(Chest. 2002;122:146-150.)
© 2002
American College of Chest Physicians
Bronchoprotective Effects of Leukotriene Receptor Antagonists in Asthma*
A Meta-analysis
Graeme P. Currie, MBChB and
Brian J. Lipworth, MD
* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland.
Correspondence to: Brian J Lipworth, MD, Professor of Allergy and Pulmonology, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland; e-mail: b.j.lipworth{at}dundee.ac.uk
 |
Abstract
|
|---|
Study objective: Cysteinyl leukotrienes are important proinflammatory mediators in the pathogenesis of asthma. Since bronchial hyperresponsiveness is a noninvasive surrogate marker of asthmatic airway inflammation, we evaluated the bronchoprotection afforded by leukotriene receptor antagonists (LTRAs).
Design: Systematic review of randomized, placebo-controlled trials in which LTRAs were administered for 
5 days. Studies in which active drug was administered as a first-line or second-line therapy were used.
Setting: MEDLINE, BIDS, and Cochrane Library data registers.
Measurements: The doubling dose/dilution difference that caused a 20% fall in the FEV1 between LTRA and placebo.
Results: Thirteen trials (353 subjects) fulfilled eligibility criteria. Combining the results the overall weighted estimated protection amounted to a 0.85 doubling dose shift (95% confidence interval, 0.69 to 1.02).
Conclusion: Since the estimated protection amounted to almost one doubling dose, this reinforces the role of LTRAs as anti-inflammatory therapy in asthma.
Key Words: asthma • bronchial hyperreactivity • leukotriene receptor antagonist
|
Introduction
|
|---|
Asthma is characterized by airway inflammation that manifests as reversible airflow limitation and airway hyperresponsiveness. Consequently, anti-inflammatory therapy plays a pivotal role in its management. Cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma, while leukotriene receptor antagonists (LTRAs) demonstrate hybrid anti-inflammatory and bronchodilatory properties.1
A meta-analysis found that LTRAs reduced exacerbations by 50% and reduced the requirement of additional antiasthma therapy.2
Current international guidelines3
recommend using an LTRA as first-line therapy patients with mild, persistent asthma, or as second-line therapy in conjunction with inhaled corticosteroids, as an alternative to increasing the dose of inhaled corticosteroid.
Bronchial hyperresponsiveness or hyperreactivity is a noninvasive surrogate marker of airway inflammation, and is a reproducible method of assessing the efficacy of antiasthma therapy in the laboratory. We examined the bronchoprotection afforded by commonly used LTRAs, namely montelukast, pranlukast, and zafirlukast. A meta-analysis was performed that evaluated the protection given with LTRA compared to placebo during long-term dosing when used as first-line or second-line therapy.
|
Materials and Methods
|
|---|
A computerized MEDLINE, BIDS, and Cochrane Library literature search was carried out from 1992 to April 2001 to identify randomized, placebo-controlled trials in which bronchoprotection was assessed using montelukast, pranlukast, and zafirlukast. The following keywords were used in the search: "leukotriene receptor antagonist," "montelukast," "pranlukast," "zafirlukast," "histamine," "methacholine," "adenosine monophosphate," and "bronchial hyperresponsiveness/hyperreactivity."
Eligibility Criteria
Eligibility criteria included the following: (1) administration of LTRA (as first-line or second-line therapy) for 5 days; (2) the doubling dose/dilution difference in provocative dose/concentration to effect a 20% fall in FEV1 was given or calculable from the text, as the 95% confidence interval (CI) vs placebo; and (3) administration of the bronchial stimuli histamine, methacholine, and adenosine monophosphate (AMP). These challenge agents were included as they are commonly used for diagnostic purposes, and can be quantified in terms of doubling doses, unlike exercise and allergen.
Statistical Analysis
All data were logarithmically converted to enable the doubling dose or dilution shift for the provocative dose or dilution to be calculated. The weighted estimate of overall protection with 95% CI was calculated from the data from each of the trials.
|
Results
|
|---|
The Quorum flow diagram illustrates the main reasons for trial exclusion (Fig 1
).4
Table 1
summarizes the demographics of the 13 eligible trials.5
6
7
8
9
10
11
12
13
14
15
16
17
Figure 2
shows the estimated protection given by LTRAs in each of the individual trials. One study evaluated protection with AMP and methacholine (Fig 2
, 9A and 9B). The overall weighted estimated protection with LTRA is shown amounting to a 0.85 doubling dose shift (95% CI, 0.69 to 1.02). A 
2 test of heterogeneity of the 13 trials (14 results) was performed, giving a 2 value of 16.55 with 13 degrees of freedom (p = 0.22).
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2. Doubling dose/dilution protection of LTRA compared to placebo. *Denotes LTRA use as second-line therapy (the others being first-line therapy). Values are shown as means and 95% CI. Overall estimated protection was 0.85 (95% CI, 0.69 to 1.02)). M = montelukast; P = pranlukast; Z = zafirlukast; e = estimated overall protection.
|
|
|
Discussion
|
|---|
Our results have shown that use of an LTRA resulted in an overall estimated protection of almost one doubling dose. All three LTRAs conferred a consistent degree of protection, and it is worth pointing out that in all but one study,16
where methacholine challenge was not the primary outcome variable, the lower end of the 95% CI excluded zero, indicating a significant effect. The degree of bronchoprotection was comparable for direct acting (eg, methacholine and histamine) or indirect acting (eg, AMP) bronchoconstrictor stimuli. Furthermore, LTRA administered as first-line or second-line therapy resulted in a similar magnitude of bronchoprotection.
Bronchial hyperresponsiveness is a hallmark feature of asthma that results in episodic bronchoconstriction when exposed to an appropriate stimulus. Indirect stimuli such as AMP act on inflammatory cells, causing the release of preformed mediators such as histamine and cysteinyl leukotrienes, whereas histamine and methacholine act directly on airway smooth muscle. These tests are commonly carried out in the laboratory and provide a means of assessing the presence and severity of bronchial hyperresponsiveness, which was the rationale behind our study. Bronchial hyperresponsiveness correlates against airway eosinophils, and when used in conjunction with conventional tests of airway caliber is a useful tool in improving asthma control and reducing exacerbations.18
Thus, bronchial hyperresponsiveness may be regarded as a surrogate marker for airway inflammation.19
We discovered 13 randomized trials that fulfilled all eligibility criteria. The length of the studies was variable, ranging from 1 to 12 weeks. However, single doses of montelukast have been shown to exhibit bronchoprotective effects in patients receiving inhaled corticosteroids.20
Furthermore, LTRAs do not show tolerance for bronchoprotective effects during long-term dosing.5
16
21
It is well recognized that suppression of the inflammatory process in asthmatics is pivotal in maintaining asthma control and prevention of long-term airway remodeling.22
23
In this respect, inhaled corticosteroids are considered as first-line antiinflammatory therapy. Inhaled corticosteroids exhibit a relatively shallow dose-response curve for anti-inflammatory efficacy and steeper curve for systemic adverse effects.24
Treatment with corticosteroids appears to have a limited impact on airway inflammation and cysteinyl leukotriene levels.25
26
27
This suggests that second-line nonsteroidal antiasthma therapy with an LTRA may have a role in achieving more complete suppression of the inflammatory cascade.
Cysteinyl leukotrienes in BAL fluid and sputum are higher in subjects with more severe asthma.25
28
LTRAs are known to attenuate the early-phase and late-phase response to inhaled allergen,29
and offer protection against a variety of bronchoconstrictor stimuli.5
6
16
Various studies have demonstrated LTRAs to reduce rescue treatment requirement, improve pulmonary function, and reduce symptoms.1
This improvement has been shown even in patients requiring high doses of inhaled cortico-steroid.30
LTRAs demonstrate disease modifying activity, as reflected by reduction in exhaled nitric oxide and airway inflammatory cells.6
31
32
Thus, the addition of a LTRA as second-line controller therapy would appear to be a reasonable option in treating patients suboptimally controlled on inhaled corticosteroids, which is supported by a further 0.85 doubling dose reduction in bronchial hyperresponsiveness from the present analysis.
It is pertinent to consider the protection conferred by the alternative option of increasing the dose of inhaled corticosteroid. In a study by Taylor et al,33
there was a 1.4 doubling dose improvement in AMP protection comparing 400 µg/d vs 1,600 µg/d of ciclesonide; in another study using AMP by Wilson and Lipworth,34
comparing 400 µg/d vs 1,600 µg/d of budesonide, there was a 1.9 doubling dose increase in protection.
It is also evident that LTRAs exhibit less bronchoprotection than low-dose inhaled corticosteroid when administered as first-line monotherapy. For example, Wilson et al15
reported a 1.1 doubling dilution greater effect in AMP challenge with budesonide, 400 µg/d, vs montelukast, 10 mg/d; Westbroek and Pasma17
found a 0.8 doubling dilution difference on histamine challenge with fluticasone, 200 µg/d, vs zafirlukast, 40 mg/d. In conclusion, LTRAs, when used as first-line or second-line preventer therapy afforded overall protection of almost one doubling dose, reinforcing their role as anti-inflammatory therapy in asthma.
|
Acknowledgements
|
|---|
The authors thank Dr. S.A. Ogston (Department of Public Health and Epidemiology, University of Dundee) for statistical advice.
|
Footnotes
|
|---|
Abbreviations: AMP = adenosine monophosphate; CI = confidence interval; LTRA = leukotriene receptor antagonist
Dr. Lipworth has received grant funding and educational support from Merck and AstraZeneca, who make leukotriene receptor antagonists.
Dr. Currie has received financial support from Merck for attending international meetings.
Received for publication September 25, 2001.
Accepted for publication January 15, 2002.
|
References
|
|---|
- Lipworth, BJ (1999) Leukotriene-receptor antagonists. Lancet 353,57-62[CrossRef][ISI][Medline]
- Barnes, NC, Miller, CJ (2000) Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials. Thorax 55,478-483[Abstract/Free Full Text]
- National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. 1997 National Institutes of Health Bethesda, MD. publication No. 97–4051
- Moher, D, Cook, DJ, Eastwood, S, et al (1999) Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement; quality of reporting of meta-analyses. Lancet 354,1896-1900[CrossRef][ISI][Medline]
- Wilson, AM, Dempsey, OJ, Sims, EJ, et al (2001) Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 119,1021-1026[Medline]
- Lipworth, BJ, Dempsey, OJ, Aziz, I, et al (2000) Effects of adding a leukotriene antagonist or a long-acting ß2-agonist in asthmatic patients with the glycine-16 ß2-adrenoceptor genotype. Am J Med 109,114-121[CrossRef][ISI][Medline]
- Fujimura, M, Sakamoto, S, Kamio, Y, et al (1993) Effect of a leukotriene antagonist, ONO-1078, on bronchial hyperresponsiveness in patients with asthma. Respir Med 87,133-138[CrossRef][ISI][Medline]
- Yoshida, S, Sakamoto, H, Ishizaki, Y, et al (2000) Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma. Clin Exp Allergy 30,64-70[CrossRef][ISI][Medline]
- Hamilton, A, Faiferman, I, Stober, P, et al (1998) Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J Allergy Clin Immunol 102,177-183[CrossRef][ISI][Medline]
- Yoshida, S, Ishizaki, Y, Shoji, T, et al (2000) Effect of pranlukast on bronchial inflammation in patients with asthma. Clin Exp Allergy 30,1008-1014[CrossRef][ISI][Medline]
- Fowler, SJ, Dempsey, OJ, Wilson, AM, et al (2001) Effects of adding either a leukotriene receptor antagonist or theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. J Allergy Clin Immunol 107,S266-S267
- Wilson, AM, Orr, LC, Sims, EJ, et al (2000) Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med 162,1297-1301[Abstract/Free Full Text]
- Dempsey, OJ, Kennedy, G, Lipworth, BJ (2002) Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low dose inhaled corticosteroid in patients with mild presistent asthma. J Allergy Clin Immunol 109,68-74[CrossRef][ISI][Medline]
- Rosenthal, R, Lavins, BJ, Hanby, LA, et al (1996) Effect of treatment with zafirlukast (ACCOLATE) on bronchial hyperresponsiveness in patients with mild-to-moderate asthma. J Allergy Clin Immunol 97(part 3),250
- Wilson, AM, Dempsey, OJ, Sims, EJ, et al (2001) A comparison of topical budesonide and oral montelukast in seasonal allergic rhinitis and asthma. Clin Exp Allergy 31,616-624[CrossRef][ISI][Medline]
- Leff, JA, Busse, WW, Pearlman, D, et al (1998) Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 339,147-152[Abstract/Free Full Text]
- Westbroek, J, Pasma, HR (2000) Effects of 2 weeks of treatment with fluticasone propionate 100 mcg b.d. by comparison with zafirlukast 20 mg b.d. on bronchial hyper-responsiveness in patients with mild to moderate asthma. Respir Med 94,112-118[CrossRef][ISI][Medline]
- Sont, JK, Willems, LN, Bel, EH, et al (1999) Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment: the AMPUL Study Group. Am J Respir Crit Care Med 159,1043-1051[Abstract/Free Full Text]
- Van Den Berge, M, Meijer, RJ, Kerstjens, HA, et al (2001) PC(20) adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine. Am J Respir Crit Care Med 163,1546-1550[Abstract/Free Full Text]
- Dempsey, OJ, Wilson, AM, Sims, EJ, et al (2000) Additive bronchoprotective and bronchodilator effects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids. Chest 117,950-953[Medline]
- Edelman, JM, Turpin, JA, Bronsky, EA, et al (2000) Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction: a randomized, double-blind trial; Exercise Study Group. Ann Intern Med 132,97-104[Abstract/Free Full Text]
- Vignola, AM, Chanez, P, Campbell, AM, et al (1998) Airway inflammation in mild intermittent and in persistent asthma. Am J Respir Crit Care Med 157,403-409[ISI][Medline]
- Lange, P, Parner, J, Vestbo, J, et al (1998) A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 339,1194-1200[Abstract/Free Full Text]
- Lipworth, BJ, Wilson, AM (1998) Dose response to inhaled corticosteroids: benefits and risks. Semin Respir Crit Care Med 19,625-646[ISI]
- Pavord, ID, Ward, R, Woltmann, G, et al (1999) Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 160,1905-1909[Abstract/Free Full Text]
- Louis, R, Lau, LC, Bron, AO, et al (2000) The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 161,9-16[Abstract/Free Full Text]
- Wenzel, SE, Szefler, SJ, Leung, DY, et al (1997) Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 156,737-743[Abstract/Free Full Text]
- Wenzel, SE, Larsen, GL, Johnston, K, et al (1990) Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis 142,112-119[ISI][Medline]
- Diamant, Z, Grootendorst, DC, Veselic-Charvat, M, et al (1999) The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 29,42-51[CrossRef][ISI][Medline]
- Virchow, CJ, Prasse, A, Naya, I, et al (2000) Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 162,578-585[Abstract/Free Full Text]
- Wada, K, Minoguchi, K, Kohno, Y, et al (2000) Effect of a leukotriene receptor antagonist, pranlukast hydrate, on airway inflammation and airway hyperresponsiveness in patients with moderate to severe asthma. Allergology International 49,63-68[CrossRef]
- Nakamura, Y, Hoshino, M, Sim, JJ, et al (1998) Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 53,835-841[Abstract/Free Full Text]
- Taylor, DA, Jensen, MW, Kanabar, V, et al (1999) A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients. Am J Respir Crit Care Med 160,237-243[Abstract/Free Full Text]
- Wilson, AM, Lipworth, BJ (2000) Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med 108,269-275[CrossRef][ISI][Medline]
TOP
Abstract
Introduction
