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Rapid Responses: Rapid Responses published:
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Non-steroidal anti-inflammatory effects of leukotriene receptor antagonists
- Graeme P. Currie, Daniel K.C. Lee, Clinical Research Fellow, and Brian J. Lipworth, Professor of Allergy & Pulmonology (1 July 2002)
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An editorial step too far?
- Richard M Brown (7 July 2002)
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Anti-leukotriene modifying drugs in chronic persistent bronchial asthma
- Dr S K Agarwal (28 July 2002)
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Side effects of Antileukotrienes
- Atef B Michael (29 July 2002)
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Conclusions on review need caution
- Mike Thomas (29 July 2002)
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The headline might be misleading.
- Yuji Oba (28 August 2002)
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responses to 4 electronic responses
- Francine M. Ducharme (11 October 2002)
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anti-leukotrienes and churg-strauss syndrome
- dr.manan vasenwala (26 July 2003)
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Graeme P. Currie, Clinical Research Fellow Asthma & Allergy Research Group, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland, UK, Daniel K.C. Lee, Clinical Research Fellow, and Brian J. Lipworth, Professor of Allergy & Pulmonology
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Sir, The systematic review by Ducharme makes a credible attempt in the evaluation of add-on effects of leukotriene receptor antagonists (LTRAs) in patients receiving inhaled corticosteroids (ICS)(1) Apart from on exacerbations, there is a paucity of data on inflammatory markers which may have inadvertently resulted in missing potentially therapeutic benefits effects of LTRAs. Since there is a relatively a shallow dose- response curve for efficacy of ICS on conventional outcomes of asthma control(2), it may not be surprising that the signal with add-on therapy with LTRAs is relatively modest. There is however considerable data supporting the anti-inflammatory activity of LTRAs as add-on to ICS. This has been shown for effects on airway hyperresponsiveness (AHR), eosinophils and exhaled nitric oxide(3- 6). In particular, for effects on AHR a recent meta-analysis showed a significant overall estimated improvement, amounting to 0.85 (95% CI 0.69- 1.02) doubling dose which was equally evident in patients irrespective of therapy with concomitant ICS(7). As with any systematic review and meta-analysis, the outcome will always be determined by the quality of the data and sensitivity of the outcome measures. A more recent multi-centre trial of 858 patients not controlled on budesonide 800µg/day, revealed significant and comparable improvements on exacerbations, lung function and peripheral blood eosinophils when comparing 3 months of randomised treatment with budesonide 800µg/day plus montelukast versus budesonide 1600µg/day alone(8). This, along with data on surrogate inflammatory markers, clearly demonstrates that LTRAs exhibit a clinically significant degree of non- steroidal anti-inflammatory therapy. References: 1. Ducharme FM. Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ 2002;324:1545. 2. Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose- response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253. 3. Lipworth BJ, Dempsey OJ, Aziz I, Wilson AM. Effects of adding a leukotriene antagonist or a long-acting beta(2)- agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype. Am J Med 2000;109:114-21. 4. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001;119:1021-6. 5. Dempsey OJ, Fowler SJ, Wilson AM, Kennedy G, Lipworth BJ. Effects of adding either a leukotriene receptor antagonist or low dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Chest 2002; (In press). 6. Sims EJ, Lipworth BJ. Sustained bronchoprotection with montelukast but not formoterol as add-on therapy in asthmatics with the homozygous glycine 16 B2 adrenoceptor genotype. J Allergy Clin Immunol 2002;109 (part 2): S157. 7. Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene receptor antagonists in asthma: a meta-analysis. Chest 2002; (In press). 8. Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, et al. Adding montelukast is at least as efficacious as doubling the budesonide dose in persistent asthma: results of the compact study. Am J Resp Crit Care Med 2002;165:A216. Conflicts of interest: The Asthma and Allergy Research Group has previously received support from MSD (who make montelukast) for performing clinical trials and attending postgraduate educational meetings. |
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Richard M Brown, General Practitioner Wilton Health Centre, Market Place, Wilton, SP2 0DS
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Editor, The headline 'Anti-leukotrienes do not benefit asthma' appeared in the 'This week in the BMJ' page on 29.6.2002. Is this editorial license taken a step too far? The paper to which this headline referred, a systematic review by Ducharme(1), concludes that 'addition of licensed doses of anti- leukotrienes(LTRAs) to inhaled steroids may modestly improve the control of asthma'. Furthermore, she adds that 'in well controlled patients additon of LTRAs is possibly associated with superior control after steroid sparing'. Currie et al in their rapid response of 1/7/2002 provide further evidence to demonstrate benefit to asthmatic patients given LTRAs in additin to inhaled steroids. Lastly, personal experience of patients responses to treatment with LTRAs in the general practice setting, though not in controlled trials, indicates that many patients receive benefit, some substantial, from addition of LTRAs to their management. In the face of this evidence, is it possible to justify a headline stating that 'LTRAs do not benefit asthma'? Might this headline lead some colleagues to draw an incorrect conclusion and deny their patients access to potentially helpful medication? Perhaps the headline writer might consider publishing a correction. References: 1. Ducharme F. Anti-leukotrienes as add-on therapy to inhaled gluco- corticoids in patients with asthma: systematic review of current evidence. BMJ 2002;324:1545-1548 2. Price DB, Hernandez D, Magyar P, Fiferman J, Beehn M, James IG. Adding Montelukast is at least as efficacious as doubling the Budesonide dose in persistent asthma. Am J Crit Care Med 2002;165:A216 Competing interests: RMB has received fees for speaking at meetings, and a travel grant, from MSD, who make Montelukast. |
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Dr S K Agarwal, Head, Department of Chest Diseases, Institute of Medical Sciences, BHU, Varanasi,India
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Inhalation of bronchodilators and corticosteroids is the mainstay of treatment for patients with asthma. Many inhaler devices and drug combinations are now available in India, and competing promotional claims confuse both prescribers and patients. The cost of the drug used in specific devices differs greatly. International guidelines are inconsistent in their recommendations for prescribing inhaler devices in different age groups. It’s strange that there are no National guidelines for the management of asthma by Indian doctors for Indian patients thus treating physicians are as confused as patients. Thus more and pharmaceutical companies are coming out with inhalers and other devices; some of them without any scientific rationale. Recently, pharmaceutical industries have launched leukotriene- modifying drugs without any definite clinical trial in Indian patients and after reading some conflicting reports about the efficacy of these drugs the Indian doctors have become more confused. I strongly feel that Indian patients should have been included in the multicentre, multinational, double-blind clinical trial to know the efficacy of new antiasthmatic drug.However,this drug I strongly feel should be effective as an antiinflammatory drog in chronic persistent bronchial asthma in about 40% of patients. Competing Interests: None |
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Atef B Michael, Specialist Registrar Birmingham Heartlands Hospital B9 5SS
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To the Editor Dear Sir, Dr F.M.Ducharme in his article, Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma, underestimates the adverse effects of anti-leukotrienes. While he mentioned some of the side effects of inhaled corticosteroids, he did not consider those of the anti- leukotrienes e.g. GI disturbances, hypersensitivity reactions including anaphylaxis, angioedema… He also did not mention the rare but serious possibility of developing Churg Strauss Syndrome. There are several reports of Churg Strauss Syndrome (CSS) associated with the use of Montelukast in the UK and Zafirlukast in the USA. Many potential mechanisms have been postulated. Doctors should monitor asthmatic patients who are started on Leukotrien Modifiers. The development of systemic symptoms (e.g. fever, worsening of pulmonary symptoms, rash, neuropathy and eosinophilia.) should prompt further investigations and Churg Strauss Syndrome has to be considered. References: (1) M.E.Wechsler et al, Leukotriene Modifiers and Churg Strauss Syndrome. Adverse effect or response to corticosteroid withdrawal? Drug safety 1999 Oct.21 (4) 241-251 (2)D’Cruz DP, Barnes NC, Lockwood CM. Difficult asthma or Churg –Strauss Syndrome? Steroids may be masking undiagnosed cases of Churg –Strauss Syndrome. BMJ 1999; 318:475-476. (3)Green R, Vayonis AG, Churg-Strauss Syndrome after Zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999; 353,725-726. (4)James FD, Montelukast and Churg –Strauss Syndrome. Chest 2001; 119:668. (5) F.M.Duchrame, Anti-Leukotrienes as add-on to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ 2002; 324:1545-1548. |
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Mike Thomas, GPIAG Clinical Research Fellow Dept of General Practice and Primary Care , University Aberdeen, AB25 2AY
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Editor The systematic review of anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma presented by Ducharme(1) illustrates the paucity of the current evidence in this area. Although the review concludes the addition of anti-leukotrienes to inhaled steroids cannot be recommended as a substitute for increasing the dose of inhaled corticosteroids, we feel that the grounds for this assertion are weak on two grounds. Firstly, when considering the primary outcome of the analysis, the reduction in risk of exacerbations requiring oral steroids, a marked trend towards improved outcomes with anti-leukotrienes was noted with an odds ratio of 0.61; as only two moderately sized eligible studies using licensed doses on anti-leukotrienes were identified, the confidence intervals were wide and just crossed the line of unity, so narrowly failing to reach statistical significance. The inclusion of two further smaller studies of higher than licensed doses of anti-leukotrienes further improved the odds ratio in favour of anti-leukotrienes and the result now did achieve statistical significance; this is of interest as there is evidence that the most commonly prescribed anti-leukotriene, montelukast, is licensed at the top of the dose-response curve and so is achieving maximum anti-leukotriene effects (2). Consistent trends to improvement with anti-leukotrienes were seen in all the other parameters of asthma control that were analysed. The number of subjects found for the direct comparison between anti-leukotrienes versus double dose of inhaled steroids was very low, but the analysis appears to indicate equivalence. Secondly, as asthma is a multi-faceted disease impacting on patient and health provider in many ways, it is important that efficacy assessments of alternative asthma interventions utilise a range of outcome measures to reflect this complexity, including symptoms, lung function, asthma related health status and health economic outcomes as well as exacerbations (3). Even when considering exacerbations alone as an outcome measure, there are many confounding factors including defining what constitutes an exacerbation and varying patient and clinician behaviour in response to worsening asthma control. Many of the studies considered in this review were not designed or powered to consider exacerbations as their main end- point, and as most were primarily powered to either look at symptom or lung function improvements, a stable baseline was required with exclusion of patients with recent exacerbations. In summary, we have concerns that as this study narrowly failed to show statistical significance in improving a single outcome measure of asthma control for anti-leukotrienes in licensed doses, it may be mis- interpreted by some as proving that anti-leukotrienes are ineffective. An analysis that is under-powered to show that an intervention is effective for a single outcome measure is very different from one proving that it is not an effective option in clinical practice. We believe the correct interpretation is that further evidence is needed in this area, and an adequately powdered randomised controlled study is needed to provide important information for a common clinical decision making scenario. Dr Mike Thomas, GPIAG Clinical Research Fellow Professor David Price, GPIAG Professor of Primary Care Respiratory Medicine Dept of General Practice and Primary Care University of Aberdeen Foresterhill Health Centre Westburn Road Aberdeen AB25 2AY Tel: 01224 554588 Fax: 01224 840683 1. Ducharme F. Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ2002;324:1545-51 2. Noonan MJ, Chervinsky P, Brandon M, Zhang J, Kundu S, McBurney J, Reiss TF. Eur Respir J 1998;11:1232-1239] 3. Barnes NC. Outcome measures in asthma. Thorax 2000;55(Suppl 1):S70-S74 |
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Yuji Oba, Assistant Professor of Medicine, Section of Respiratory and Critical Care Medicine University of Missouri-Kansas City, 64108
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To the Editor, I agree with Brown’s opinion in his electronic letter published on July 7, 2002 that the headline ‘ Anti-Leukotrienes do not benefit asthma’ might be misleading. Recent studies indicate that montelukast is a useful agent for treatment of exercise-induced asthma. (1,2) Compared with inhaled salmeterol, Montelukast provided more consistent inhibition of exercise- induced bronchoconstriction without tolerance. Antileukotriene therapy has also shown promise in the treatment and prevention of aspirin-induced asthma. (3,4) Ducharme’s systematic review (5) suggests very modest effects of anti- leukotrienes on asthma control and glucocorticoid sparing. But anti- leukotrienes may benefit certain subgroups of asthmatic patients. 1.Edelman, JM, Turpin, JA, Bronsky, EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Exercise Study Group. Ann Intern Med 2000; 132:97. 2.Villaran, C, O'Neill, SJ, Helbling, A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol 1999; 104:547. 3.Nasser, SM, Bell, GS, Foster, S, et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax 1994; 49:749. 4.Dahlen SE. Malmstrom K. Nizankowska E. Dahlen B. Kuna P. Kowalski M., et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. American Journal of Respiratory & Critical Care Medicine. 165(1):9-14, 2002 Jan 1. 5.Ducharme F. Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ 2002; 324:1545-51 |
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Francine M. Ducharme, Associate Professor of Pediatrics McGill University Health Centre, 2300 Tupper Street, Montreal, Quebec, H3H 1P3
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Non-steroidal anti-inflammatory effects of leukotriene receptor antagonists Dear Dr Currie, Dr Lee, and Professor Lipworth, There is indeed considerable data supporting the anti-inflammatory activity of LTRA as measured in provocation tests or inflammatory markers (e.g.: blood eosinophils, exhaled nitric oxide). However, our main concern, as clinicians, is whether this anti-inflammatory activity translates into clinical benefit to the patient. The current evidence suggests that the clinical effect is relatively modest. I am anxiously looking for the publication of the study by Price et al. to help quantify the magnitude of effect expected of adding LTRAs to inhaled steroids as compared to increasing the dose of inhaled steroids in poorly controlled asthmatics. There is only one available, yet unpublished, trial currently available. Due to the paucity of data, no conclusion can be drawn at this time regarding this treatment alternative. Of interest, a recently updated meta-analysis on LTRAs vs. ICS as single agents confirms that the corticosteroids-sparing effect of LTRAs is clearly less than 400mcg/day of CFC-beclomethasone-equivalent.* The magnitude of effect is supported by the results of the present meta- analysis as well. It is unlikely that the addition of this new trial would identify a greater effect than that observed in both meta-analyses. Until new data prove us wrong, the use of LTRAs as add-on therapy to inhaled steroids cannot be recommended as a substitute to increasing the dose of inhaled steroids, unless we expect the patient to achieve control with a modest increase in inhaled steroids (<400 mcg/day of beclomethasone-equivalent). Thank you for your comment. I look forward to updating the review with new trials. * Ducharme FM, Hicks GC. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma (Review). In: THE COCHRANE DATABASE SYST REV – The Cochrane Library 2000;(3), New update: 2002;(3): [CD002314] _______________________________________________________ Anti-leukotriene modifying drugs in chronic persistent asthma Dear Dr Agarwal: Thank you for your comments. It is indeed desirable that patients of all countries participate in randomised controlled trials, as there are instances where, due to different criteria, patient characteristics, environmental and/or genetic factors, the response to an agent may be different to what is observed elsewhere. Unfortunately, large multicentre trials do not report differences in response observed in individual countries, perhaps because of the relatively small number of patients originating from each country precluding analysis, perhaps because of marketing strategy, perhaps because of no difference, etc.. With regards to your perception of effectiveness, it is interesting to note that although some early trials of LTRAs have reported the proportion of so-called “responders”, none of the eligible trials have done the same. Thus, the results of individual and pooled trials pertain to the average response of individuals. There remains an unconfirmed possibility that some patients may respond dramatically better than the average. If this were the case, there is no indication at all as to the characteristics of responders. _________________________________________________ Side effects of antileukotrienes Dear Dr Michael: The side effects discussed in the systematic review pertain only to those systematically documented in individual trials and reported in their final report. Obviously, we have no data on non-reported adverse effects. Although pooling of data from trials is useful to quantify the risk of common side effects, a trial is an inappropriate design for quantifying the risk of RARE side effects. Rare side effects are best identified by post-marketing surveillance as for the Churg-Strauss syndrome and by case- control studies. Thus, as for any new drug, the risk of rare or long-term side effects associated with LTRAs remains unquantified. _______________________________________________________ Conclusions on review need caution Dear Dr. Thomas: The objectives of the systematic review are to present available evidence even if unsatisfying at this time. Clinicians must know whether there is firm evidence or not to prescribe a given drug. With regard to the effect of adding LTRAs to inhaled steroids or doing nothing (an alternative unlikely to be chosen by clinicians) for poorly controlled asthmatics, the effect of LTRAs on the prevention of exacerbations requiring systemic steroids is not statistically significant. In other words, there is more than 5% chance of obtaining such a result just by chance. New trials may decrease this chance to less than 5% in which case, a 40% reduction in exacerbations would indeed be clinically meaningful. New trials may also work in the opposite direction and establish this drug as not useful for preventing exacerbations: there is 95% chance that the true relative risk lies between a risk of 1.05 (in favour of placebo) to 0.36 (in favour of LTRA). Can we get a hint of future directions based on secondary outcomes? Sure, there is a significant group difference in favour of LRTA in two clinical outcomes, but the effect is not clinically important: a 7 L/min group difference in PEF and a reduction of 0.3 puffs/day of rescue ß2- agonists. There is no group difference observed in the change from baseline in FEV1. It is thus probably safe to conclude the addition of anti-leukotrienes to inhaled steroids may modestly increase asthma control as compared to placebo. But, who would chose the placebo (or rather status quo) for poorly controlled patients? Our alternatives would be to add-on LTRA or long- acting ß2-agonists or increase the dose of inhaled steroids. Comparing LTRA vs. long-acting ß2-agonists as add-on to inhaled steroids is the topic of another review. Currently, there is only one, still unpublished, trial comparing the addition of licensed doses of LTRA to inhaled steroids vs. increasing the dose of inhaled steroids. The results do not show equivalence; this would imply that, by our definition, the estimate and the confidence interval of the relative risk would lie between 0.9 and 1.1. The observed RR of moderate exacerbations (i.e.: requiring systemic steroids) is 2.3 with 95% CI of 0.61 to 8.73. This result do not show equivalence; if anything, the effect would favour increasing the dose of inhaled steroids by only 400-500 mcg/day. 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 group difference of 7 L/min in peak expiratory flow rate. Any practice variation in the prescription of systemic steroids does not bias the results, as it will be randomly distributed between groups; it only requires a greater sample size to display a significant group difference. Although trials were not powered to detect a group difference in exacerbations, pooling of data in a systematic review will eventually provide sufficient power to clarify the issue. At this time, where there is insufficient data to firmly conclude on the risk of exacerbations due to paucity of trials, one must try to predict the future based on the more sensitive secondary outcomes. Improvement in pulmonary function tests and reduction in use of rescue ß2-agonists are sufficiently modest to be perceived as non-clinically important. LTRA appears as only modestly better than placebo, but less effective than a low dose of beclomethasone- equivalent. The message is not to prevent physicians to use LTRAs, only to help them anticipate the magnitude of benefit to be derived from their use. Currently, the evidence suggests only a modest benefit. |
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dr.manan vasenwala, consultant-cardiologist k.k.heart center, aligarh-202002.india
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when severe asthmatics are treated with these agents, there is a dramatic control which leads to tapering of steroid. this can precipitate an underlying css. this may be incorrectly attributed as a side effect of anti-leukotrienes. ref: Difficult asthma or Churg-Strauss syndrome? David P D'Cruz, Neil C Barnes, and C Martin Lockwood BMJ 1999; 318: 475-476. [Full text] [PDF] Competing interests: None declared |
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