, not subgroup, data; reporting did not allow investigation of the potential differences in response due to various patients’ characteristics. There are also no head-to-head comparison of montelukast and zafirlukast. However, the difference in efficacy between anti-leukotrienes was explored with the residual chi squared test for heterogeneity: no significant difference between agents was observed (chi-squared=1.86, df=1, p>0.10). Although the power of this test will be increased with new trials, at present, there is no evidence to substantiate an important difference in efficacy between anti-leukotrienes. A second concern pertains to the fact that including patients already on inhaled glucocorticoids may have selected “responders” to inhaled glucocorticoids, such as perhaps in Laviolette’s study.(1) Although the treatment received during the short run-in period is fairly well described, the treatment received by participants prior to study entry is infrequently reported. This may indeed introduce an un-recognised systematic bias. Yet the bias may work in both directions, that is, non- responders to inhaled glucocorticoids may also be more willing to be randomized to anti-leukotrienes, possibly overestimating the beneficial effect of anti-leukotrienes. The best way to evaluate the possible direction of a selection bias is to report the non-participation rate among eligible approached patients. For example, the extension study “A” by Williams and collaborators(2) reported a 51% dropout from the primary study (testing beclomethasone vs. placebo. vs. montelukast), highlighting possible self-selection of only patients who believed they were responsive to the drugs tested in the extension study. Open label trials further increases the risk of selection bias, in that patients are more likely to participate in an open label trial if they believe they will respond to one of the tested agents and know they can drop out after the assignment is known. This may explain the discordant result of paediatric open-label extension study by Maspero and collaborators,(3) following a primary study of cromoglycate vs. montelukast. Therefore, selection bias of participants in randomized trials likely exists and may influence the direction of results: high refusal rate (at screening) and/or differential withdrawal rates (after randomization) are source of concerns. Reporting of trials should be improved to adequately describe these rates. Are the results of included trials biased by the selection of participants? A closer look at the included trials revealed 4 trials that clearly excluded patients with any intake of inhaled glucocorticoids in the preceding 1 month (4,5,6) or 2 months (7) prior to study entry. Conversely, 5 trials included the need for a daily controller (usually inhaled steroids) as pre-requisite for study enrolment. (1,3,8,9,10) The remaining 4 trials, reported mixed intake of controller (11) or failed to report any selection criteria on prior medication. (12,13,14) Restricting analyses to the 4 trials with “steroid-naïve” patients show a statistically significant increased risk of exacerbations requiring systemic steroids (RR=1.97, 95% CI: 1.08, 3.65) and of withdrawals because of poor asthma control (RR=1.99, 95% CI: 1.14, 3.45) in patients receiving anti-leukotrienes. Thus, the results of this meta-analysis appear robust to the patients' intake of medication prior to randomisation. I agree with your concern regarding selection bias; better reporting in randomized trials and in meta-analyses of randomized trials is clearly desired to adequately address this important issue. Sincerely, Francine M. Ducharme 1. Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999; 160(6):1862-1868. 2. Williams B, Noonan G, Reiss TF, et al. Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older. Clin Exp Allergy 2001; 31(6):845-854 3. Maspero JF, Duenas-Meza E, Volovitz B, et al. Oral montelukast versus inhaled beclomethasone in 6- to 11-year-old children with asthma: results of an open-label extension study evaluating long-term safety, satisfaction, and adherence with therapy. Curr Med Res Opin 2001; 17(2):96 -104 4. Busse W, Wolfe J, Storms W, et al. Fluticasone propionate compared with zafirlukast in controlling persistent asthma: a randomized double- blind, placebo-controlled trial. J Fam Pract 2001; 50(7):595-602 5.Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med 1999; 130(6):487-495 6. Korenblat P, Chervinsky P, Wenzel S, Faiferman I, Bakst A. Pranlukast (Ultair) reduce health care utilization and improves quality of life in adults patients with mild-to moderate asthma. Am J Respir Crit Care Med 1998;157:A411 7.Busse W, Raphael GD, Galant S, et al. Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: A randomized clinical trial. J Allergy Clin Immunol 2001; 107(3):461-468 8. Hughes GL, Edelman J, Turpin J, et al. Randomized, open-label pilot study comparing the effects of montelukast sodium tablets, fluticasone aerosol inhaler, and budesonide dry powder inhaler on asthma control in mild asthmatics. Merck Research Laboratories 1999. 9. Kim KT, Ginchansky EJ, Friedman BF, et al. Fluticasone propionate versus zafirlukast: effect in patients previously receiving inhaled corticosteroid therapy. Ann Allergy Asthma Immunol 2000; 85(5):398-406 10. Skalky CS, Edelman J, Polis A, Bird S, Gormley C, Israel E. Montelukast sodium (MK) compared to inhaled beclomethasone dipropionate (BD) in adults asthmatics: a randomized clinical trial. J Allergy Clin Immunol 1999;103(1 part 2);S228. 11. Laitinen LA, Naya IP, Binks S, Harris A. Comparative efficacy of zafirlukast & low dose steroids in asthmatics on prn beta2-agonists. Eur Respir J 1997; 10: 419-420 12. Baumgartner RA, Polis A, Angner R, Bird S, Reiss TF. Comparison between montelukast and inhaled beclomethasone therapy in chronic asthma: a double-blind, placebo-controlled, parallel study in asthmatic patients. Merck Research Laboratories 1999. 13. Yamauchi K, Tanifuji Y, Pan LH, et al. Effects of pranlukast, a leukotriene receptor antagonist, on airway inflammation in mild asthmatics. J Asthma 2001; 38(1):51-57. 14.Yamauchi K, Tanifuji Y, Pan LH, et al. Effects of pranlukast, a leukotriene receptor antagonist, on airway inflammation in mild asthmatics. J Asthma 2001; 38(1):51-57. Competing interests: None declared |
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