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ORIGINAL ARTICLE
Year : 2007  |  Volume : 2  |  Issue : 3  |  Page : 99-102
Blocking leukotrienes optimize asthma control: The BLOC survey


1 Riyadh Military Hospital, Riyadh, Saudi Arabia
2 King Saud bin Abdulaziz University for Health Sciences and King Abdulaziz Medical City, Riyadh, Saudi Arabia

Date of Submission12-Feb-2007
Date of Acceptance17-Jun-2007

Correspondence Address:
Majdy M Idrees
Riyadh Military Hospital, PO Box 7897 (Local C-110), Riyadh 11159
Saudi Arabia
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DOI: 10.4103/1817-1737.33696

PMID: 19727354

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   Abstract 

Objective: The aim of this study was to evaluate asthma control after the introduction of a leukotriene modifier (Montelukast), in addition to the current controller asthma therapies, in patients with inadequately controlled mild-to-moderate persistent asthma. Asthma control and patient perception were assessed prior to, and 4 weeks after, the introduction of Montelukast, and the pre-introduction and post-introduction results were compared.
Materials and Methods:
A cross-sectional, observational study collected information on 1,490 eligible adult asthmatic patients in Saudi Arabia. The eligibility criteria included patients aged 15 years or more with symptomatic mild-to-moderate persistent asthma despite treatment with inhaled corticosteroids with or without long-acting beta agonist; also, the patient should attend the initial visit and follow-up visits after at least 4 weeks.
Results: Of the 1,490 eligible patients, 79.5% received inhaled corticosteroids alone, and the remaining 20.5% received combination of inhaled corticosteroids and long-acting bronchodilator. Despite the treatment with daily controller medications, asthma symptoms persisted in more than two-thirds of the study population. Upon adding Montelukast, more than 80% of patients reported improvement in symptoms, which was consistent in all patients irrespective of corticosteroid type or dose (stratum) or the addition of long-acting β2-agonist. At the follow-up visit, 92.2% of patients reported that they felt better on Montelukast.
Conclusion:
Leukotriene modifier Montelukast has significant additive benefits in the management of patients who suffer from mild-to-moderate asthma and who are inadequately controlled on inhaled corticosteroids therapy with or without long-acting bronchodilator.


Keywords: Asthma, inflammation


How to cite this article:
Idrees MM, Al Moamary MS. Blocking leukotrienes optimize asthma control: The BLOC survey. Ann Thorac Med 2007;2:99-102

How to cite this URL:
Idrees MM, Al Moamary MS. Blocking leukotrienes optimize asthma control: The BLOC survey. Ann Thorac Med [serial online] 2007 [cited 2019 Dec 11];2:99-102. Available from: http://www.thoracicmedicine.org/text.asp?2007/2/3/99/33696


Asthma is a complex respiratory disorder characterized by reversible airflow obstruction and bronchial hyper-reactivity. [1] In recent years, the understanding of the mechanism underlying allergic asthma has grown, and this has resulted in complex paradigms to define the immunobiology of the disorder. [1] These paradigms conceive of asthma as a disorder with complex genetic and environmental interactions that affect the developing immune system and ultimately result in the episodic release of procontractile mediators, including leukotrienes and prostaglandins, causing susceptible individuals to wheeze. [2]

Not all asthmatics can be adequately controlled with high-dose inhaled corticosteroid (ICS) alone or in combination with long-acting bronchodilators (LABA). The Global Initiatives for Asthma (GINA) recommended leukotriene modifiers as add-on therapy in patients with uncontrolled moderate persistent asthma and also as alternative to long-acting bronchodilator in moderate persistent asthma. [1] This was further stratified by the newly released update from GINA in November 2006, where more evidence is available with respect to efficacy of leukotriene modifiers in patients with uncontrolled asthma. [2],[3],[4]

The objective of this observational cross-sectional survey was to evaluate asthma control and patient perception after the introduction of a leukotriene modifier, Montelukast, in addition to the current controller asthma therapies, in patients with inadequately controlled mild-to-moderate persistent asthma. Asthma control and patient perception were assessed prior to, and 4 weeks after, the introduction of Montelukast, and the pre-introduction and post-introduction results were compared.


   Materials and Methods Top


This observational, cross-sectional, prospective survey recruited asthmatic patients from the general practice setting in the major cities of the Kingdom of Saudi Arabia: Riyadh, Jeddah, Mecca, Medina, Dammam, Abha, Kamis Mushate, Jubail, Qasim, Yanbu and Jizan. The study was conducted in the period between December 2003 and July 2004. Recruited patients were above the age of 15, with mild-to-moderate persistent asthma, who were still uncontrolled despite ICS therapy at any dose with or without LABA. Patients were selected by physicians in the general practice setting, where both parties volunteered and were unpaid. Patients on Montelukast were excluded. It was mandatory for the patients to attend the initial first and second visits and complete the questionnaires in order to be eligible for the final analysis.

The patients were evaluated twice. At the first visit, the current asthma symptoms were recorded and described by (a) asthma-related difficulty in sleeping, (b) early morning awakening, (c) limitation of activities and (d) short-acting β2-agonist (SABA) use twice or more per week. Patients were informed about the cross-sectional survey objectives and the leukotriene modifiers as one of the recommended standard option for a patient with uncontrolled mild and moderate persistent asthma. [1] All patients were started on oral Montelukast 10 mg daily at the initial visit.

The second visit was scheduled at the discretion of the participants. However, it was recommended to be performed at least 4 weeks after the first visit. At the second visit, the patients were asked to fill in a report, commenting on the change of their symptoms (Less, Unchanged, More) in regard to (a) early morning awakening, (b) difficulty with sleep due to asthma, (c) limitations of activities due to asthma and (d) SABA use twice or more times a week. Patients were classified into three strata based on the dose of ICS: stratum I with ICS ≤400 g/day, stratum II with dose between 401 and 800 g/day and stratum III with dose ≥800 g/day.

' P ' value was calculated by Chi-square test. P value more than 0.05 was considered not significant. P value of less than 0.05 but more than 0.01 was rated as significant, 0.01 to 0.001 as highly significant and <0.001 as very highly significant.


   Results Top


Of the 1,687 patients recruited in the study, 1,490 patients (88.3%) were eligible and attended the second visit. [Table - 1] shows the demographic data of patients at the initial visit, their prescribed treatment and stratum based on ICS dose. [Table - 2] shows the symptoms reported by the patients at the initial visit with reference to the type of controller therapy. Patients on combined ICS and LABA reported less symptoms compared to ICS alone except for limitation of activities, where no significant difference was observed. The symptoms reported with reference to ICS type and strata are reported in [Table - 3].

At the second visit after adding Montelukast, 1,296 out of 1,490 (87%) patients reported improvement. The observed improvement was consistent for all symptoms addressed, i.e., early morning awakening, difficulty in sleeping, limitations of activities and SABA use twice or more times a week [Figure - 1]. [Figure - 1] also shows that the observed benefits by adding Montelukast were not significantly different, whether the patients were on ICS alone or on combination of ICS and LABA.

At the second visit after adding Montelukast, there was reported symptomatic improvement regardless of the type of ICS. The improvement was universal to all the reported symptoms by the patients [Figure - 2]. However, there was significant difference between Fluticasone and the other ICS when combined with Montelukast with respect to improvement in the symptom 'difficulty with sleep' ( P = 0.009). [Figure - 3] shows that the reported symptomatic improvement was consistent in all strata and ICS doses. There was less improvement in the symptom 'difficulty in sleeping' in patients of stratum 3 when Montelukast was combined with high dose of ICS ( P < 0.001).

When Montelukast was combined with ICS alone, 1,103 patients (93.2%) reported feeling better at the second visit, while 271 patients (88.4%) felt better after adding Montelukast to the combination of ICS and LABA ( P = 0.007). [Table - 4] shows that overall patient perception of improvement was consistent with reference to different types of ICS and strata.


   Discussion Top


Leukotrienes are considered to be important components in the treatment of asthma inflammation as some asthmatics cannot be controlled by other modalities like ICS and LABA. [2],[5] The cysteinyl leukotrienes (CysLT), LTC4, LTD4 and LTE4 have been shown to be essential mediators in asthma, making them obvious targets for therapy. These cysteinyl leukotrienes, previously known as the slow-reacting substance of anaphylaxis (SRS-A), mediate many of the features of asthma, including bronchial constriction, bronchial hyper-reactivity, edema and eosinophilia. [2],[5] Data show that selective cysteinyl leukotriene receptor antagonists (CysLTRAs) effectively reverse these pathologic changes. However, corticosteroids do not block the leukotriene-mediated pathway of inflammation. [2],[5],[6],[7] Corticosteroids do not inhibit the production of CysLTs in vivo, suggesting that CysLTRAs and corticosteroids affect different targets. The anti-inflammatory properties of CysLTRAs seem to be additive to those of β2-agonists and corticosteroids. [8],[9]

In our survey of 1,490 patients with persistent asthma symptoms despite regular use of ICS with or without LABA, Montelukast was added to the standard treatment as per GINA guidelines. [1] Of the patients having symptoms at the start of the study, adding Montelukast led to beneficial results, and the vast majority of patients reported improvement in sleep, less frequent early morning awakening, better ability to perform daily activities and decreased need for rescue medication, as well as improved quality of life.

The anti-inflammatory properties of Montelukast seem to be additive to those of ICS. The complementary benefits of Montelukast are due to blockade of the leukotriene pathway - key mediators in asthmatic inflammation that are not blocked by steroids. [5] Recent data has clearly shown that airways inflammation in asthma improved but persisted despite treatment with ICS or oral prednisolone. [10] Furthermore, treatment with ICS has no significant effect on the leukotrienes' inflammatory mediators in asthma. [2],[11],[12] It has been found that at least dual pathways of inflammation exist in asthma - the prostaglandin cytokines pathway and leukotrienes pathway. [13] Different clinical trials have shown the benefit of adding anti-leukotrienes to ICS, confirming the presence of dual pathways of inflammation. [14],[15],[16] All these data suggest that Montelukast is an important therapeutic agent in the management of uncontrolled asthma as an add-on therapy to ICS.

The results in our study were consistent with those of Malonne et al. in the nationwide Belgium ASTHMA survey among general practitioners (GPs) to evaluate the impact of Montelukast on the control of asthma symptoms, after at least 4 weeks of treatment. [2] Of the patients having symptoms at the start of the study, 87% reported amelioration in sleep while on Montelukast therapy; 80%, less frequent early morning awakening; 85%, better ability to perform daily activities; and 77%, decreased need for rescue medication. [2] Moreover, a recent multicenter study evaluated the effects of addition of Montelukast on patients with mild-to-moderate asthma with seasonal rhinitis who were maintained on ICS (alone or in combination with LABA). Upon completing 12 months of consecutive Montelukast, there was significant reduction in asthma attacks, asthma-related emergency visits, hospitalization and oral steroids use. [17]

Our study is an observational survey, and its results should be considered as such. The important limitation for all observational studies is the lack of control and blind randomization. In our study, we did not account for patient's adherence to therapy, the presence of comorbid conditions such as allergic rhinitis, gastroesophageal reflux or the presence of any occupational or environmental triggers. However, despite these limitations, the importance of observational data is the reflection of reality, far from the 'unreal' strict patients' monitoring that usually takes place in randomized controlled trials.

 
   References Top

1.Global Strategy for Asthma Management and Prevention. Global initiative for Asthma management (GINA) workshop report. NIH Publication No 02-3659; 2005 update. GINA reports are available at www.ginasthma.org  Back to cited text no. 1    
2.Malonne H, Lachman A, Van den Brande P. Impact of montelukast on symptoms in mild-to-moderate persistent asthma and exercise-induced asthma: Results of the ASTHMA survey. Adding Singulair Treatment to handle symptoms in mild to moderate asthmatics. Curr Med Res Opin 2002;18:512-9.  Back to cited text no. 2    
3.Bisgaard H. Role of Leukotrienes in asthma pathophysiology. Pediatr Pulmonol 2000;30:166-76.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Dupont L, Potvin E, Korn D, Lachman A, Dramaix M, Gusman J, et al . Improving asthma control in patients suboptimally controlled on inhaled steroids and long-acting beta2-agonists: Addition of montelukast in an open-label pilot study. Curr Med Res Opin 2005;21:863-9.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Devillier P, Baccard N, Advenier C. Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: An update. Part II: Clinical studies with leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma. Pharmacol Res 1999;40:15-29.  Back to cited text no. 5    
6.O'Shaughnessy K, Wellings R, Gillies B, Fuller RW. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis 1993;147:1472-6.  Back to cited text no. 6    
7.Dworski R, Fitzgerald GA, Oates JA, Sheller JR. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 1994;149:953-9.  Back to cited text no. 7  [PUBMED]  
8.Pavord I, Ward R, Woltmann G, Wardlaw AJ, Sheller JR, Dworski R. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 1999;160:1905-9.  Back to cited text no. 8    
9.Bisgaard H. Role of Leukotrienes in asthma pathophysiology. Pediatr Pulmonol 2000;30:166-76.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Luis R, Lau L, Bron A, Roldaan A, Radermeker M, Djukanovi R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000;161:9-16.  Back to cited text no. 10    
11.Pavord L, Ward R, Woltmann G, Wardlaw A, Sheller J, Dworski R. Induced sputum eicosanoid concentrations in asthma. Am J Resp Crit Care Med 1999;160:1905-9.  Back to cited text no. 11    
12.Price D, Ryan D, Pearce L, Bride F. The air study: Asthma in real life. Asthma J 1999;4:74-8.  Back to cited text no. 12    
13.Henderson W, Tang L, Chu S, Taso S, Chiang G, Jones F, et al . A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Resp Crit Care Med 2002;165:108-16.  Back to cited text no. 13    
14.Vaquerizo MJ, Casan P, Castillo J, Perpiρa M, Sanchis J, Sobradillo V, et al . Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma. Thorax 2003;58:204-11.   Back to cited text no. 14    
15.Bjermer L, Bisgaard H, Bousquet J, Fabbri A, Fabbri LM, Greening A, Haahtela T, et al . Montelukast or salmeterol combined with an inhaled steroid in adult asthma: Design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial. Respir Med 2000;94:612-21.  Back to cited text no. 15    
16.Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, et al . Randomized controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003;58:211-6.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Borderias L, Mincewicz G, Paggiaro P, Guilera M, Sazonov Kocevar V, Taylor SD, et al . Asthma control in patients with asthma and allergic rhinitis receiving add-on montelukast therapy for 12 months: A retrospective observational study. Curr Med Res Opin 2007;23:721-30.  Back to cited text no. 17    


    Figures

  [Figure - 1], [Figure - 2], [Figure - 3]
 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4]

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