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Lung

, Volume 193, Issue 4, pp 477–486 | Cite as

The Effectiveness of Anti-leukotriene Agents in Patients with COPD: A Systemic Review and Meta-analysis

  • Jong Hoo Lee
  • Hyun Jung Kim
  • Yee Hyung KimEmail author
Article

Abstract

Background

Anti-leukotriene (anti-LT) agents have been not yet established for effectiveness in patients with chronic obstructive pulmonary disease (COPD). We performed a systematic review and meta-analysis to assess whether anti-LT agents have the responsiveness for COPD patients.

Methods

MEDLINE, EMBASE, Cochrane Central Register, and Korea Med were searched for relevant clinical trials to review.

Results

Seven studies involving 342 patients were finally analyzed. Pooled estimation from three randomized controlled studies did not demonstrate that anti-LT agents increased forced expiratory volume in 1 s [overall effect: 0.09 L, 95 % confidence interval (CI) −0.04 to 0.21; P = 0.17; I 2  = 41.0 %] or forced vital capacity (overall effect: 0.04 L, 95 % CI −0.04 to 0.11; P = 0.64; I 2 = 0.0 %). As for inflammatory markers, anti-LT agents did not affect the level of myeloperoxidase (standardized mean difference, −0.15; 95 % CI −0.65 to 0.36) or LTB4 (standardized mean difference, −0.41; 95 % CI −0.96 to 0.13). They reduced the frequency of dyspnea [relative risk (RR) 0.43; 95 % CI 0.29 to 0.64] and sputum (RR 0.37; 95 % CI 0.22 to 0.63), based on overall estimation from two non-randomized studies. However, our review revealed that there are few well-designed, randomized controlled studies with large sample sizes and long treatment durations.

Conclusion

Although symptomatic improvements were demonstrated in some studies, there is a lack of evidence to support the therapeutic efficacy of anti-LT agents in patients with COPD. Further large-scale, long-term studies are needed to identify predictive factors for COPD patients who may benefit from anti-LT agents.

Keywords

Leukotrienes Anti-leukotriene modifiers Chronic obstructive pulmonary disease Treatment 

Introduction

Leukotrienes (LTs) are generated through the 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) metabolism [1]. LTs can be classified into two types: leukotriene B4 (LTB4) and cysteinyl leukotrienes (Cys-LTs), including LTC4, LTD4, and LTE4 [1]. LTB4, one of the major eicosanoids of the 5-LO pathway, is a potent chemoattractant for neutrophils [1], which are key cells involved in the development and progression of chronic obstructive pulmonary disease (COPD) and several types of asthma, including asthma in smokers [1]. Cys-LTs constrict airway smooth muscle, induce mucous secretion, increase vascular permeability, and decrease mucociliary clearance [1]. Anti-leukotriene (anti-LT) agents to suppress the activity of LTs are largely classified into two groups: LT receptor antagonists (LTRAs) and LT synthesis inhibitors (LTSIs). LTRAs exert inhibitory activities to Cys-LTs at the receptor level, and include montelukast, zafirlukast, and pranlukast. LTSIs, including zileuton, BAYx1005, and MK-0591, suppress production of LTB4 through blocking 5-LO or 5-LO lipoxygenase activating protein (FLAP).

Several studies have demonstrated that LTs play a significant pathophysiological role in asthma [2, 3], and anti-LT agents are effective in the treatment of asthma [4]. Based upon existing evidence, current international guidelines for asthma treatment state that anti-LT agents can be used as a second-line monotherapy, as an alternative to β2-agonists, or as an additional option in patients with poorly controlled asthma despite combination treatment with inhaled corticosteroids/β2-agonists [5, 6].

On the contrary, anti-LT agents have not been officially approved for treatment of COPD. However, animal studies demonstrated 5-LO knockout mice had resistance to development of emphysema resulting from cigarette smoking [7], and montelukast was effective in ameliorating eosinophilic and neutrophilic inflammation as well as development of experimentally induced lung emphysema [8]. Some of clinical studies showed that LTB4 might be an exacerbation-associated inflammatory biomarker in COPD [9, 10]. Additionally, although studies have revealed that different inflammatory cells and mediators are involved in COPD and asthma, some patients with COPD have biological and physiological features consistent with asthma, and vice versa [11]. These means that an agent used in COPD or asthma could potentially be effective in the treatment of the other disease. For example, it has been shown that tiotropium, an anticholinergic first-line agent for the treatment of COPD, is effective in treating chronic asthma [12, 13, 14]. Numerous reports have also shown that anti-LT agents have additional benefits in other inflammatory diseases [4]. So, it is plausible to consider anti-LT agents as a therapeutic option in COPD.

Although short- and long-acting inhaled β2-agonists, anticholinergics, corticosteroids, and phosphodiesterase (PDE) inhibitors are available for patients with COPD, clinical response to each agent varies among individuals, and is insufficient in some patients with COPD. This indicates the need for novel or additional effective agents for COPD. Current international guidelines for COPD treatment state that anti-LT agents have not been adequately studied in patients with COPD and can therefore not be recommended [15]. Since the 2000s, several randomized controlled or observational trials of anti-LT agents in patients with COPD have been published. However, these studies suffer from small sample sizes, and it is unclear whether anti-LT agents are effective in treating COPD. Accordingly, we assessed whether anti-LT agents are effective agents for the treatment of COPD based on a systematic review of clinical trial data.

Methods

Data Sources and Search Strategy

To identify potentially relevant articles, a comprehensive search of four electronic databases (MEDLINE, EMBASE, Cochrane Central Register, and Korea Med) was performed up to July, 2014. Searches were limited to human studies reported in English. A highly sensitive search strategy was adopted using the following words and medical subject heading (MeSH) terms: antileukotrienes, antileukotriene, leukotriene antagonists, leukotriene receptor antagonists, montelukast, pranlukast, zafirlukast, zileuton, toluenesulfonyl, tosyl, lyprinol, pobilukast, verlukast, lung diseases, obstructive, pulmonary disease, chronic obstructive, pulmonary emphysema, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, chronic obstructive lung disease, obstructive lung disease, obstructive pulmonary disease, obstructive lung diseases, obstructive pulmonary diseases, and COPD. In addition, we performed a manual search of the references listed in relevant review articles. As this study was a systemic review of published articles, neither informed consent nor ethics approval was required.

Inclusion Criteria

A systematic review and meta-analysis were performed in studies that met the following criteria: (1) a randomized controlled or an non-randomized study that targeted adults over 40 years of age using anti-LT agents; (2) a treatment duration ≥2 weeks; (3) post-bronchodilator forced expiratory volume in 1 s (FEV1) <80 % of the predicted value; and (4) smoking history more than 10 pack-years. Studies targeting patients with asthma, overlap syndrome, or bronchiectasis were excluded.

Study Selection and Data Extraction

Two pulmonologists (JHL and YHK) independently retrieved potentially relevant studies and reviewed each study according to the predefined criteria for eligibility, and finally extracted data. Any disagreement in the process of study selection or data extraction was resolved through consensus. A predefined form was used to extract data from each study. We used only officially published data. Primary outcomes were changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). We also assessed changes in biological markers, acute exacerbation, and the frequency of the respiratory symptoms of sputum and dyspnea in response to anti-LT treatment, as well as changes in the requirement for oxygen therapy.

Quality Assessment

We used Cochrane Collaboration’s tool to assess the risk of bias of randomized controlled studies. A score of “high,” “low,” or “unclear” was assigned to the following items: (1) sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective outcome reporting, and (7) other sources of bias.

We also used the Newcastle-Ottawa quality assessment scale to assess the risk of bias in non-randomized studies. This scale uses a star system to assess the quality of a study in three domains: selection of study groups; comparability of groups; and ascertainment of outcomes. Studies that received a star in every domain were judged to be of “high” quality.

Statistical Analysis

Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analyses. Statistical significance was evaluated using a raw mean difference for continuous variables and risk ratios with 95 % confidence intervals (CIs) for dichotomous variables. Heterogeneity was assessed using I 2 statistics on a scale of 0–100 %. I 2 > 50 % indicated the presence of significant between-study heterogeneity. If necessary, we also investigated the influence of an individual study on the overall effect estimates by removing each study in turn to explore the robustness of the pooled effect. Subgroups were analyzed as necessary. Because the number of included trials was low, we could not estimate potential publication bias with a funnel plot for all outcomes. A P value <0.05 was considered statistically significant.

Results

Identification of Eligible Trials

A total of 896 published articles were initially identified through database searches. Six articles were identified by reviewing other sources. After removing duplicated articles, 730 articles were screened. Of these, 21 articles underwent a full-text review. Fourteen articles were excluded for the reasons presented in Fig. 1. Finally, seven trials were included in the final analysis, involving a total of 342 COPD patients [16, 17, 18, 19, 20, 21, 22]. Four of the trials had a randomized controlled design [16, 17, 18, 19], while the other three trials were non-randomized, observational studies [20, 21, 22]. The features of studies included for review are shown in Table 1. Assessment of quality for randomized controlled studies and non-randomized studies is demonstrated in Fig. 2 and Table 2, respectively.
Fig. 1

Flow chart of study selection

Table 1

Characteristics of the studies included in the meta-analysis

Study

Design

Patients (no.)

Age (mean ± SD)

Duration of trial

Population

Anti-leukotriene agents

Intervention protocol

Primary end-point

Main conclusion

Randomized controlled studies

 Woodruff [16]

Single-center, double-blind, placebo-controlled, parallel RCT

119

63 ± 9

2 weeks

COPD exacerbation

Zileuton

Zileuton 600 mg qid versus placebo

Hospital length of stay

Zileuton reduced urinary LTE4 level

No differences in hospital stay

 Gronke [17]

Single-center, double-blind, crossover RCT

24

64 ± 5

4 weeks

Moderate COPD

LTB019

LTB019 240 mg qd versus placebo

Sputum neutrophil numbers and percentages

No effect on sputum neutrophils or related cytokine levels

 Celik [18]

Single-center, single-blind, controlled, RCT

117

65 ± 9

2 months

Moderate to severe COPD

Montelukast

Ipratropium bromide 40 µg qid, formoterol 12 µg bid, and montelukast 10 mg qd versus ipratropium bromide and formoterol

No remarks

Montelukast improved lung function and symptom score

 Gompertz [19]

Single-center, double-blind, placebo-controlled, parallel RCT

17

67 ± 6

2 weeks

Moderate to severe COPD

BAYx1005

BAYx1005, 500 mg bid versus placebo

Neutrophilic bronchial inflammatory markers

BAYx1005 can reduce neutrophilic bronchial inflammation

Non-randomized, observational studies

 Moosavi [20]

Single-center, prospective, single-arm study

25

67 ± 5

2 weeks

Moderate to severe COPD

Zafirlukast

Zafirlukast 40 mg

Lung function

No bronchodilatory effect

 Gueli [21]

Single-center, a prospective single-arm study

20

72 ± 6

12 months

Mild to moderate COPD

Montelukast

Montelukast 10 mg

No remarks

Montelukast reduced LTB4 and IL-8 levels, and was associated with a decrease in the number of outpatient clinic visits, hospitalizations, and the duration of hospitalization

 Rubinstein [22]

Single-center, a retrospective, single-arm study

20

71 ± 10

At least 12 months

Moderate to severe COPD

Montelukast

Montelukast 10 mg

No remarks

Montelukast reduced the frequency of symptoms

No bronchodilatory effect

Fig. 2

Risk of bias summary (a) and risk of bias graph (b) for the randomized controlled studies included in the meta-analysis

Table 2

Quality assessment for non-randomized studies though Newcastle-Ottawa scale

Study

Selection of exposed and non-exposed cohorts

Comparability

Outcome of interest

Overall quality

Representativeness of exposed cohort

Selection of non-exposed cohort

Ascertainment of exposure

Outcome present at start of study

Comparability of cohorts

Assessment of outcome

Length of follow-up

Adequacy of follow-up

Moosavi [20]

NA

NA

Low

Gueli et al. [21]

NA

NR

NA

Low

Rubinstein [22]

NA

NA

Low

Studies that received a star in all of three domains were judged to be of “high” quality. Retrospective studies were all assumed to have adequate follow-up

NR not reported, NA not applicable

Bronchodilatory Effects

Overall, five studies reported FEV1 and FVC, respectively. In three randomized controlled studies [16, 17, 18], a random effect model showed that FEV1 and FVC improved by 0.09 L (95 % CI −0.04 to 0.21; P = 0.17; I 2  = 41.0 %) and 0.04 L (95 % CI −0.04 to 0.11; P = 0.37; I 2 = 0.0 %), respectively. However, these estimates did not reach statistical significance (Fig. 3a, b).
Fig. 3

Meta-analysis of the differences (L) in forced expiratory volume in 1 s (a) and forced vital capacity (b) for anti-leukotriene agents versus control in randomized controlled studies. LT leukotriene, SD standard difference, IV inverse variance, CI confidence interval, df degrees of freedom

Of three non-randomized studies, data regarding bronchodilator effects were available in two studies [18, 19] that assessed the efficacy of LTRAs. These studies were analyzed by a generic inverse variation method. There was no statistically significant improvement in FEV1 (overall effect: 0.03 L, 95 % CI −8.44 to 8.50; P = 0.99; I 2 = 0.0 %; Fig. 4).
Fig. 4

Meta-analysis of differences (%) in forced expiratory volume in 1 s for anti-leukotriene agents in non-randomized, observational studies. LT leukotriene, SD standard difference, IV inverse variance, CI confidence interval, df degrees of freedom

Effect on Biomarkers

We retrieved biomarker data from three randomized controlled studies [16, 17, 19]. Figure 5 shows the pooled biomarker data. Myeloperoxidase (MPO) [17, 19] and leukotriene B4 (LTB4) [16, 19] were assessed in two studies, respectively. There was no significant reduction in MPO level in response to treatment with anti-LT agents (standardized mean difference, −0.15; 95 % CI −0.65 to 0.36; P = 0.57; I 2 = 0 %). Furthermore, anti-LT agents did not decrease the level of LTB4 (standardized mean difference, −0.41; 95 % CI −0.96 to 0.13; P = 0.14; I 2 = 0 %).
Fig. 5

Meta-analysis of differences in the levels of myeloperoxidase (a) and leukotriene B4 (b) for anti-leukotriene agents versus control in randomized controlled studies. LT leukotriene, Std standard, SD standard difference, IV inverse variance, CI confidence interval, df degrees of freedom

Effect on Clinical Symptoms

We evaluated changes in dyspnea, sputum, and the need for oxygen therapy based on data reported in two non-randomized observational studies [21, 22]. In these studies, dyspnea and sputum were self-reported symptoms, and supplemental oxygen was discontinued or prescribed if transcutaneous oxyhemoglobin saturation was 90 % and above or 88 % and below, respectively. Treatment with anti-LT agents significantly reduced the number of patients with dyspnea [relative risk (RR) 0.43; 95 % CI 0.29 to 0.64; P < 0.0001; I 2 = 0.0 %] and sputum (RR 0.37; 95 % CI 0.22 to 0.63; P = 0.0003; I 2 = 0.0 %; Fig. 6a, b). In contrast, the need for oxygen therapy was not significantly reduced by anti-LT agents treatment (RR 0.69; 95 % CI 0.34 to 1.43; P = 0.32; I 2 = 0.0 %; Fig. 6c).
Fig. 6

Meta-analysis of the number of patients whose dyspnea (a) and sputum (b) remained, and who needed oxygen therapy (c) while administering anti-leukotriene agents in non-randomized, observational studies. LT leukotriene, M–H Mantel–Haenszel, CI confidence interval, df degrees of freedom

Discussion

None of the current COPD guidelines recommend anti-LT agents for COPD patients [15]. One reason for this is that existing clinical studies are not sufficiently large-scaled and/or well-designed to be conclusive. Systematic review and meta-analysis allow pooling of data from several clinical studies. We identified a total of seven clinical studies: four randomized controlled studies and three observational studies. Meta-analysis of these seven studies revealed that anti-LT agents are not effective in treating COPD.

The bronchodilatory effect of an agent is the one of the most important parameters considered in clinical studies of chronic airway diseases. Most clinical studies therefore evaluate lung function, especially FEV1, as a primary outcome. Although a few studies showed that anti-LT agents have a bronchodilatory effect in asthma or COPD [18, 23, 24], pooled estimates of FEV1 and FVC from the included studies, both randomized and non-randomized, showed that anti-LT treatment did not have a significant effect on FEV1 or FVC (Figs. 3, 4). This means that anti-LT agents have little bronchodilatory effect in patients with COPD. This is not unexpected, because anti-LT agents are not classified as bronchodilators, even in asthma guidelines [5, 25]. The short treatment duration (2 weeks to 2 months) may also have contributed to this outcome.

The anti-inflammatory effect of a given drug for treating chronic airway disease is also regarded as an important parameter to evaluate in clinical trials of drug efficacy. Because COPD is, in general, associated with excess neutrophilic activity, the anti-inflammatory effect of an agent, especially on neutrophils, is important for treating COPD. For example, PDE inhibitors such as roflumilast have been used as an adjuvant therapy to long-acting bronchodilators in some patients with severe COPD [15]. Anti-LT agents are classified into LTRAs and LTSIs. They have inhibitory activities on the 5-LO pathway, leading to a reduction in LTB4, which is a potent chemoattractant for inflammatory cells including lymphocytes, prolongs neutrophil survival, and delay neutrophil apoptosis [26]. Based on these results, anti-LT agents can be expected to have an effect on COPD.

In addition to the anti-inflammatory effect of anti-LT agents themselves, the overlap between asthma and COPD should also be considered. A subgroup of COPD patients shares clinical and biological features with asthma patients. Several studies have established increased production of cys-LTs and LTB4 in sputum or exhaled breath condensate of COPD patients [27, 28, 29, 30]. Similarly, a proportion of asthma patients have physiological and inflammatory profiles similar to COPD patients. For example, patients with non-eosinophilic phenotype asthma usually have a lower response to inhaled corticosteroids, the most important agent for asthma treatment [31]. Current-smoking asthmatics have less eosinophils and more neutrophils in their sputum and blood than never-smoking asthmatics [32], which are similar characteristics to COPD patients. A recent randomized controlled study showed that montelukast significantly increased the mean percentage of days with asthma control in a population of asthmatic patients actively smoking cigarettes [33]. In addition, airway inflammatory features during exacerbation in asthma and COPD are similar, and it was reported that Cys-LT1 receptor expression increased in the bronchial mucosa of patients with severe exacerbation of COPD [34]. Anti-LT agents therefore appear to be a logical treatment option for COPD.

To determine if clinical evidence supported the anti-inflammatory effect of anti-LT agents in COPD, we assessed changes in biological or inflammatory markers through pooled estimation. Unfortunately, we were able to evaluate only two biomarkers associated with inflammation: MPO and LTB4. Pooled analysis did not demonstrate a reduction in levels of these markers in response to anti-LT treatment (Fig. 5). Reasons for this negative outcome include the small number of studies (n = 2) included in our review and short duration of treatment (<4 weeks). Levels of other biological markers could potentially be influenced by anti-LT agents; however, no other markers reported in the clinical studies were suitable for pooled estimation.

Changes in symptoms are also important in COPD treatment. We assessed two symptoms—dyspnea and sputum—from two studies. Although our statistical analysis showed that these symptoms improved (Fig. 6a, b), we could not make a definitive conclusion, because each study had methodological limitations and the pooled estimates were based on data from observational studies.

In special, acute exacerbation as a primary end-point is one of the most important issues in that it is associated with rapid decline of lung function, poor quality of life, and mortality. However, it was unfortunate that none of the studies we included evaluated changes in exacerbation events due to the short treatment duration. Because of a lack of evidence as to exacerbation, we could not conclude whether anti-LT agents reduce the frequency of acute exacerbation or prolong time to the first exacerbation in patients with COPD or not. We need to keep in mind that COPD is a heterogenous disease. Many studies have shown that a proportion of COPD patients have eosinophil-dominant inflammation even in stable stage as well as increased sputum eosinophil count at the time of exacerbation [35]. This subgroup, namely COPD with eosinophilia, gets more benefit from inhaled corticosteroids. This suggests that a COPD subgroup shares a common pathophysiology with asthma and further might have benefit even from anti-LT agents as well as corticosteroids. Additionally, since smoking results in increased urinary excretion of LTs [36, 37], anti-LT agents might exert synergic effect in combination with bronchodilator with or without inhaled corticosteroids in current smoker with COPD. Therefore, we cannot completely rule out possibility that anti-LT agents can reduce acute exacerbation in a proportion of COPD patients.

Overall, our study revealed a paucity of randomized controlled studies of anti-LT treatment of COPD patients. Existing studies involved only a small number of COPD patients and treatment duration was short. The primary end-point and severity of disease varied among studies. In addition, we have to consider possibility that studies could include smokers with asthma. Because it is sometimes difficult to separate out COPD and asthma, a small portion of patients enrolled in COPD studies might be actually asthmatics with smoking history. Therefore, some of positive effects might be attributed to incomplete differentiation between COPD and asthma, not anti-LT agents itself. These limitations prohibited us from drawing strong conclusions.

In conclusion, our systemic review and meta-analysis did not demonstrate that anti-LT agents significantly improved lung function or decreased levels of inflammatory markers such as MPO and LTB4 in COPD patients. Furthermore, although anti-LT agents had a significant effect on the symptoms of dyspnea and sputum, the methodological limitations of the included studies prevented us from reaching a firm conclusion. Accordingly, anti-LT agents cannot be recommended in COPD patients until large-scale, well-designed, and long-term studies demonstrate the effectiveness of anti-LT agents in patients with COPD.

Notes

Acknowledgments

This work was supported by the research grant from Jeju National University Hospital. Jong Hoo Lee and Yee Hyung Kim planned this study, reviewed trials, collected and analyzed data. Jong Hoo Lee made the first draft of the manuscript. Yee Hyung Kim and Hyun Jung Kim revised the manuscript.

Conflict of interest

None.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Internal Medicine, School of Medicine, Jeju National University HospitalJeju National UniversityJeju CityKorea
  2. 2.Department of Preventive Medicine, Institute for Evidence-based Medicine, College of MedicineKorea UniversitySeoulKorea
  3. 3.Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at GangdongSchool of Medicine, Kyung Hee UniversitySeoulRepublic of Korea

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