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The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials
Review
The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials Gustavo J. Rodrigo, MD,* and Anahi Yan˜ez, MD†
Objective: To evaluate the effect of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of seasonal allergic rhinitis. Data Sources: The MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health), and Cochrane databases; review articles; and references of included trials. Study Selection: Published (1966 –2005) randomized controlled trials with nasal and eye symptoms and quality-of-life scores as primary outcomes. Results: Seventeen studies including 6,231 adults with seasonal allergic rhinitis were selected. Oral leukotriene antagonists significantly reduced daytime nasal symptoms (standardized mean difference [SMD], ⫺0.24; 95% confidence interval [CI], ⫺0.33 to ⫺0.16), nighttime nasal symptoms (SMD, ⫺0.23; 95% CI, ⫺0.30 to ⫺0.16), and eye symptoms and significantly improved quality of life compared with placebo. There were no significant differences between oral leukotriene antagonists and oral histamine H1 antagonists on nasal and eye symptoms and quality-of-life overall score. We also found that leukotriene receptor antagonists were inferior to intranasal corticosteroids for decreasing daytime (SMD, 0.41; 95% CI, 0.27 to 0.56) and nighttime nasal symptoms. The combination of leukotriene receptor antagonists plus histamine H1 antagonists produced greater relief of eye symptoms compared with histamine H1 antagonists alone. Finally, intranasal corticosteroids significantly reduced nasal congestion compared with leukotriene receptor antagonists plus histamine H1 antagonists. Conclusions: Leukotriene receptor antagonists were better than placebo, equivalent to oral histamine H1 antagonists, and inferior to intranasal corticosteroids for treating seasonal allergic rhinitis. Alternatively, leukotriene receptor antagonists plus histamine H1 antagonists were more effective than histamine H1 antagonists alone but inferior to intranasal corticosteroids. Ann Allergy Asthma Immunol. 2006;96:779–786.
INTRODUCTION Allergic rhinitis is the most common allergic disease, affecting approximately 20% of the population in developed countries.1 A large body of data establishes that intranasal corticosteroids and oral histamine H1 antagonists are the mainstay of therapy for rhinitis.2,3 Furthermore, there is a lot of evidence that suggests that intranasal corticosteroids are more effective than oral4 and topical5 histamine H1 antagonists at relieving nasal symptoms. The guidelines also recognize that leukotriene receptor antagonists can have a role in the treatment of allergic rhinitis. In the past few years, several clinical trials have been conducted to evaluate the efficacy and safety of leukotriene receptor antagonists in allergic rhinitis, but they have produced conflicting results. Until now, to our knowledge, there has been no attempt to evaluate this effect * Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, and Clinica Respirar, Benito Nardone, Montevideo, Uruguay. † Fundacio´n CIDEA, Ciudad Auto´noma de Buenos Aires, Buenos Aires, Argentina. Received for publication July 19, 2005. Accepted for publication in revised form October 10, 2005.
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in a systematic manner. Only nonsystematic (state-of-the-art) reviews have been published.6 –9 To address this issue, we performed a systematic review with meta-analysis of randomized controlled trials to analyze the effect of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of seasonal allergic rhinitis. METHODS Search Strategy and Selection Criteria The search was conducted using 5 strategies to identify potentially relevant trials. First, we queried the MEDLINE (January 1966 to September 2005), EMBASE (January 1974 to September 2005), and CINAHL (Cumulative Index to Nursing and Allied Health) (January 1982 to September 2005) databases using the following Medical Subject Heading full text and key words: leukotriene receptor antagonists OR antileukotrienes OR montelukast OR zafirlukast OR pranlukast OR zileuton AND rhinitis OR hay fever. Second, an advanced search of the Cochrane Controlled Trials Register (third quarter 2005) was completed using the previously mentioned search strategy to identify any additional trials.
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Third, references from included studies, reviews, and texts were searched for citations. Fourth, a hand search of the top 10 allergy journals was performed. Finally, unpublished data were requested from the primary authors when necessary. Trials published solely in abstract form were excluded. Included studies met the following criteria. First, the target population was children and adolescents (6 –17 years old) and adults (ⱖ18 years old) with seasonal allergic rhinitis. We did not consider studies on the treatment of asthma or nasal polyps. Second, the intervention consisted of oral leukotriene receptor antagonists either as monotherapy or combined with oral histamine H1 antagonists vs placebo or intranasal corticosteroids or oral histamine H1 antagonists or intranasal corticosteroids plus oral histamine H1 antagonists. Third, the study design consisted of randomized and placebo-controlled trials without language restrictions. Fourth, the primary outcomes were daytime and nighttime nasal symptoms (including composite symptom scores), eye symptoms, and quality of life. We excluded studies that reported only nasal challenge with specific allergens. Secondary outcome measures included peak nasal inspiratory flow and rhinomanometry. Assessments included 2 to 4 weeks of treatment. Data Abstraction and Validity Evaluation Titles, abstracts, and citations were independently reviewed by 2 reviewers (G.J.R. and A.Y.) to evaluate potential relevance for full review. From the full text, both reviewers independently evaluated studies for inclusion based on the criteria of population, intervention, study design, and outcomes. Data extraction included the following items: (1) age, sex, number of patients studied, patient demographics, and withdrawals (population); (2) agent, dose, route of delivery, and duration of therapy (intervention); (3) concurrent treatments (control); (4) outcomes; and (5) method of randomization and allocation concealment (design). Any disagreement regarding study inclusion was resolved by consensus. The methodological quality of each trial was evaluated using the 5-point scale (0 ⫽ worst and 5 ⫽ best) described by Jadad et al.10 This instrument assesses the adequacy of randomization, blinding, and the handling of withdrawals and dropouts. Data Analysis The data were combined in a meta-analysis by means of random-effects models.11 For continuous outcomes, the weighted mean difference (for variables using the same unit of measure) or the standardized mean difference (SMD, reported in SD units) (for variables using different units of measure) and the 95% confidence interval were calculated. We tested for heterogeneity by using the DerSimonian and Laird Q statistic. We also measured heterogeneity by using the I2 test.12 Values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. Otherwise, P ⬍ .05 using a 2-tailed test was considered statistically significant. When heterogeneity was found, subgroup analyses were performed in an attempt to explain the findings. Sensitivity analysis was performed to identify sources of
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heterogeneity. These subgroups included intensity of protocol, cotherapies, and the methodological quality of the studies. The meta-analysis was performed using a software program (Review Manager 4.2.8; Cochrane Collaboration, Oxford, England). RESULTS A total of 76 studies were examined in full text for possible inclusion; 59 studies were excluded for the following reasons: published only in abstract form (n ⫽ 8), nonrandomized trials (n ⫽ 20), only asthma outcomes (n ⫽ 10), reviews (n ⫽ 11), use of nasal provocation stimuli (n ⫽ 8), data used in previous trials (n ⫽ 1), and patients with perennial rhinitis (n ⫽ 1). Finally, 17 randomized controlled trials13–29 including 6,260 adults were available for analysis (Table 1). There was total agreement between the 2 independent reviewers on inclusion of studies and Jadad study quality grading. All eligible studies were described as randomized controlled trials. Four studies were from Great Britain,15–17,21 2 were from Italy,26,27 1 was from Poland,28 2 were from Sweden,13,20 and 8 were from the United States.14,18,19,22–25,29 They were published between 1999 and 2004. Sixteen trials used montelukast as the leukotriene receptor antagonist, and only 1 trial used zafirlukast.13 Most of the studies were categorized as highquality trials (Jadad score ⱖ3). Studies of Leukotriene Receptor Antagonists as Monotherapy Eight studies13,14,18 –20,24,25,28 compared oral leukotriene receptor antagonists with placebo. The following outcomes were analyzed: daytime and nighttime nasal symptoms,14,18 –20,24,25 rhinoconjunctivitis quality of life,14,18,19,24,25 and eye symptoms (mean change from baseline or absolute values).14,24,25 Pooled analysis showed that oral leukotriene receptor antagonists significantly reduced daytime and nighttime nasal symptoms and eye symptoms compared with placebo (Table 2 and Fig 1). Also, leukotriene receptor antagonists produced significantly greater improvement compared with placebo in the quality-of-life overall score. No significant heterogeneity was demonstrated, which accepts the null hypothesis of similar treatment effects (low or null heterogeneity in all outcomes). Six studies14,18,19,24,25,28 compared oral leukotriene receptor antagonists with oral histamine H1 antagonists. Five studies14,18,19,24,25 used loratadine, and 1 study28 used cetirizine as histamine H1 antagonists. There were no significant differences in composite (daytime and nighttime) nasal symptoms,14,18,19,24,25 quality-of-life overall score,14,18,19,24,25, and eye symptoms14,24,25 in terms of mean change from baseline or absolute values (Table 2 and Fig 2). All comparisons were montelukast, 10 mg, vs loratadine, 10 mg. Again, these effects were homogeneous between studies (I2 ⫽ 0% in all outcomes). A leukotriene receptor antagonist was compared with intranasal corticosteroids in 3 studies.13,20,22 However, only 2
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Table 1. Characteristics of the 17 Trials Included in the Review Trial
Design
Patients, No. Jadad (age range, y) score
Duration of protocol, wk
Protocol
Outcomes
Pullerits et al, 199913
R, DB
62 (16–45)
3
3
Meltzer et al, 200014
R, DB
460 (15–75)
5
2
Wilson et al, 200015
R, SB
38 (16–65)
3
4
Wilson et al, 200116
R, SB, CO
22
3
2
Wilson et al, 200117
R, SB, CO
21
2
2
Nayak et al, 200118
R, DB, M
907 (15–82)
5
2
Philip et al, 200219 Pullerits et al, 200220
R, DB, M R, DB
1,302 (15–81) 62 (15–49)
4 2
2 8
Wilson et al, 200221
R, SB, CO
37
3
2
Ratner et al, 200322 Saengpanich et al, 200323
R, DB, M R, DB
705 (⬎15) 63 (⬎18)
2 3
2 2
van Adelsberg et al, 200324
R, DB, M
1,079 (15–82)
3
4
Z 20 mg ⫻2 vs BE 0.2 mg ⫻2 M 10 mg vs M 20 mg vs L 10 mg vs M 20 mg ⫹ L 10 mg vs PL C 10 mg vs C 10 mg ⫹ M 10 mg vs C 10 mg ⫹ M 20 mg M 10 mg ⫹ C 10 mg vs M 0.2 mg vs PL M 10 mg ⫹ C 10 mg vs B 0.2 mg ⫹ 0.4 mg vs PL M 10 mg vs L 10 mg vs M 10 mg ⫹ L 10 mg vs PL M 10 mg vs L 10 mg vs PL M 10 mg vs M 10 mg ⫹ L 10 mg vs F 0.2 mg vs PL M 10 mg ⫹ L 10 mg vs FE 120 mg vs PL M 10 mg vs F 0.2 mg M 10 mg ⫹ L 10 mg vs F 0.1 mg M 10 mg vs L 10 mg vs PL
van Adelsberg et al, 200325
R, DB, M
1,214 (15–85)
5
2
M 10 mg vs L 10 mg vs PL
Ciprandi et al, 200426
R, DB
60
3
2
Di Lorenzo et al, 200427
R, DB
100 (12–50)
4
6
Kurowski et al, 200428
R, DB
60 (18–35)
4
6
Moinuddin et al, 200429
R, DB
68 (18–45)
5
2
M 10 mg ⫹ C 10 mg vs M 10 mg ⫹ D 5 mg M 10 mg ⫹ F 0.2 mg vs M Nasal symptoms, eosinophil 10 mg ⫹ C 10 mg vs F 0.2 count mg ⫹ C 10 mg vs F 0.2 mg vs PL M 10 mg vs C 10 mg vs M Nasal and eye symptoms 10 mg ⫹ C 10 mg vs PL M 10 mg ⫹ L 10 mg vs FE Nasal symptoms, NPIF 60 mg ⫹ P 120 mg ⫻2
Total symptom score Nasal symptoms, QOL
Nasal and eye symptoms, NPIF Nasal and eye symptoms, NPIF, rhinomanometry Nasal and eye symptoms, NPIF, rhinomanometry Nasal symptoms, QOL Nasal symptoms, QOL Total symptom score Nasal and eye symptoms, NIPF Nasal symptoms Nasal and eye symptoms, QOL Nasal and eye symptoms, QOL, eosinophil count Nasal and eye symptoms, QOL, eosinophil count Nasal symptoms
Abbreviations: B, budesonide; BE, beclomethasone; C, cetirizine; CO, crossover; D, desloratadine; DB, double blind; F, fluticasone; FE, fexofenadine; L, loratadine; M, montelukast; Z, zafirlukast; NPIF, nasal peak inspiratory flow; P, pseudoephedrine; PL, placebo; QOL, quality of life; R, randomized; SB, single blind.
studies20,22 reported scores for daytime and nighttime nasal symptoms (change from baseline and absolute values). We found a significance difference in favor of topical corticosteroids (fluticasone) for decreasing daytime and nighttime nasal symptoms compared with leukotriene receptor antagonists (montelukast) (Table 2). These were again homogeneous findings (I2 ⫽ 0%). However, there was insufficient information to pool other outcomes. Studies of Leukotriene Receptor Antagonists Combined With Histamine H1 Antagonists Five studies14,15,18,21,28 tested the efficacy of leukotriene receptor antagonists plus oral histamine H1 antagonists compared
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with oral histamine H1 antagonists alone. Two studies14,18 compared montelukast-loratadine with loratadine alone, 1 study21 compared montelukast-loratadine with fexofenadine alone, and 1 study15 compared montelukast-cetirizine with cetirizine alone. Because of the small number of trials, differences in drugs and doses were not taken into account in the analysis. Only 3 studies14,15,21 reported eye symptoms. There was insufficient information to pool daytime nasal symptoms and quality of life. The combination of leukotriene receptor antagonists plus histamine H1 antagonists produced greater relief of eye symptoms compared with histamine H1 antagonists alone (Table 3 and Fig 3). This effect was homogeneous between studies (I2 ⫽ 0%).
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Table 2. Summary of Data From Studies of Oral Leukotriene Receptor Antagonists as Monotherapy Outcome
Studies, No.
SMD (95% CI)
P value
I2, %
Studies that compared oral leukotriene receptor antagonists with placebo (negative SMD values favored leukotriene receptor antagonists) Daytime nasal symptoms14,18–20,24,25 6 ⫺0.24 (⫺0.33 to ⫺0.16) ⬍.001 29 Nighttime nasal symptoms14,18–20,24,25 6 ⫺0.23 (⫺0.30 to ⫺0.16) ⬍.001 1 RQOL14,18,19,24,25 5 ⫺0.27 (⫺0.34 to ⫺0.19) ⬍.001 0 Eye symptoms14,24,25 3 ⫺0.17 (⫺0.27 to ⫺0.08) ⬍.001 18 Studies that compared oral leukotriene receptor antagonists with oral histamine H1 antagonists (negative SMD values favored leukotriene receptor antagonists) Composite (daytime and nighttime nasal 5 0.04 (⫺0.04 to 0.11) .37 0 symptoms14,18,19,24,25 RQOL14,18,19,24,25 5 0.04 (⫺0.04 to 0.12) .36 0 Eye symptoms14,24,25 3 ⫺0.02 (⫺0.09 to 0.13) .72 0 Studies that compared oral leukotriene receptor antagonists with topical corticosteroids (positive SMD values favored corticosteroids) Daytime nasal symptoms20,22 2 0.41 (0.27 to 0.56) ⬍.001 0 Nighttime nasal symptoms20,22 2 0.33 (0.18 to 0.48) ⬍.001 0 Abbreviations: CI, confidence interval; RQOL, rhinoconjunctivitis quality of life; SMD, standardized mean difference.
Figure 1. Pooled standardized mean differences (SMDs) in daytime nasal symptoms of studies comparing oral leukotriene receptor antagonists (treatment) with placebo (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
Five studies16,17,20,23,27 compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with intranasal corticosteroids. Scores for global nasal symptoms were reported in all the studies. Corticosteroids showed a trend toward greater relief of nasal symptoms, with low heterogeneity between studies (Table 3 and Fig 4). On the other hand, intranasal corticosteroids significantly reduced nasal congestion compared with leukotriene receptor antagonists plus histamine H1 antagonists.16,17,23,27 However, there was significant heterogeneity between the studies (I2 ⫽ 88%). When the low-quality studies16,17 were removed, homogeneity was achieved. There was insufficient information to pool other outcomes.
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Finally, there was insufficient information to pool other comparisons, such as oral leukotriene receptor antagonists plus oral histamine H1 antagonists compared with corticosteroids plus oral histamine H1 antagonists27; oral leukotriene receptor antagonists plus cetirizine compared with oral leukotriene receptor antagonists plus desloratadine26; montelukast, 10 mg, plus oral histamine H1 antagonists compared with montelukast, 20 mg, plus oral histamine H1 antagonists15; and oral leukotriene receptor antagonists plus histamine H1 antagonists compared with histamine H1 antagonists plus pseudoephedrine.29 A low incidence of adverse effects was observed.14,19,22,24 Most adverse events were rated mild, and there was no
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Figure 2. Pooled standardized mean differences (SMDs) in composite (daytime and nighttime) nasal symptoms of studies comparing oral leukotriene receptor antagonists (treatment) with oral histamine H1 antagonists (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary. Table 3. Summary of Data From Studies of Oral Leukotriene Receptor Antagonists Combined With Oral Histamine H1 Antagonists Outcome
Studies, No.
SMD (95% CI)
P value
Studies that compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with antagonists (negative values favored the combination of leukotriene receptor antagonists and oral antagonists) Eye symptoms14,15,21 3 ⫺0.30 (⫺0.53 to ⫺0.06) Studies that compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with corticosteroids (positive values favored corticosteroids) Total nasal symptoms16,17,20,23,27 5 0.23 (⫺0.13 to 0.60) Nasal congestion16,17,23,27 4 0.97 (0.01 to 1.92)
I2, %
oral histamine H1 histamine H1 .01 topical .22 .05
0
43 88
Abbreviations: CI, confidence interval; SMD, standardized mean difference.
Figure 3. Pooled standardized mean differences (SMDs) in eye symptoms of studies comparing oral leukotriene receptor antagonists plus oral histamine H1 antagonists (treatment) compared with oral histamine H1 antagonists (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
difference between groups. One of the most frequently reported adverse events was headache (3%–5% of patients treated with oral leukotriene receptor antagonists). DISCUSSION Meta-analysis is a statistical method that combines the results of several studies into a single outcome. Thus, by combining
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the samples of the individual studies, this method greatly increases the overall sample size, which increases the statistical power of the analysis and the precision of the estimate of the treatment effect. The purpose of this systematic review was to determine the efficacy of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of allergic rhinitis. This review identified dif-
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Figure 4. Pooled standardized mean differences (SMDs) in total nasal symptoms of studies comparing oral leukotriene receptor antagonists with oral histamine H1 antagonists (treatment) with topical corticosteroids (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
ferent comparisons. As monotherapy, data showed that oral leukotriene receptor antagonists are more effective than placebo. Thus, leukotriene receptor antagonists reduced nasal (daytime and nighttime) and eye symptoms and improved the quality-of-life overall score. Furthermore, the results were homogeneous between the studies of the different measured outcomes. The analysis of studies that compared leukotriene receptor antagonists with oral histamine H1 antagonists demonstrated similar efficacy of both drugs at relieving allergic rhinitis symptoms. There were no differences in terms of nasal (daytime and nighttime) and eye symptoms and qualityof-life overall score. Again, the results were homogeneous between the studies of all measured outcomes. Finally, although there were only 2 studies comparing oral leukotriene receptor antagonists with intranasal corticosteroids, the pooled analysis showed that intranasal fluticasone provided significantly greater relief of daytime and nighttime nasal symptoms. The results were homogeneous. In the studies that evaluated the use of leukotriene receptor antagonists combined with other drugs for the treatment of allergic rhinitis, the combination of leukotriene receptor antagonists and histamine H1 antagonists was significantly more effective than histamine H1 antagonists alone. Thus, leukotriene receptor antagonists plus oral histamine H1 antagonists reduced eye symptoms. This indicates that this combination provides an additive effect compared with histamine H1 antagonists alone. Nevertheless, this conclusion is limited by the small number of pooled studies. On the other hand, intranasal corticosteroids showed a trend toward greater relief of nasal symptoms and a significant effect on nasal congestion. However, this last comparison presented high heterogeneity between the studies. The fact that fluticasone was more effective than the combination of leukotriene receptor antagonists and histamine H1 antagonists on nasal congestion is concordant with the effect of corticosteroids on the late phase of the allergic response. Because histamine and leukotrienes
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are not significant mediators of the late-phase allergic response, histamine H1 antagonists and leukotriene receptor antagonists are not usually effective at relieving late-phase symptoms, such as nasal congestion. In summary, the data suggest that intranasal corticosteroids are more effective than the combination of leukotriene receptor antagonists plus histamine H1 antagonists in alleviating nasal symptoms. Finally, in this review we also looked at adverse effects. However, they were difficult to analyze because of insufficient information to be pooled. A low incidence of adverse effects was observed, and most of them were rated mild or moderate. It is difficult to estimate in clinical terms the effect size obtained in the different comparisons because data were combined in the meta-analysis using the SMDs. However, if we interpret the effect size as small if it is 0.2 SD unit or less, as large if it is 0.8 SD unit or greater, and as medium otherwise, most of the differences between groups could be considered moderate, except the comparison between oral leukotriene receptor antagonists plus oral histamine H1 antagonists and intranasal corticosteroids (there was a large effect favoring topical corticosteroids). This study met most of the methodological criteria suggested for scientific reviews.30 A comprehensive search of the published literature for potentially relevant studies was conducted using a systematic strategy to avoid bias. All 17 trials were randomized and mostly13 double blind. All the studies included in the comparisons of leukotriene receptor antagonists as monotherapy were based on double-blind studies. We did not impose restrictions by language or year of publication, and the search results were complemented by hand searching of relevant journals. In addition, we evaluated the consistency of effects between studies to determine the generalizability of the findings; thus, we obtained low or null values of heterogeneity in almost all group comparisons. However, we cannot fully exclude publication bias because
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we did not perform a statistical test because these tests have very low power in meta-analyses of small numbers of trials. 14.
CONCLUSION This systematic review of the treatment of seasonal allergic rhinitis found evidence that leukotriene receptor antagonists as monotherapy were better than placebo, equivalent to oral antihistamines, and inferior to intranasal corticosteroids in terms of nasal and eye symptoms or quality of life in the first 2 comparisons and nasal symptoms in the last comparison. Alternatively, pooled data from studies that used oral leukotriene receptor antagonists combined with other drugs showed that leukotriene receptor antagonists plus antihistamines were more effective than an antihistamine alone but inferior to intranasal corticosteroids. However, these last 2 conclusions are limited by the small number of pooled studies and by the presence of heterogeneity between studies. Overall, these findings confirm the superiority of topical corticosteroids to antihistamines4 and also to leukotriene receptor antagonists and their combinations. REFERENCES 1. Nathan RA, Meltzer EO, Seiner JC, et al. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99: S808 –S814. 2. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact its impact on asthma. J Allergy Clin Immunol. 2001;108(suppl):S147–S334. 3. van Cauwenberge P, Bachert C, Passalacqua G, et al; European Academy of Allergology and Clinical Immunology. Consensus statement on the treatment of allergic rhinitis. Allergy. 2000;55: 116 –134. 4. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ. 1997;317: 1624 –1629. 5. Yan˜ez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2002;89:479 – 484. 6. Busse WW. The role of leukotriene in asthma and allergic rhinitis. Clin Exp Allergy. 1996;26:868 – 879. 7. Lipworth BJ. Emerging role of antileukotriene therapy in allergic rhinitis. Clin Exp Allergy. 2001;31:1813–1821. 8. Meltzer EO. Clinical evidence for antileukotriene therapy in the management of allergic rhinitis. Ann Allergy Asthma Immunol. 2002;88(suppl):23–29. 9. Nathan RA. Pharmacotherapy for allergic rhinitis: a critical review of leukotriene receptor antagonists compared with other treatments. Ann Allergy Asthma Immunol. 2003;90:182–191. 10. Jadad AR, Moore RA, Carrol D. Assessing the quality of reports of randomized controlled trials: is blinding necessary? Control Clin Trials. 1995;134:1–12. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 12. Higgins JPT, Thompson SG, Deecks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. 13. Pullerits T, Praks L, Skoogh BE, et al. Randomized placebocontrolled study comparing a leukotriene receptor antagonist
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plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis. Clin Exp Allergy. 2004;34:259 –267. 28. Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy. 2004;59:280 –288. 29. Moinuddin R, deTineo M, Maleckar B, et al. Comparison of the combination of fexofenadine-pseudoephedrine and loratadinemontelukast in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2004;92:73–79.
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30. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Lancet. 1999;354:1896 –1900. Requests for reprints should be addressed to: Gustavo J. Rodrigo, MD Departamento de Emergencia Hospital Central de las Fuerzas Armadas Av. 8 de Octubre 3020 Montevideo 11600, Uruguay E-mail: [email protected].
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The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials Gustavo J. Rodrigo, MD,* and Anahi Yan˜ez, MD†
Objective: To evaluate the effect of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of seasonal allergic rhinitis. Data Sources: The MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health), and Cochrane databases; review articles; and references of included trials. Study Selection: Published (1966 –2005) randomized controlled trials with nasal and eye symptoms and quality-of-life scores as primary outcomes. Results: Seventeen studies including 6,231 adults with seasonal allergic rhinitis were selected. Oral leukotriene antagonists significantly reduced daytime nasal symptoms (standardized mean difference [SMD], ⫺0.24; 95% confidence interval [CI], ⫺0.33 to ⫺0.16), nighttime nasal symptoms (SMD, ⫺0.23; 95% CI, ⫺0.30 to ⫺0.16), and eye symptoms and significantly improved quality of life compared with placebo. There were no significant differences between oral leukotriene antagonists and oral histamine H1 antagonists on nasal and eye symptoms and quality-of-life overall score. We also found that leukotriene receptor antagonists were inferior to intranasal corticosteroids for decreasing daytime (SMD, 0.41; 95% CI, 0.27 to 0.56) and nighttime nasal symptoms. The combination of leukotriene receptor antagonists plus histamine H1 antagonists produced greater relief of eye symptoms compared with histamine H1 antagonists alone. Finally, intranasal corticosteroids significantly reduced nasal congestion compared with leukotriene receptor antagonists plus histamine H1 antagonists. Conclusions: Leukotriene receptor antagonists were better than placebo, equivalent to oral histamine H1 antagonists, and inferior to intranasal corticosteroids for treating seasonal allergic rhinitis. Alternatively, leukotriene receptor antagonists plus histamine H1 antagonists were more effective than histamine H1 antagonists alone but inferior to intranasal corticosteroids. Ann Allergy Asthma Immunol. 2006;96:779–786.
INTRODUCTION Allergic rhinitis is the most common allergic disease, affecting approximately 20% of the population in developed countries.1 A large body of data establishes that intranasal corticosteroids and oral histamine H1 antagonists are the mainstay of therapy for rhinitis.2,3 Furthermore, there is a lot of evidence that suggests that intranasal corticosteroids are more effective than oral4 and topical5 histamine H1 antagonists at relieving nasal symptoms. The guidelines also recognize that leukotriene receptor antagonists can have a role in the treatment of allergic rhinitis. In the past few years, several clinical trials have been conducted to evaluate the efficacy and safety of leukotriene receptor antagonists in allergic rhinitis, but they have produced conflicting results. Until now, to our knowledge, there has been no attempt to evaluate this effect * Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, and Clinica Respirar, Benito Nardone, Montevideo, Uruguay. † Fundacio´n CIDEA, Ciudad Auto´noma de Buenos Aires, Buenos Aires, Argentina. Received for publication July 19, 2005. Accepted for publication in revised form October 10, 2005.
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in a systematic manner. Only nonsystematic (state-of-the-art) reviews have been published.6 –9 To address this issue, we performed a systematic review with meta-analysis of randomized controlled trials to analyze the effect of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of seasonal allergic rhinitis. METHODS Search Strategy and Selection Criteria The search was conducted using 5 strategies to identify potentially relevant trials. First, we queried the MEDLINE (January 1966 to September 2005), EMBASE (January 1974 to September 2005), and CINAHL (Cumulative Index to Nursing and Allied Health) (January 1982 to September 2005) databases using the following Medical Subject Heading full text and key words: leukotriene receptor antagonists OR antileukotrienes OR montelukast OR zafirlukast OR pranlukast OR zileuton AND rhinitis OR hay fever. Second, an advanced search of the Cochrane Controlled Trials Register (third quarter 2005) was completed using the previously mentioned search strategy to identify any additional trials.
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Third, references from included studies, reviews, and texts were searched for citations. Fourth, a hand search of the top 10 allergy journals was performed. Finally, unpublished data were requested from the primary authors when necessary. Trials published solely in abstract form were excluded. Included studies met the following criteria. First, the target population was children and adolescents (6 –17 years old) and adults (ⱖ18 years old) with seasonal allergic rhinitis. We did not consider studies on the treatment of asthma or nasal polyps. Second, the intervention consisted of oral leukotriene receptor antagonists either as monotherapy or combined with oral histamine H1 antagonists vs placebo or intranasal corticosteroids or oral histamine H1 antagonists or intranasal corticosteroids plus oral histamine H1 antagonists. Third, the study design consisted of randomized and placebo-controlled trials without language restrictions. Fourth, the primary outcomes were daytime and nighttime nasal symptoms (including composite symptom scores), eye symptoms, and quality of life. We excluded studies that reported only nasal challenge with specific allergens. Secondary outcome measures included peak nasal inspiratory flow and rhinomanometry. Assessments included 2 to 4 weeks of treatment. Data Abstraction and Validity Evaluation Titles, abstracts, and citations were independently reviewed by 2 reviewers (G.J.R. and A.Y.) to evaluate potential relevance for full review. From the full text, both reviewers independently evaluated studies for inclusion based on the criteria of population, intervention, study design, and outcomes. Data extraction included the following items: (1) age, sex, number of patients studied, patient demographics, and withdrawals (population); (2) agent, dose, route of delivery, and duration of therapy (intervention); (3) concurrent treatments (control); (4) outcomes; and (5) method of randomization and allocation concealment (design). Any disagreement regarding study inclusion was resolved by consensus. The methodological quality of each trial was evaluated using the 5-point scale (0 ⫽ worst and 5 ⫽ best) described by Jadad et al.10 This instrument assesses the adequacy of randomization, blinding, and the handling of withdrawals and dropouts. Data Analysis The data were combined in a meta-analysis by means of random-effects models.11 For continuous outcomes, the weighted mean difference (for variables using the same unit of measure) or the standardized mean difference (SMD, reported in SD units) (for variables using different units of measure) and the 95% confidence interval were calculated. We tested for heterogeneity by using the DerSimonian and Laird Q statistic. We also measured heterogeneity by using the I2 test.12 Values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. Otherwise, P ⬍ .05 using a 2-tailed test was considered statistically significant. When heterogeneity was found, subgroup analyses were performed in an attempt to explain the findings. Sensitivity analysis was performed to identify sources of
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heterogeneity. These subgroups included intensity of protocol, cotherapies, and the methodological quality of the studies. The meta-analysis was performed using a software program (Review Manager 4.2.8; Cochrane Collaboration, Oxford, England). RESULTS A total of 76 studies were examined in full text for possible inclusion; 59 studies were excluded for the following reasons: published only in abstract form (n ⫽ 8), nonrandomized trials (n ⫽ 20), only asthma outcomes (n ⫽ 10), reviews (n ⫽ 11), use of nasal provocation stimuli (n ⫽ 8), data used in previous trials (n ⫽ 1), and patients with perennial rhinitis (n ⫽ 1). Finally, 17 randomized controlled trials13–29 including 6,260 adults were available for analysis (Table 1). There was total agreement between the 2 independent reviewers on inclusion of studies and Jadad study quality grading. All eligible studies were described as randomized controlled trials. Four studies were from Great Britain,15–17,21 2 were from Italy,26,27 1 was from Poland,28 2 were from Sweden,13,20 and 8 were from the United States.14,18,19,22–25,29 They were published between 1999 and 2004. Sixteen trials used montelukast as the leukotriene receptor antagonist, and only 1 trial used zafirlukast.13 Most of the studies were categorized as highquality trials (Jadad score ⱖ3). Studies of Leukotriene Receptor Antagonists as Monotherapy Eight studies13,14,18 –20,24,25,28 compared oral leukotriene receptor antagonists with placebo. The following outcomes were analyzed: daytime and nighttime nasal symptoms,14,18 –20,24,25 rhinoconjunctivitis quality of life,14,18,19,24,25 and eye symptoms (mean change from baseline or absolute values).14,24,25 Pooled analysis showed that oral leukotriene receptor antagonists significantly reduced daytime and nighttime nasal symptoms and eye symptoms compared with placebo (Table 2 and Fig 1). Also, leukotriene receptor antagonists produced significantly greater improvement compared with placebo in the quality-of-life overall score. No significant heterogeneity was demonstrated, which accepts the null hypothesis of similar treatment effects (low or null heterogeneity in all outcomes). Six studies14,18,19,24,25,28 compared oral leukotriene receptor antagonists with oral histamine H1 antagonists. Five studies14,18,19,24,25 used loratadine, and 1 study28 used cetirizine as histamine H1 antagonists. There were no significant differences in composite (daytime and nighttime) nasal symptoms,14,18,19,24,25 quality-of-life overall score,14,18,19,24,25, and eye symptoms14,24,25 in terms of mean change from baseline or absolute values (Table 2 and Fig 2). All comparisons were montelukast, 10 mg, vs loratadine, 10 mg. Again, these effects were homogeneous between studies (I2 ⫽ 0% in all outcomes). A leukotriene receptor antagonist was compared with intranasal corticosteroids in 3 studies.13,20,22 However, only 2
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Table 1. Characteristics of the 17 Trials Included in the Review Trial
Design
Patients, No. Jadad (age range, y) score
Duration of protocol, wk
Protocol
Outcomes
Pullerits et al, 199913
R, DB
62 (16–45)
3
3
Meltzer et al, 200014
R, DB
460 (15–75)
5
2
Wilson et al, 200015
R, SB
38 (16–65)
3
4
Wilson et al, 200116
R, SB, CO
22
3
2
Wilson et al, 200117
R, SB, CO
21
2
2
Nayak et al, 200118
R, DB, M
907 (15–82)
5
2
Philip et al, 200219 Pullerits et al, 200220
R, DB, M R, DB
1,302 (15–81) 62 (15–49)
4 2
2 8
Wilson et al, 200221
R, SB, CO
37
3
2
Ratner et al, 200322 Saengpanich et al, 200323
R, DB, M R, DB
705 (⬎15) 63 (⬎18)
2 3
2 2
van Adelsberg et al, 200324
R, DB, M
1,079 (15–82)
3
4
Z 20 mg ⫻2 vs BE 0.2 mg ⫻2 M 10 mg vs M 20 mg vs L 10 mg vs M 20 mg ⫹ L 10 mg vs PL C 10 mg vs C 10 mg ⫹ M 10 mg vs C 10 mg ⫹ M 20 mg M 10 mg ⫹ C 10 mg vs M 0.2 mg vs PL M 10 mg ⫹ C 10 mg vs B 0.2 mg ⫹ 0.4 mg vs PL M 10 mg vs L 10 mg vs M 10 mg ⫹ L 10 mg vs PL M 10 mg vs L 10 mg vs PL M 10 mg vs M 10 mg ⫹ L 10 mg vs F 0.2 mg vs PL M 10 mg ⫹ L 10 mg vs FE 120 mg vs PL M 10 mg vs F 0.2 mg M 10 mg ⫹ L 10 mg vs F 0.1 mg M 10 mg vs L 10 mg vs PL
van Adelsberg et al, 200325
R, DB, M
1,214 (15–85)
5
2
M 10 mg vs L 10 mg vs PL
Ciprandi et al, 200426
R, DB
60
3
2
Di Lorenzo et al, 200427
R, DB
100 (12–50)
4
6
Kurowski et al, 200428
R, DB
60 (18–35)
4
6
Moinuddin et al, 200429
R, DB
68 (18–45)
5
2
M 10 mg ⫹ C 10 mg vs M 10 mg ⫹ D 5 mg M 10 mg ⫹ F 0.2 mg vs M Nasal symptoms, eosinophil 10 mg ⫹ C 10 mg vs F 0.2 count mg ⫹ C 10 mg vs F 0.2 mg vs PL M 10 mg vs C 10 mg vs M Nasal and eye symptoms 10 mg ⫹ C 10 mg vs PL M 10 mg ⫹ L 10 mg vs FE Nasal symptoms, NPIF 60 mg ⫹ P 120 mg ⫻2
Total symptom score Nasal symptoms, QOL
Nasal and eye symptoms, NPIF Nasal and eye symptoms, NPIF, rhinomanometry Nasal and eye symptoms, NPIF, rhinomanometry Nasal symptoms, QOL Nasal symptoms, QOL Total symptom score Nasal and eye symptoms, NIPF Nasal symptoms Nasal and eye symptoms, QOL Nasal and eye symptoms, QOL, eosinophil count Nasal and eye symptoms, QOL, eosinophil count Nasal symptoms
Abbreviations: B, budesonide; BE, beclomethasone; C, cetirizine; CO, crossover; D, desloratadine; DB, double blind; F, fluticasone; FE, fexofenadine; L, loratadine; M, montelukast; Z, zafirlukast; NPIF, nasal peak inspiratory flow; P, pseudoephedrine; PL, placebo; QOL, quality of life; R, randomized; SB, single blind.
studies20,22 reported scores for daytime and nighttime nasal symptoms (change from baseline and absolute values). We found a significance difference in favor of topical corticosteroids (fluticasone) for decreasing daytime and nighttime nasal symptoms compared with leukotriene receptor antagonists (montelukast) (Table 2). These were again homogeneous findings (I2 ⫽ 0%). However, there was insufficient information to pool other outcomes. Studies of Leukotriene Receptor Antagonists Combined With Histamine H1 Antagonists Five studies14,15,18,21,28 tested the efficacy of leukotriene receptor antagonists plus oral histamine H1 antagonists compared
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with oral histamine H1 antagonists alone. Two studies14,18 compared montelukast-loratadine with loratadine alone, 1 study21 compared montelukast-loratadine with fexofenadine alone, and 1 study15 compared montelukast-cetirizine with cetirizine alone. Because of the small number of trials, differences in drugs and doses were not taken into account in the analysis. Only 3 studies14,15,21 reported eye symptoms. There was insufficient information to pool daytime nasal symptoms and quality of life. The combination of leukotriene receptor antagonists plus histamine H1 antagonists produced greater relief of eye symptoms compared with histamine H1 antagonists alone (Table 3 and Fig 3). This effect was homogeneous between studies (I2 ⫽ 0%).
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Table 2. Summary of Data From Studies of Oral Leukotriene Receptor Antagonists as Monotherapy Outcome
Studies, No.
SMD (95% CI)
P value
I2, %
Studies that compared oral leukotriene receptor antagonists with placebo (negative SMD values favored leukotriene receptor antagonists) Daytime nasal symptoms14,18–20,24,25 6 ⫺0.24 (⫺0.33 to ⫺0.16) ⬍.001 29 Nighttime nasal symptoms14,18–20,24,25 6 ⫺0.23 (⫺0.30 to ⫺0.16) ⬍.001 1 RQOL14,18,19,24,25 5 ⫺0.27 (⫺0.34 to ⫺0.19) ⬍.001 0 Eye symptoms14,24,25 3 ⫺0.17 (⫺0.27 to ⫺0.08) ⬍.001 18 Studies that compared oral leukotriene receptor antagonists with oral histamine H1 antagonists (negative SMD values favored leukotriene receptor antagonists) Composite (daytime and nighttime nasal 5 0.04 (⫺0.04 to 0.11) .37 0 symptoms14,18,19,24,25 RQOL14,18,19,24,25 5 0.04 (⫺0.04 to 0.12) .36 0 Eye symptoms14,24,25 3 ⫺0.02 (⫺0.09 to 0.13) .72 0 Studies that compared oral leukotriene receptor antagonists with topical corticosteroids (positive SMD values favored corticosteroids) Daytime nasal symptoms20,22 2 0.41 (0.27 to 0.56) ⬍.001 0 Nighttime nasal symptoms20,22 2 0.33 (0.18 to 0.48) ⬍.001 0 Abbreviations: CI, confidence interval; RQOL, rhinoconjunctivitis quality of life; SMD, standardized mean difference.
Figure 1. Pooled standardized mean differences (SMDs) in daytime nasal symptoms of studies comparing oral leukotriene receptor antagonists (treatment) with placebo (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
Five studies16,17,20,23,27 compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with intranasal corticosteroids. Scores for global nasal symptoms were reported in all the studies. Corticosteroids showed a trend toward greater relief of nasal symptoms, with low heterogeneity between studies (Table 3 and Fig 4). On the other hand, intranasal corticosteroids significantly reduced nasal congestion compared with leukotriene receptor antagonists plus histamine H1 antagonists.16,17,23,27 However, there was significant heterogeneity between the studies (I2 ⫽ 88%). When the low-quality studies16,17 were removed, homogeneity was achieved. There was insufficient information to pool other outcomes.
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Finally, there was insufficient information to pool other comparisons, such as oral leukotriene receptor antagonists plus oral histamine H1 antagonists compared with corticosteroids plus oral histamine H1 antagonists27; oral leukotriene receptor antagonists plus cetirizine compared with oral leukotriene receptor antagonists plus desloratadine26; montelukast, 10 mg, plus oral histamine H1 antagonists compared with montelukast, 20 mg, plus oral histamine H1 antagonists15; and oral leukotriene receptor antagonists plus histamine H1 antagonists compared with histamine H1 antagonists plus pseudoephedrine.29 A low incidence of adverse effects was observed.14,19,22,24 Most adverse events were rated mild, and there was no
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Figure 2. Pooled standardized mean differences (SMDs) in composite (daytime and nighttime) nasal symptoms of studies comparing oral leukotriene receptor antagonists (treatment) with oral histamine H1 antagonists (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary. Table 3. Summary of Data From Studies of Oral Leukotriene Receptor Antagonists Combined With Oral Histamine H1 Antagonists Outcome
Studies, No.
SMD (95% CI)
P value
Studies that compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with antagonists (negative values favored the combination of leukotriene receptor antagonists and oral antagonists) Eye symptoms14,15,21 3 ⫺0.30 (⫺0.53 to ⫺0.06) Studies that compared oral leukotriene receptor antagonists plus oral histamine H1 antagonists with corticosteroids (positive values favored corticosteroids) Total nasal symptoms16,17,20,23,27 5 0.23 (⫺0.13 to 0.60) Nasal congestion16,17,23,27 4 0.97 (0.01 to 1.92)
I2, %
oral histamine H1 histamine H1 .01 topical .22 .05
0
43 88
Abbreviations: CI, confidence interval; SMD, standardized mean difference.
Figure 3. Pooled standardized mean differences (SMDs) in eye symptoms of studies comparing oral leukotriene receptor antagonists plus oral histamine H1 antagonists (treatment) compared with oral histamine H1 antagonists (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
difference between groups. One of the most frequently reported adverse events was headache (3%–5% of patients treated with oral leukotriene receptor antagonists). DISCUSSION Meta-analysis is a statistical method that combines the results of several studies into a single outcome. Thus, by combining
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the samples of the individual studies, this method greatly increases the overall sample size, which increases the statistical power of the analysis and the precision of the estimate of the treatment effect. The purpose of this systematic review was to determine the efficacy of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of allergic rhinitis. This review identified dif-
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Figure 4. Pooled standardized mean differences (SMDs) in total nasal symptoms of studies comparing oral leukotriene receptor antagonists with oral histamine H1 antagonists (treatment) with topical corticosteroids (control). Evaluation included 2 to 4 weeks of treatment. The width of the horizontal line represents the 95% confidence interval (CI) around the point estimate. The size of the point estimate represents the relative weight (%) of each study in the pool summary.
ferent comparisons. As monotherapy, data showed that oral leukotriene receptor antagonists are more effective than placebo. Thus, leukotriene receptor antagonists reduced nasal (daytime and nighttime) and eye symptoms and improved the quality-of-life overall score. Furthermore, the results were homogeneous between the studies of the different measured outcomes. The analysis of studies that compared leukotriene receptor antagonists with oral histamine H1 antagonists demonstrated similar efficacy of both drugs at relieving allergic rhinitis symptoms. There were no differences in terms of nasal (daytime and nighttime) and eye symptoms and qualityof-life overall score. Again, the results were homogeneous between the studies of all measured outcomes. Finally, although there were only 2 studies comparing oral leukotriene receptor antagonists with intranasal corticosteroids, the pooled analysis showed that intranasal fluticasone provided significantly greater relief of daytime and nighttime nasal symptoms. The results were homogeneous. In the studies that evaluated the use of leukotriene receptor antagonists combined with other drugs for the treatment of allergic rhinitis, the combination of leukotriene receptor antagonists and histamine H1 antagonists was significantly more effective than histamine H1 antagonists alone. Thus, leukotriene receptor antagonists plus oral histamine H1 antagonists reduced eye symptoms. This indicates that this combination provides an additive effect compared with histamine H1 antagonists alone. Nevertheless, this conclusion is limited by the small number of pooled studies. On the other hand, intranasal corticosteroids showed a trend toward greater relief of nasal symptoms and a significant effect on nasal congestion. However, this last comparison presented high heterogeneity between the studies. The fact that fluticasone was more effective than the combination of leukotriene receptor antagonists and histamine H1 antagonists on nasal congestion is concordant with the effect of corticosteroids on the late phase of the allergic response. Because histamine and leukotrienes
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are not significant mediators of the late-phase allergic response, histamine H1 antagonists and leukotriene receptor antagonists are not usually effective at relieving late-phase symptoms, such as nasal congestion. In summary, the data suggest that intranasal corticosteroids are more effective than the combination of leukotriene receptor antagonists plus histamine H1 antagonists in alleviating nasal symptoms. Finally, in this review we also looked at adverse effects. However, they were difficult to analyze because of insufficient information to be pooled. A low incidence of adverse effects was observed, and most of them were rated mild or moderate. It is difficult to estimate in clinical terms the effect size obtained in the different comparisons because data were combined in the meta-analysis using the SMDs. However, if we interpret the effect size as small if it is 0.2 SD unit or less, as large if it is 0.8 SD unit or greater, and as medium otherwise, most of the differences between groups could be considered moderate, except the comparison between oral leukotriene receptor antagonists plus oral histamine H1 antagonists and intranasal corticosteroids (there was a large effect favoring topical corticosteroids). This study met most of the methodological criteria suggested for scientific reviews.30 A comprehensive search of the published literature for potentially relevant studies was conducted using a systematic strategy to avoid bias. All 17 trials were randomized and mostly13 double blind. All the studies included in the comparisons of leukotriene receptor antagonists as monotherapy were based on double-blind studies. We did not impose restrictions by language or year of publication, and the search results were complemented by hand searching of relevant journals. In addition, we evaluated the consistency of effects between studies to determine the generalizability of the findings; thus, we obtained low or null values of heterogeneity in almost all group comparisons. However, we cannot fully exclude publication bias because
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we did not perform a statistical test because these tests have very low power in meta-analyses of small numbers of trials. 14.
CONCLUSION This systematic review of the treatment of seasonal allergic rhinitis found evidence that leukotriene receptor antagonists as monotherapy were better than placebo, equivalent to oral antihistamines, and inferior to intranasal corticosteroids in terms of nasal and eye symptoms or quality of life in the first 2 comparisons and nasal symptoms in the last comparison. Alternatively, pooled data from studies that used oral leukotriene receptor antagonists combined with other drugs showed that leukotriene receptor antagonists plus antihistamines were more effective than an antihistamine alone but inferior to intranasal corticosteroids. However, these last 2 conclusions are limited by the small number of pooled studies and by the presence of heterogeneity between studies. Overall, these findings confirm the superiority of topical corticosteroids to antihistamines4 and also to leukotriene receptor antagonists and their combinations. REFERENCES 1. Nathan RA, Meltzer EO, Seiner JC, et al. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99: S808 –S814. 2. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact its impact on asthma. J Allergy Clin Immunol. 2001;108(suppl):S147–S334. 3. van Cauwenberge P, Bachert C, Passalacqua G, et al; European Academy of Allergology and Clinical Immunology. Consensus statement on the treatment of allergic rhinitis. Allergy. 2000;55: 116 –134. 4. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ. 1997;317: 1624 –1629. 5. Yan˜ez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2002;89:479 – 484. 6. Busse WW. The role of leukotriene in asthma and allergic rhinitis. Clin Exp Allergy. 1996;26:868 – 879. 7. Lipworth BJ. Emerging role of antileukotriene therapy in allergic rhinitis. Clin Exp Allergy. 2001;31:1813–1821. 8. Meltzer EO. Clinical evidence for antileukotriene therapy in the management of allergic rhinitis. Ann Allergy Asthma Immunol. 2002;88(suppl):23–29. 9. Nathan RA. Pharmacotherapy for allergic rhinitis: a critical review of leukotriene receptor antagonists compared with other treatments. Ann Allergy Asthma Immunol. 2003;90:182–191. 10. Jadad AR, Moore RA, Carrol D. Assessing the quality of reports of randomized controlled trials: is blinding necessary? Control Clin Trials. 1995;134:1–12. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 12. Higgins JPT, Thompson SG, Deecks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. 13. Pullerits T, Praks L, Skoogh BE, et al. Randomized placebocontrolled study comparing a leukotriene receptor antagonist
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plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis. Clin Exp Allergy. 2004;34:259 –267. 28. Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy. 2004;59:280 –288. 29. Moinuddin R, deTineo M, Maleckar B, et al. Comparison of the combination of fexofenadine-pseudoephedrine and loratadinemontelukast in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2004;92:73–79.
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30. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Lancet. 1999;354:1896 –1900. Requests for reprints should be addressed to: Gustavo J. Rodrigo, MD Departamento de Emergencia Hospital Central de las Fuerzas Armadas Av. 8 de Octubre 3020 Montevideo 11600, Uruguay E-mail: [email protected].
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