Download A Network Meta-analysis of Randomized Controlled Trials Focusing

American Journal of Therapeutics 0, 1–11 (2015)
A Network Meta-analysis of Randomized Controlled Trials
Focusing on Different Allergic Rhinitis Medications
Juan Xiao, MM,1 Wen-Xu Wu, MB,2* Yuan-Yuan Ye, MM,3 Wen-Jun Lin, MM,4
and Lu Wang, MM4
This study is aimed to investigate the effectiveness of 4 allergic rhinitis (AR) drugs (loratadine, cetirizine,
montelukast, and desloratadine) in reducing functional problems in patients, as indicated by rhinoconjunctivitis quality of life questionnaire scores. After an exhaustive search of electronic databases containing published scientific literature, high-quality randomized controlled trials relevant to our study
were selected based on a stringent predefined inclusion and exclusion criteria. Statistical analyses were
conducted using STATA 12.0 and comprehensive meta-analysis (CMA 2.0) software. The literature
search broadly identified 386 studies, and after a multistep screening and elimination process, a total
of 13 randomized controlled trials contributed to this network meta-analysis. These 13 high-quality
studies contained a combined total of 6867 patients with AR on 4 different medications. The results
of network meta-analysis revealed that, compared with placebo, all 4 mediations treated AR effectively
[cetirizine: mean: 20.62, 95% confidence intervals (95% CI) 5 20.90 to 20.34, P , 0.001; loratadine:
mean: 20.32, 95% CI 5 20.55 to 20.097, P 5 0.005; montelukast: mean: 20.28, 95% CI 5 20.54 to
20.023, P 5 0.033; desloratadine: mean: 20.39, 95% CI 5 20.60 to 20.18, P , 0.001]. A comparison of
surface under the cumulative ranking curve values of these 4 interventions clearly showed that cetirizine
is the most optimal medication for AR treatment. In conclusion, this network meta-analysis provides the
first evidence that cetirizine is the most efficacious treatment for AR compared with loratadine, montelukast, and desloratadine, significantly reducing the functional problems in patients with AR.
Keywords: allergic rhinitis, rhinoconjunctivitis quality of life questionnaire, loratadine, cetirizine,
montelukast, desloratadine
INTRODUCTION
Allergic rhinitis (AR) is a symptomatic and inflammatory disorder of nasal mucosa, characterized by
nasal itching, paroxysmal repetitive sneezing, watery
rhinorrhea, reduced sense of smell, and nasal
1
Department of Liver Transplantation, The First Hospital of
Zhejiang University, Hangzhou, China; 2Departments of Science
and Education; 3The Operating Room; and 4Departments of
Orthopaedic, The First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China.
The authors have no conflicts of interest to declare.
*Address for correspondence: Department of Science and Education,
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325016, China. E-mail: [email protected]
congestion.1,2 AR is classified as seasonal or perennial,
depending on the sensitization to cyclic pollens or yearround allergens, such as dust mites, molds, and animal
dander.3 Interestingly, the number of patients with AR,
particularly with pollinosis, has markedly increased in
recent years.4 Epidemiologic studies revealed that AR
affects approximately 500 million people worldwide,
with high prevalence reported from industrialized nations, especially English-speaking countries.5 AR can
occur at any age, although most people first develop
symptoms in early childhood or young adulthood.6
The underlying disease mechanisms indicate that
AR is part of a systemic inflammatory response and is
associated with other inflammatory disorders of
mucous membranes, such as asthma, rhinosinusitis,
chronic otitis media, and allergic conjunctivitis.7,8
Poorly controlled AR symptoms result in decreased
www.americantherapeutics.com
2
health-related quality of life, daytime fatigue, poor sleep
quality, impaired learning and cognitive functions, and
decreased long-term productivity.6,9,10 The pathogenesis of AR involves both genetic and environmental factors and is aggravated by indoor and outdoor
environmental allergens.11 Therapeutic approach to
AR includes preventing allergen exposure or irritant
contact, pharmacotherapy, and immunotherapy.7 Several previous studies have demonstrated that antihistamines and leukotriene (LT) antagonists are the
commonly used agents for the treatment of AR.12,13
Histamine is the most common mediator in early
allergic response and cause smooth muscle contraction,
increase vascular permeability, and elevate mucus
secretion and sensory nerve stimulation, among other
symptoms of AR.14 The AR medications loratadine, cetirizine, and desloratadine are second-generation antihistamines effective in relieving histamine-mediated
symptoms.15,16 Notably, loratadine and desloratadine
have significantly reduced capabilities to cross the
blood–brain barrier; therefore, they exhibit reduced central nervous system side effects such as drowsiness.
Although the 2 drugs effectively stabilize ocular and
nasal symptoms, they have little effect in relieving nasal
congestion and are generally combined with nasal decongestants in formulations.14,17 The safety and efficacy
of cetirizine has been demonstrated in both perennial
AR and seasonal allergic rhinitis (SAR),18 and cetirizine
is effective in relieving allergic conjunctivitis symptoms
and nasal congestion.19,20 LT antagonists also play significant roles in treatment of AR.17 Montelukast is one
of the most commonly used agents in this category and
is considered to be effective in patients with SAR and
improves nasal obstruction.21 A number of studies have
shown that loratadine, cetirizine, desloratadine, and
montelukast have significant efficacy in AR management.18,22,23 However, the performance ranking of efficacy of these 4 drugs remains unknown, including the
comparison of their rhinoconjunctivitis quality of life
questionnaire (RQLQ) scores in patients with AR.9,24
Traditional meta-analyses combine the results of
homogeneous studies conducted on the same topic, and
the framework does not allow simultaneous comparisons
between more than 2 interventions.25 However, compared with the traditional meta-analysis, network metaanalysis framework enables indirect comparison using
a common comparator when a direct trial is not accessible
and also combines direct and indirect analytical approaches to simultaneously compare several interventions.26,27 Therefore, this study conducted a systematic
review including both traditional meta-analysis and network meta-analysis to evaluate more precisely the effects
of loratadine, cetirizine, desloratadine, and montelukast
on the RQLQ scores of patients with AR.
American Journal of Therapeutics (2015) 0(0)
Xiao et al
MATERIALS AND METHODS
Literature search
This systematic review was performed in accordance
with PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) guidelines. To retrieve relevant literature comparing drugs treatment in AR, we
comprehensively searched the following electronic databases: PubMed, Ovid, EBSCO, Springerlink, Wiley, Web
of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases (last updated search in October 2014), regardless
of language. Keywords used included placebo, loratadine, cetirizine, montelukast, desloratadine and allergic
rhinitis, Pollen Allergy and pollinosis in combination
with the Boolean operators AND, OR, and NOT. We
also manually searched related bibliographies to identify
studies that were missed in the electronic search.
Inclusion and exclusion criteria
Studies were selected for our network meta-analysis if
they met the following inclusion criteria: (1) study
design: randomized controlled trail (RCT), (2) interventions: drugs treatment in study group versus placebo treatment in control group, (3) study subject:
clinically diagnosed patients with AR based on the
AR and its impact on asthma (ARIA) guideline revised
by World Health Organization (WHO) in 2008,28 (4)
course of treatment $2 weeks, and (5) RQLQ was used
for the evaluation of quality of life for patients with
AR. The exclusion criteria were (1) insufficient data, (2)
non-RCT, (3) duplicated publications, and (4) combination use of drugs or treatments mixed with psychological intervention.
Data extraction and quality assessment
All data from eligible trials were extracted independently by 2 investigators using a standard form and
the following information was collected: first author,
publication year, country, ethnicity, language, disease,
age, gender, and number of cases. Any disagreements
on the merits of the extracted data were resolved by
discussion with the third investigator. Methodological
quality of the included RCTs was evaluated using
Cochrane Collaboration’s tool for assessing risk of bias
by 2 or more investigators.29 The risk of bias covers 6
domains, including random sequence generation, allocation concealment, blinding of participants or blinding outcome assessment, incomplete outcome data,
selective reporting, and other bias. The detailed assessment criteria were (1) whether allocation sequence is
generated properly, (2) whether the method used to
www.americantherapeutics.com
Number
First author
Year Country Drug 1 Drug 2
Gender (M/F)
Age (yrs)
Interventions
Drug 1
Drug 2
Drug 1
Drug 2
30.6 6 12.14
Drug 1
Drug 2
USA
228
225
101/127
104/121
31.9 6 12.22
USA
USA
USA
USA
431
301
155
301
431
149
149
155
143/288
110/191
53/102
110/191
150/281
63/86
63/86
53/102
37.8
37
35
37
Noonan et al41
van Adelsberg et al42
van Adelsberg et al42
van Adelsberg et al42
2003
2003
2003
2003
USA
USA
USA
USA
202
180
448
180
198
451
451
448
63/139
61/119
147/301
61/119
72/198
150/301
150/301
147/301
35.8 6 10.6
39 6 13 (15–79)
36 6 13 (15–82)
39 6 13 (15–79)
37.4 6 11.1
36 6 12 (15–82)
36 6 12 (15–82)
36 6 13 (15–82)
Cetirizine 10 mg
Loratadine 10 mg
Montelukast 10 mg
Loratadine 10 mg
Philip et al43
2004
USA
415
416
150/265
147/269
2005
2005
2005
Japan
Japan
Japan
28
30
28
27
27
30
14/14
14/16
14/14
11/16
11/16
14/16
33.6 6 13.7
(15–80)
34.6
34.6
34.1
Montelukast 10 mg
Hyo et al44
Hyo et al44
Hyo et al44
33.0 6 13.2
(15–78)
32.5
34.1
32.5
Loratadine 10 mg
Cetirizine 10 mg
Loratadine 10 mg
Pradalier et al45
Bachert and Maurer24
Demoly et al47
Holmberg et al48
Bousquet et al16
Jauregui et al15
2007 France
2010 Belgium
2009 France
2009 France
2010
USA
2011 Spain
234
242
118
293
360
242
249
245
115
291
356
245
121/113
126/116
58/60
NR
151/209
NR
129/120
118/127
44/71
NR
157/199
NR
32.7 6 10.7
29.8 6 10.6
40.3 6 13.8
NR
34.0 6 12.1
NR
32.4 6 11
30.6 6 10.6
39.2 6 12.4
NR
33.9 6 12.3
NR
Desloratadine
Desloratadine
Desloratadine
Desloratadine
Desloratadine
Desloratadine
6
6
6
6
10.8
13
11
13
36.5
37
37
35
6
6
6
6
10.6
13
13
11
Loratadine 10 mg
Placebo
Cetirizine 10 mg
Loratadine 10 mg
Montelukast 10 mg
Loratadine 10 mg
Placebo
Placebo
Placebo
Montelukast
10 mg
Placebo
Placebo
Placebo
Montelukast
10 mg
Placebo
5
5
5
5
5
5
mg
mg
mg
mg
mg
mg
Placebo
Placebo
Cetirizine
10 mg
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
F, female; M, male; NR, not reported.
3
American Journal of Therapeutics (2015) 0(0)
Van Cauwenberge and 2000
Juniper38
2002
Murray et al39
40
Nayak et al
2002
Nayak et al40
2002
Nayak et al40
2002
Drugs Treatment and Allergic Rhinitis
www.americantherapeutics.com
Table 1. The baseline characteristics for the included studies.
4
Xiao et al
human experimentation (REC Central) and with the
Helsinki Declaration of 1975, as revised in 2008.
Statistical analysis
FIGURE 1. Cochrane Collaboration’s tool for assessing
risk of bias of included RCTs.
Statistical analysis was conducted with STATA statistical
software (version 12.0; Stata Corp, College Station, TX)
and comprehensive meta-analysis (CMA 2.0) software.
Standard mean difference (SMD) with 95% confidence
intervals (95% CI) was calculated by applying a fixedeffects model or random-effects model for evaluating the
effects of the intervention group and control group on
RQLQ of patients with AR. The pooled effect size was
assessed using Z test.30 The Cochran’s Q-statistic (P ,
0.05 was considered significant) and I2 test (0%, no heterogeneity; 100%, maximal heterogeneity) were also
applied to reflect the heterogeneity among studies.31,32
A random-effects model was applied on case of an evidence of significant heterogeneity (P , 0.05 or I2 test
exhibited .50%), otherwise a fixed-effects model was
used.33 Network meta-analysis integrates data from
a network of trials involving more than 2 interventions.
The synthesis of indirect evidence (information about 2
intervention obtained from a common comparator) and
direct evidence (studies comparing the interventions
directly) enhances the precision in evaluation and produces a relative ranking of all the treatments for the
studied outcome.34 In each closed loop, we use the
inconsistency factor (IF) to evaluate the heterogeneity
among studies. If the 95% CIs of IF values are truncated
at zero, it suggests that the direction of the IF is unimportant.35 Funnel plots to identify the presence of smallstudy effects provide further validation of the reliability
of the results.36 The assumption of consistency models
allows the presence of heterogeneity of the intervention
effects among studies while no significant differences in
study design. After the generation of heterogeneity
matrix, frequentist method was used for the fitted model
to calculate the ranking probabilities.37
RESULTS
conceal the allocation sequence is appropriate, (3)
whether the intended blinding was effective, (4)
whether the incomplete outcome data are dealt with
appropriately, (5) state how selective outcome reporting was examined and what was found, and (6)
whether any other important concerns about bias are
covered in the other domains in the tool.
Ethical standards
The authors assert that all procedures contributing to
this work comply with the ethical standards of the
relevant national and institutional guidelines on
American Journal of Therapeutics (2015) 0(0)
Baseline characteristics of included studies
A total of 386 articles relevant to drugs treatment in
AR were initially reviewed. After excluding duplicates
(n 5 2), letters or reviews (n 5 5), nonhuman studies
(n 5 12), and studies unrelated to research topics (n 5
307) and 60 full-text articles remained. Thirteen studies15,16,38–48 ultimately met the inclusion criteria, after
we removed studies that were not RCTs (n 5 18) and
studies not associated with AR (n 5 5), and had no
relevance to the network (n 5 24). A combined total of
6867 patients with AR were enrolled in the 13 selected
www.americantherapeutics.com
Drugs Treatment and Allergic Rhinitis
5
FIGURE 2. Forest plots for comparison of effects on RQLQ scores of patients with AR between the intervention group
and control group.
RCTs (665 patients in loratadine group, 657 patients in
cetirizine group, 975 patients in montelukast, 1413 patients in desloratadine group, and 3157 patients in placebo group), and these studies were published
between 1998 and 2014. Of these 13 high-quality RCTs,
1 study was performed in Asians and 12 studies were
performed in whites. Three of the studies are 3-arm
trials and the rest are 2-arm trials, a total of 19 comparisons. The baseline characteristics of included studies and Cochrane assessment of risk of bias are
displayed in Table 1 and Figure 1, respectively.
Results of traditional meta-analysis
Heterogeneity test revealed a significant heterogeneity
among studies (I2 5 99.1%, P , 0.001), thus a randomeffects model was applied. Meta-analysis results
revealed that compared with placebo treatment, 3
medications loratadine, cetirizine, and desloratadine
effectively reduced the RQLQ scores of patients with
AR (loratadine: SMD 5 21.88, 95% CI 5 22.73
to 21.03, P , 0.001; cetirizine: SMD 5 21.36, 95%
CI 522.38 to 20.34, P 5 0.009; desloratadine:
SMD 5 20.91, 95% CI 5 21.80 to 20.02, P 5 0.045),
whereas montelukast and placebo did not show
statistically significant differences (SMD 5 21.64,
95% CI 5 23.53 to 20.25, P 5 0.089) (Figure 2). The
results of sensitivity analyses demonstrated that any
single study had no significant influence on the overall
effect size (SMDs) when comparing the differences of
RQLQ scores of the 4 antihistamine drugs and placebo
for AR treatment (Figures 3A–D).
www.americantherapeutics.com
Evidence network
The evidence network is shown in Figure 4. Connecting lines represent direct comparisons between 2
connected interventions and pairs of interventions
without connection can be compared indirectly
through network meta-analysis. The width of lines
corresponds to the number of trials. The size of nodes corresponds to the overall sample size of intervention. The color of lines represents the risk of bias
of enrolled trials. This study included 4 antihistamine drugs, loratadine, cetirizine, desloratadine,
and montelukast.
Contribution plot of network meta-analysis
Each direct comparison in network meta-analysis contributes differently to the evaluation of the network
pooled effects, and the details were shown in Figure 5:
(1) 4 of the studies had the direct comparison between
loratadine and placebo, whose percentage contribution
to loratadine and cetirizine, loratadine and montelukast, and loratadine and desloratadine was 50%, 50%,
and 50%, respectively; 25% to the whole network
meta-analysis; (2) 3 of the studies had the direct comparison between cetirizine and placebo, whose percentage contribution to loratadine and cetirizine,
cetirizine and montelukast, and cetirizine and desloratadine was 50%, 50%, and 50%, respectively; 25%
contribution to the whole network meta-analysis; (3)
3 of the studies had the direct comparison between
montelukast and placebo, whose percentage contribution to loratadine and montelukast, cetirizine and
montelukast, and montelukast and desloratadine was
American Journal of Therapeutics (2015) 0(0)
6
Xiao et al
FIGURE 3. Sensitivity analysis about the effects difference in rhinoconjunctivitis quality of life questionnaire (RQLQ)
scores of allergic rhinitis (AR) patients between intervention groups and placebo group: (A) loratadine group versus
placebo group; (B) cetirizine group versus placebo group; (C) montelukast group versus placebo group; (D) desloratadine group versus placebo group.
50%, 50%, and 50%, respectively; 25% contribution to
the whole network meta-analysis; (4) 6 of the studies
had the direct comparison between desloratadine and
American Journal of Therapeutics (2015) 0(0)
placebo, whose percentage contribution to loratadine
and desloratadine, cetirizine and desloratadine, and
montelukast and desloratadine was 50%, 50%, and
www.americantherapeutics.com
Drugs Treatment and Allergic Rhinitis
7
Comparisons of efficacy
FIGURE 4. The evidence network of enrolled studies in
this network meta-analysis.
50%, respectively; 25% contribution to the whole network meta-analysis.
Evaluating and presenting assumptions of network
meta-analysis
Inconsistency plot was applied to test the heterogeneity among studies in closed loop of this network
meta-analysis (Figure 6). This network meta-analysis
consisted of 2 triangular loops, including loratadine–
cetirizine–placebo loop and loratadine–montelukast–
placebo loop. The 95% CIs of IF values were truncated
at zero, suggesting there was no significant inconsistency. The P values of the 2 triangular loops (P 5 0.450
and 0.970, respectively) further confirmed that the
direct comparisons and indirect comparisons of the 4
drugs had consistency.
Network meta-analysis results demonstrated that
compared with placebo, the 4 drugs, cetirizine, loratadine, montelukast, and desloratadine, effectively treated AR (cetirizine: mean: 20.62, 95% CI 5 20.90 to
20.34, P , 0.001; loratadine: mean: 20.32, 95% CI 5
20.55 to 20.097, P 5 0.005; montelukast: mean: 20.28,
95% CI 5 20.54 to 20.023, P 5 0.033; desloratadine:
mean: 20.39, 95% CI 5 20.60 to 20.18, P , 0.001).
After ignoring covariance, further analysis suggested
significant differences among the results (Table 2). Relative efficacy of the 4 drugs is shown in Figure 7 (black
corresponds to 95% CI and red corresponds to 95%
predictive intervals).
Ranking of interventions
The cumulative probability ranking of interventions is
shown in Figure 8. The surface under the cumulative
ranking curve values of the 5 interventions were 8.5%
for placebo, 50.3% for loratadine, 87.1% for cetirizine,
44.5% for montelukast, and 59.6% for desloratadine,
suggesting that cetirizine is the most optimal drug
for AR treatment compared with loratadine, montelukast, and desloratadine.
Assessment of publication bias
Figure 9 shows the funnel plot for the 5 interventions
network, which provides an indication for the
presence of small-study effect. All the included studies symmetrically distribute around the vertical line
(x 5 0), suggesting no small-study effect in the
network.
FIGURE 5. Contribution plot of enrolled studies in this network meta-analysis.
www.americantherapeutics.com
American Journal of Therapeutics (2015) 0(0)
8
Xiao et al
FIGURE 6. Inconsistency test for direct and indirect comparison: (A) placebo; (B) loratadine; (C) cetirizine; (D) montelukast;
(E) desloratadine.
DISCUSSION
The present network meta-analysis was based on 13
RCTs involving 6867 individuals and compared the
effects of 4 drugs on the RQLQ scores in patients with
AR. Our results demonstrated that compared with placebo, cetirizine, loratadine, montelukast, and desloratadine are effective in treating AR. Surface under the
cumulative ranking curve values of these interventions
suggested that cetirizine is the most optimal drug for
the treatment of AR. Atopy is an exaggerated IgEmediated immune response in a type I-hypersensitive
reaction mounted against ubiquitous and innocuous
environmental allergens, and AR is an atopic disease.49 In response to antigens entering into the
mucous membrane, IgE antibodies in the regional
lymphatic tissues and nasal mucosa bind to the antigens and cause release of histamine, proteases, and
chemotactic factors.7 The antigen–antibody reaction
also triggers production of other chemical mediators,
such as prostaglandins and peptide LTs, which stimulates the sensory nerve endings and blood vessels of
the nasal mucosa to cause pain, sneezing, pruritus,
watery rhinorrhea, and nasal congestion.17 LTs and
histamine generated by mast cells and other inflammatory cells cause vasodilation, nasal mucosal swelling, mucus hypersecretion, and increased capillary
permeability.12,50 For these reasons, antihistamines
and LT antagonists are widely used for the treatment
of AR.12,13 Our study involved 3 antihistamine drugs,
loratadine, cetirizine, and desloratadine. Previous
RCTs showed that, compared with placebo, the
second-generation antihistamines loratadine, cetirizine, and desloratadine are effective at relieving
histamine-mediated symptoms in AR.15,16 Other studies revealed that compared with loratadine and desloratadine, allergic conjunctivitis symptom and
nasal congestion were effectively treated with cetirizine, with an added benefit of lack of sedation.14,17,19
Montelukast is one of the most commonly used LT
antagonist and is effective in patients with SAR and
improves nasal obstruction.21 Recent studies have revealed that montelukast improves disease-specific
quality of life in patients with persistent AR better
than placebo.9,23 Consistent with most previous studies, our result confirm that compared with placebo,
effective AR treatment is achieved with cetirizine, loratadine, montelukast, and desloratadine. However,
ranking of efficacy of the 4 interventions in AR treatment is unknown.
Our study represents the first work to exploit network meta-analysis framework to simultaneously compare the effects of different drugs on RQLQ scores in
patients with AR. The result of our study demonstrated
Table 2. Therapeutic efficacy of each drug compared with placebo.
Therapeutic efficacy (correlation not ignored)
Drug
Mean
Loratadine
Cetirizine
Montelukast
Desloratadine
20.32
20.62
20.28
20.39
95% CI
20.55
20.90
20.54
20.60
to
to
to
to
20.097
20.34
20.023
20.18
American Journal of Therapeutics (2015) 0(0)
Therapeutic efficacy (correlation ignored)
Z
P
Mean
22.79
24.30
22.14
23.62
0.005
0.000
0.033
0.000
20.33
20.63
20.28
20.39
95% CI
20.57
20.93
20.56
20.61
to
to
to
to
20.091
20.33
20.013
20.17
Z
P
22.71
24.18
22.05
23.48
0.007
0.000
0.040
0.000
www.americantherapeutics.com
Drugs Treatment and Allergic Rhinitis
9
FIGURE 7. The confidence intervals of estimates (black corresponds to 95% CI and red corresponds to 95% predictive
intervals).
that cetirizine is the optimal drug for the treatment of
AR, when compared with 3 other interventions. The
strengths of our network meta-analysis are first, we
compared interventions indirectly when no head-tohead trial existed to obtain more precise efficacy
estimates. Second, our updated integration of existing
evidence provides new insights about the quality of
life of patients with AR, with important implications
in future research. Finally, the 95% CI of IF values are
truncated at zero, suggesting there is no inconsistency
in our network meta-analysis. Our study also has
limitations. First, only 13 RCTs were enrolled in our
FIGURE 8. Plots of the surface under the cumulative ranking curves for all treatments in the AR network.
www.americantherapeutics.com
American Journal of Therapeutics (2015) 0(0)
10
FIGURE 9. Publications bias assessment for the 13 RCTs.
study, and the number of included studies was relatively small. Second, because of the limited data on
other drugs from our enrolled trials, we were able to
analyze only 4 drugs and other drugs were not considered for analysis. Third, our network metaanalysis did not perform subgroup stratification
based on drug dosage because of the lack of relevant
details in selected studies. Finally, although all the
enrolled RCTs mentioned the study design as
a blinded, randomized, controlled method, there
was no detailed evidence of randomization, which
might have impacted our results.
CONCLUSIONS
This network meta-analysis provides strong evidence that
cetirizine is the most optimal drug for the treatment of AR
compared with placebo, loratadine, montelukast, and desloratadine. The use of cetirizine significantly reduced
functional problems in patients with AR. Our conclusions
will need to be confirmed by a more adequately designed
study with large sample size and a more appropriate
multivariate analysis for future clinical applications.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to reviewers for their critical comments.
REFERENCES
1. Krouse HJ, Krouse JH. Allergic rhinitis: diagnosis through
management. Nurse Pract. 2014;39:20–28; quiz 29.
American Journal of Therapeutics (2015) 0(0)
Xiao et al
2. Small P, Kim H. Allergic rhinitis. Allergy Asthma Clin
Immunol. 2011;7(Suppl 1):S3.
3. Becker S, Pflugbeil C, Groger M, et al. Olfactory dysfunction in seasonal and perennial allergic rhinitis. Acta Otolaryngol. 2012;132:763–768.
4. Okubo K, Kurono Y, Fujieda S, et al. Japanese guideline
for allergic rhinitis. Allergol Int. 2011;60:171–189.
5. Eriksson J, Ekerljung L, Ronmark E, et al. Update of
prevalence of self-reported allergic rhinitis and chronic
nasal symptoms among adults in Sweden. Clin Respir J.
2012;6:159–168.
6. Meltzer EO, Gross GN, Katial R, et al. Allergic rhinitis
substantially impacts patient quality of life: findings
from the Nasal Allergy Survey Assessing Limitations.
J Fam Pract. 2012;61:S5–S10.
7. Greiner AN, Hellings PW, Rotiroti G, et al. Allergic rhinitis. Lancet. 2011;378:2112–2122.
8. Akbar NA, Zacharek MA. Vitamin D: immunomodulation of asthma, allergic rhinitis, and chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2011;19:
224–228.
9. Ciebiada M, Ciebiada MG, Kmiecik T, et al. Quality of
life in patients with persistent allergic rhinitis treated
with montelukast alone or in combination with levocetirizine or desloratadine. J Investig Allergol Clin Immunol.
2008;18:343–349.
10. Dykewicz MS, Hamilos DL. Rhinitis and sinusitis.
J Allergy Clin Immunol. 2010;125:S103–S115.
11. Marple BF. Allergic rhinitis and inflammatory airway
disease: interactions within the unified airspace. Am J
Rhinol Allergy. 2010;24:249–254.
12. Cobanoglu B, Toskala E, Ural A, et al. Role of leukotriene
antagonists and antihistamines in the treatment of allergic rhinitis. Curr Allergy Asthma Rep. 2013;13:203–208.
13. Cingi C, Gunhan K, Gage-White L, et al. Efficacy of leukotriene antagonists as concomitant therapy in allergic
rhinitis. Laryngoscope. 2010;120:1718–1723.
14. Sur DK, Scandale S. Treatment of allergic rhinitis. Am
Fam Physician. 2010;81:1440–1446.
15. Jauregui I, Bartra J, del Cuvillo A, et al. Bilastine and
quality of life. J Investig Allergol Clin Immunol. 2011;21
(Suppl 3):16–23.
16. Bousquet J, Bachert C, Canonica GW, et al. Efficacy of
desloratadine in persistent allergic rhinitis—a GA(2)LEN
study. Int Arch Allergy Immunol. 2010;153:395–402.
17. Min YG. The pathophysiology, diagnosis and treatment
of allergic rhinitis. Allergy Asthma Immunol Res. 2010;2:
65–76.
18. Ellis AK, Zhu Y, Steacy LM, et al. A four-way, doubleblind, randomized, placebo controlled study to determine the efficacy and speed of azelastine nasal spray,
versus loratadine, and cetirizine in adult subjects with
allergen-induced seasonal allergic rhinitis. Allergy
Asthma Clin Immunol. 2013;9:16.
19. Hoyte FC, Katial RK. Antihistamine therapy in allergic
rhinitis. Immunol Allergy Clin North Am. 2011;31:509–543.
20. Lee CF, Sun HL, Lu KH, et al. The comparison of cetirizine, levocetirizine and placebo for the treatment of
www.americantherapeutics.com
Drugs Treatment and Allergic Rhinitis
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
childhood perennial allergic rhinitis. Pediatr Allergy Immunol. 2009;20:493–499.
Blaiss MS. Allergic rhinitis: direct and indirect costs.
Allergy Asthma Proc. 2010;31:375–380.
Simons FE, Simons KJ. H1 antihistamines: current status and future directions. World Allergy Organ J. 2008;1:
145–155.
Cingi C, Ozlugedik S. Effects of montelukast on quality
of life in patients with persistent allergic rhinitis. Otolaryngol Head Neck Surg. 2010;142:654–658.
Bachert C, Maurer M. Safety and efficacy of desloratadine in subjects with seasonal allergic rhinitis or chronic
urticaria: results of four postmarketing surveillance studies. Clin Drug Investig. 2010;30:109–122.
Peruzzi M, De Luca L, Thomsen HS, et al. A network
meta-analysis on randomized trials focusing on the preventive effect of statins on contrast-induced nephropathy. Biomed Res Int. 2014;2014:213239.
Sutton A, Ades AE, Cooper N, et al. Use of indirect and
mixed treatment comparisons for technology assessment. Pharmacoeconomics. 2008;26:753–767.
Liao WC, Chien KL, Lin YL, et al. Adjuvant treatments
for resected pancreatic adenocarcinoma: a systematic
review and network meta-analysis. Lancet Oncol. 2013;
14:1095–1103.
Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis
and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)
LEN and AllerGen). Allergy. 2008;63(Suppl 86):8–160.
Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in
randomized trials. BMJ. 2011;343:d5928.
Chen H, Manning AK, Dupuis J. A method of moments
estimator for random effect multivariate meta-analysis.
Biometrics. 2012;68:1278–1284.
Jackson D, White IR, Riley RD. Quantifying the impact of
between-study heterogeneity in multivariate meta-analyses. Stat Med. 2012;31:3805–3820.
Peters JL, Sutton AJ, Jones DR, et al. Comparison of two
methods to detect publication bias in meta-analysis.
JAMA. 2006;295:676–680.
Zintzaras E, Ioannidis JP. Heterogeneity testing in metaanalysis of genome searches. Genet Epidemiol. 2005;28:
123–137.
Chaimani A, Higgins JP, Mavridis D, et al. Graphical
tools for network meta-analysis in STATA. PLoS One.
2013;8:e76654.
Song F, Altman DG, Glenny AM, et al. Validity of indirect comparison for estimating efficacy of competing
interventions: empirical evidence from published metaanalyses. BMJ. 2003;326:472.
Egger M, Davey Smith G, Schneider M, et al. Bias in
meta-analysis detected by a simple, graphical test. BMJ.
1997;315:629–634.
White IR, Barrett JK, Jackson D, et al. Consistency and
inconsistency in network meta-analysis: model estimation
www.americantherapeutics.com
11
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
using multivariate meta-regression. Res Synth Methods.
2012;3:111–125.
Van Cauwenberge P, Juniper EF. Comparison of the efficacy, safety and quality of life provided by fexofenadine
hydrochloride 120 mg, loratadine 10 mg and placebo
administered once daily for the treatment of seasonal
allergic rhinitis. Clin Exp Allergy. 2000;30:891–899.
Murray JJ, Nathan RA, Bronsky EA, et al. Comprehensive evaluation of cetirizine in the management of seasonal allergic rhinitis: impact on symptoms, quality of
life, productivity, and activity impairment. Allergy
Asthma Proc. 2002;23:391–398.
Nayak AS, Philip G, Lu S, et al. Efficacy and tolerability
of montelukast alone or in combination with loratadine
in seasonal allergic rhinitis: a multicenter, randomized,
double-blind, placebo-controlled trial performed in the
fall. Ann Allergy Asthma Immunol. 2002;88:592–600.
Noonan MJ, Raphael GD, Nayak A, et al. The healthrelated quality of life effects of once-daily cetirizine
HCl in patients with seasonal allergic rhinitis: a randomized double-blind, placebo-controlled trial. Clin Exp
Allergy. 2003;33:351–358.
van Adelsberg J, Philip G, Pedinoff AJ, et al. Montelukast
improves symptoms of seasonal allergic rhinitis over
a 4-week treatment period. Allergy. 2003;58:1268–1276.
Philip G, Nayak AS, Berger WE, et al. The effect of montelukast on rhinitis symptoms in patients with asthma
and seasonal allergic rhinitis. Curr Med Res Opin. 2004;
20:1549–1558.
Hyo S, Fujieda S, Kawada R, et al. The efficacy of shortterm administration of 3 antihistamines vs placebo under
natural exposure to Japanese cedar pollen. Ann Allergy
Asthma Immunol. 2005;94:457–464.
Pradalier A, Neukirch C, Dreyfus I, et al. Desloratadine improves quality of life and symptom severity
in patients with allergic rhinitis. Allergy. 2007;62:
1331–1334.
Bachert C, Kuna P, Sanquer F, et al. Comparison of the
efficacy and safety of bilastine 20 mg vs desloratadine 5
mg in seasonal allergic rhinitis patients. Allergy. 2009;64:
158–165.
Demoly P, Dreyfus I, Dhivert-Donnadieu H, et al. Desloratadine for the treatment of cypress pollen-induced
allergic rhinitis. Ann Allergy Asthma Immunol. 2009;64:
103:260–266.
Holmberg K, Tonnel AB, Dreyfus I, et al. Desloratadine
relieves nasal congestion and improves quality-of-life in
persistent allergic rhinitis. Allergy. 2009;1663–1670.
Okubo K, Kurono Y, Fujieda S, et al. Japanese guideline
for allergic rhinitis 2014. Allergol Int. 2014;63:357–375.
Klimek L, Hogger P, Pfaar O. Mechanism of action of nasal
glucocorticosteroids in the treatment of allergic rhinitis.
Part 1: pathophysiology, molecular basis [in German].
HNO. 2012;60:611–617.
American Journal of Therapeutics (2015) 0(0)