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LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis
Journal Pre-proof Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis Luigino Calzetta, Fabiano Di Marco, Francesco Blasi, Mario Cazzola, Stefano Centanni, Claudio Micheletto, Andrea Rossi, Paola Rogliani PII:
S1094-5539(19)30162-2
DOI:
https://doi.org/10.1016/j.pupt.2019.101855
Reference:
YPUPT 101855
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 3 July 2019 Revised Date:
14 October 2019
Accepted Date: 14 October 2019
Please cite this article as: Calzetta L, Di Marco F, Blasi F, Cazzola M, Centanni S, Micheletto C, Rossi A, Rogliani P, Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis, Pulmonary Pharmacology & Therapeutics (2019), doi: https://doi.org/10.1016/ j.pupt.2019.101855. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: a network meta-analysis 1
2
3
1
4
Luigino Calzetta , Fabiano Di Marco *, Francesco Blasi , Mario Cazzola , Stefano Centanni , 5
6
1
Claudio Micheletto , Andrea Rossi , Paola Rogliani
1. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy 2. Department of Health Sciences, University of Milan, Respiratory Unit ASST – Papa Giovanni XXIII Hospital, Bergamo, Italy 3. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Department of Internal Medicine, Respiratory Unit and Adult Cystic Fibrosis Center, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy 4. Department of Health Sciences, University of Milan Respiratory Unit, ASST Santi Paolo e Carlo, Milan, Italy 5. Cardio-Thoracic Department, Respiratory Unit, Integrated University Hospital, Verona, Italy 6. Respiratory Section, Department of Medicine, University of Verona, Italy
Correspondence: Fabiano Di Marco Department of Health Sciences, University of Milan, Respiratory Unit ASST – Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy Tel: +39 035 2673444 Email [email protected].
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Abstract Background: Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixeddose combinations (FDCs) and LABA/long-acting muscarinic antagonist (LAMA) FDCs are extensively used to treat chronic obstructive pulmonary disease (COPD). The aim of the present network meta-analysis was to assess the comparative efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. Methods: A network meta-analysis (≥3 nodes, Bayesian method) was performed by searching for randomized clinical trials (RCTs) that compared the impact of different LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. The primary endpoints were: the change from baseline in trough forced expiratory volume in 1 s (FEV1) and the risk of exacerbation of COPD (AECOPD). The secondary endpoints were: peak FEV1, St’ George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), and rescue medication use. Results: Data of 17,734 COPD patients were extracted from 16 RCTs. The length of treatment ranged from 6 weeks to 52 weeks. All LABA/LAMA FDCs, except aclidinium/formoterol, produced a statistically significant improvement compared to ICS/LABAs in trough FEV1. The surface under the cumulative ranking curve (SUCRA) analysis indicated that umeclidinium/vilanterol, glycopyrronium/indacaterol and glycopyrrolate/formoterol fumarate were the most effective FDCs in improving trough FEV1. Across the FDCs analyzed for the risk of AECOPD, glycopyrronium/indacaterol significantly reduced the exacerbation risk compared to fluticasone propionate/salmeterol and resulted
2
the most effective combination in the SUCRA analysis. Similar trend were also observed for the peak FEV1. No significant differences were detected across the investigated FDCs regarding SGRQ, TDI, and use of rescue medication. Conclusions: The results of this meta-analysis show that LABA/LAMA combinations are consistently more effective than ICS/LABA FDCs for most of the evaluated outcomes. However, differences have also been observed between FDCs belonging to the same class. Across the investigated LABA/LAMA FDCs, glycopyrronium/indacaterol revealed a consistent and robust efficacy profile. Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, longacting β2 agonist, long-acting muscarinic antagonist, network meta-analysis, trough forced expiratory volume in 1 s, exacerbation
3
1. Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document states that “Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disorder characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” [1]. Therapeutic strategies for COPD aim to prevent the deterioration of lung function, alleviate symptoms, and prevent exacerbations [2]. The pharmacological armamentarium of COPD include short-acting bronchodilators, long-acting bronchodilators such as muscarinic antagonists (LAMA) and longacting β-agonists (LABA), and inhaled corticosteroids (ICS) [3]. The international GOLD document suggests as initial strategy the use of a single bronchodilator and, in case of persistent symptoms and/or exacerbations, they recommend to escalate to a dual therapy with LABA/LAMA fixed-dose combinations (FDCs) or ICS/LABA FDCs (in case of high blood eosinophil count) [1, 4]. For patients treated with a dual therapy who continue to experience severe symptom burden and frequent exacerbations, the same document suggests to consider switching inhaler device or molecules or to step up to triple therapy (ICS/LABA/LAMA) in case of high blood eosinophil count [1, 4]. Given the variety of available pharmacologic treatments for COPD, the choice of appropriate dual therapy is crucial to reduce the frequency and severity of symptoms and possible complications, and to establish the next therapy. Despite international recommendations and recent evidence supporting the efficacy of bronchodilators (as monotherapy or in combination) in the early 4
stage of the disease, ICS/LABA are often inappropriately prescribed as initial therapy, leading to the inevitable drift to triple therapy and overuse of ICS [5]. Symptomatic patients with a history of frequent exacerbations (moderate-tosevere COPD) have been suggested as the appropriate candidates for regular ICS treatment in addition to long acting bronchodilators [6]. So far, several randomized controlled trials (RCTs) have evaluated the efficacy of dual therapy strategies for the maintenance treatment of COPD [7-9], however studies evaluating the most effective combination of drugs, including newer agents in different doses, have not been conducted yet. The aim of the present network meta-analysis is to compare the efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. In particular, this study aimed to compare and rank LABA/LAMA FDCs and ICS/LABA FDCs on trough forced expiratory volume in 1 s (FEV1) and risk of acute exacerbation of COPD (AECOPD).
2. Materials and methods 2.1. Search strategy This network meta-analysis has been registered in PROSPERO (registration number: CRD42018093075), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [10]. The PRISMA flow diagram is reported in Figure 1. This quantitative synthesis satisfied all the recommended items reported by the PRISMA-P checklist (Table S1) [10].
5
Two reviewers performed a comprehensive literature search for randomized controlled trials (RCTs) evaluating the effects of LABA/LAMA FDCs vs. ICS/LABA FDCs in COPD patients. The PICO (Patient problem, Intervention, Comparison, and Outcome) framework was used to develop the literature search strategy, as previously described [11]. Namely, the "Patient problem” included
subject
affected
by
COPD;
the
“Intervention”
regarded
the
administration of LABA/LAMA FDC therapy; the “Comparison” was performed with regard to ICS/LABA FDC therapy; the “Outcomes” were lung function, risk of acute exacerbation of COPD (AECOPD), health-related quality of life (HRQoL), dyspnea, and rescue medication. The terms “COPD” or “chronic obstructive pulmonary disease” were searched for the patient problem; the terms “aclidinium AND formoterol” OR “glycopyrronium AND formoterol” OR “glycopyrrolate AND formoterol” OR “glycopyrronium AND indacaterol” “glycopyrrolate AND indacaterol” OR “tiotropium AND olodaterol” OR “umeclidinium AND vilanterol” were searched for
the
intervention;
the
terms
“fluticasone
AND
salmeterol”
OR
“beclomethasone AND formoterol” OR “budesonide AND formoterol” OR “fluticasone AND vilanterol” were searched for the comparison. The literature search was performed in Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Embase, EU Clinical Trials Register, Google Scholar, MEDLINE, Scopus, and Web of Science databases in order to provide for relevant studies lasting ≥6 weeks and available up to October 30, 2018. No language restriction was applied. Literature search results were uploaded to Eppi-Reviewer 4 (EPPI-Centre Software. London, UK), a web-based software program for managing and 6
analysing data in literature reviews that facilitates collaboration across reviewers during the study selection process. 2.2. Study selection High quality RCTs involving COPD patients that directly compared LABA/LAMA FDCs vs. ICS/LABA FDCs, different LABA/LAMA FDCs or different ICS/LABA FDC each other, were included in this network meta-analysis. Two reviewers independently checked the relevant studies identified from literature searches obtained from the already mentioned databases. The studies were selected in agreement with the above-mentioned criteria, and any difference in opinion about eligibility was resolved by consensus. 2.3. Quality score, risk of bias and evidence profile The Jadad score, with a scale ranging from 1 to 5 (score of 5 being the best quality), was used to assess the quality of the RCTs concerning the likelihood of biases related to randomization, double blinding, withdrawals and dropouts [12]. A Jadad score ≥3 was defined to identify high-quality studies. Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus. The risk of bias was assessed via the consistency/inconsistency analysis to check whether the outcomes resulting from the consistency and inconsistency models fit adequately with the line of equality, as previously described [13]. Furthermore, the inconsistency of evidence was also assessed by quantifying the inconsistency factor, indicating whether one of the treatment had a different effect when it was compared with the others [14]. The quality of the evidence was assessed for primary endpoints in agreement with the Grading of
7
Recommendations Assessment, Development, and Evaluation (GRADE) system [15]. 2.4. Data extraction Data from included RCTs were extracted and checked for study characteristics and duration, treatments, main inclusion criteria, age, gender, smoking habit, lung function, AECOPD, HRQoL, dyspnea, rescue medication and Jadad score. Due to the complexity of this meta-analysis, data have been extracted in agreement with DECiMAL recommendations [16]. 2.5. Endpoints The primary endpoints of this meta-analysis were the impact of LABA/LAMA FDCs on the change from baseline in trough forced expiratory volume in 1 s (FEV1) (study duration ≥6 weeks) and the risk of AECOPD (study duration ≥24 weeks), compared to ICS/LABA FDCs. The secondary endpoints were the impact of LABA/LAMA FDCs on peak FEV1, St’ George's Respiratory Questionnaire
(SGRQ),
Transition
Dyspnea
Index
(TDI),
and
rescue
medication, compared to ICS/LABA FDCs. 2.6. Data analysis The network meta-analysis was performed to determine the impact of LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. A full Bayesian evidence network including at least three nodes was used (chains: 4; initial values scaling: 2.5; tuning iterations: 20.000; simulation iterations: 50.000; tuning interval: 10). The convergence diagnostics for consistency and inconsistency were assessed via the Brooks-Gelman-Rubin
8
method, as previously described [17]. Results of the network meta-analysis were expressed as relative effect (RE) and 95% credible interval (95%CrI). The follow-up duration could not be consistent across the RCTs included in this meta-analysis. Therefore, dichotomous have been normalized as a function of person-time (namely person-half year) [18]. This method, supported by the Cochrane Collaboration and successfully used in recent meta-analyses [14, 1921] involves the conversion of the measures into a common metric (events per person-time) prior to meta-analyze the data, leading to improved estimates of effect, precision, and clinical interpretability of results [19, 20]. The probability that each intervention arm was the most effective was calculated by counting the proportion of iterations of the chain in which each intervention arm had the highest mean difference. The surface under the cumulative ranking curve (SUCRA), representing the summary of these probabilities, was also calculated [22]. The SUCRA is 1 when a treatment is considered to be the best, and 0 when a treatment is considered to be the worst [23]. The SUCRA analysis was performed to rank the efficacy of each FDC included in the network metaanalysis. OpenMetaAnalyst software [24] was used for performing the meta-analysis, GraphPad Prism (CA, US) software to graph the data, and GRADEpro GDT to assess the quality of evidence [15]. The statistical significance was assessed for P<0.05.
3. Results 3.1. Study characteristics
9
Data obtained from 17,734 COPD patients (42.9% treated with LABA/LAMA FDC, 57.1% treated with ICS/LABA FDC) were selected from 14 studies (25-38) including 16 RCTs published between 2010 and 2018. The relevant studies and patients’ characteristics are described in Table 1, and Figure 2 shows the network across the treatments involved in the Bayesian analysis. All the RCTs included in this meta-analysis were published as full-text papers and had a Jadad score ≥3. The length of treatment ranged from 6 weeks to 52 weeks. 3.2. Primary endpoints The change from baseline in trough FEV1 induced by the investigated FDCs is reported in Table 2 (lower diagonal). The network meta-analysis indicated that the LABA/LAMA FDCs, but not aclidinium/formoterol 400/12 µg BID, generally produced a statistically significant (P<0.05) improvement in trough FEV1 compared to ICS/LABA FDCs. In particular, umeclidinium/vilanterol 62.5/25 µg OD, glycopyrronium/indacaterol 50/110 µg OD, glycopyrronium/indacaterol 15.6/27.5 µg BID, and tiotropium/olodaterol 5/5 µg OD were significantly (P<0.05) more effective than fluticasone propionate/salmeterol 500/50 µg BID. The SUCRA analysis shown in Table 3 indicated that umeclidinium/vilanterol 62/25
µg
OD,
glycopyrronium/indacaterol
50/110
µg
OD
and
glycopyrronium/indacaterol 15.6/27.5 µg BID were the most effective FDCs (upper quartile in the SUCRA ranking); followed by glycopyrrolate/formoterol 18/9.6 µg BID, tiotropium/olodaterol 5/5 µg OD, fluticasone furoate/vilanterol 100/25 µg OD, budesonide/formoterol 400/12 µg BID and beclomethasone dipropionate/formoterol 200/12 µg BID (second and third quartile in the SUCRA ranking); followed by fluticasone propionate/salmeterol 500/50 µg BID,
10
fluticasone propionate/salmeterol 250/50 µg BID, and aclidinium/formoterol 400/12 µg BID (lower quartile in the SUCRA ranking). Not all the FDCs included in this meta-analysis permitted a network including at least three nodes with respect to the impact of AECOPD. It was possible to create two group of Bayesian evidence, as shown in Table 2 (upper diagonal). Across the investigated FDCs, only glycopyrronium/indacaterol 50/110 µg OD significantly (P<0.05) protected against the risk of AECOPD compared to ICS/LABA FDCs. Conversely, glycopyrrolate/formoterol 18/9.6 µg BID was significantly (P<0.05) less effective than a ICS/LABA FDC in reducing the risk of AECOPD. The SUCRA analysis showed that glycopyrronium/indacaterol 50/110 µg OD was the best treatment to reduce the risk of AECOPD (upper quartile in the SUCRA ranking); followed by budesonide/formoterol 400/12 µg BID and beclomethasone dipropionate/formoterol 200/12 µg BID (third quartile in the SUCRA ranking); followed by aclidinium/formoterol 400/12 µg BID (second quartile in the SUCRA ranking); followed by fluticasone propionate/salmeterol 500/50 µg BID and glycopyrrolate/formoterol 18/9.6 µg BID (lower quartile in the SUCRA ranking) (Table 3). 3.3. Secondary endpoints Across the investigated FDCs, only glycopyrronium/indacaterol 50/110 µg OD, tiotropium/olodaterol 5/5 µg OD, and glycopyrrolate/formoterol 18/9.6 µg BID significantly (P<0.05) improved peak FEV1 compared to ICS/LABA FDCs (Table S2). No significant differences were detected across the investigated FDCs with respect to the change from baseline in SGRQ, TDI, and use of rescue medication (Table S3-S6). Specific SUCRA analysis of secondary endpoints is reported on Table 3. 11
3.4. Bias and quality of evidence The inconsistency factor resulting from the network meta-analysis was not significant (P>0.05), and the overall consistency/inconsistency analysis indicated that all points fit adequately with the line of equality (trough FEV1: R2 0.98, slope 0.99 and 95%CI 0.96 – 1.04; AECOPD: R2 0.99, slope 1.01 and 95%CI 0.97 – 1.05). Detailed quality of evidence across the investigated FDCs is shown in Table 2.
4. Discussion The results of this network meta-analysis demonstrate that LABA/LAMA FDCs are consistently superior to ICS/LABA FDCs for most of the evaluated outcomes. However, not all LABA/LAMA FDCs were more beneficial compared to LABA/ICS FDCs. In fact, differences have also been observed between FDCs
belonging
to
the
same
class.
Umeclidinium/vilanterol
and
glycopyrronium/indacaterol significantly improved (P<0.05) trough FEV1, compared to fluticasone propionate/salmeterol or fluticasone furoate/vilanterol. However, the differences in trough FEV1 were generally <100 mL, namely the minimal clinical important difference (MCID) for trough FEV1 that has been proposed so far, in the comparison with placebo, based on clinical anchoring to endpoints such as exacerbations, perception of dyspnea, and decline in lung function, but not survival [39, 40]. Across the investigated LABA/LAMA combinations, umeclidinium/vilanterol and glycopyrronium/indacaterol were more effective (P<0.05) on trough FEV1 than aclidinium/formoterol, with increased trough FEV1 ranging from 94 to 105 mL. The SUCRA analysis showed that 5 LABA/LAMA FDCs out of 6 had the highest probability of being the best therapies with regard to trough FEV1 (in order, 12
umeclidium/vilanterol,
glycopyrronium/indacaterol
glycopyrronium/indacaterol
15.6/27.5
µg
BID,
50/110
µg
OD,
glycopyrrolate/formoterol
fumarate and tiotropium/olodaterol). Differences in the trough FEV1 impact across the investigated LABA/LAMA FDCs could be related to the characteristics of populations recruited in the selected trials. IMPACT [26] and FLAME [31] trials enrolled patients affected by moderate-to-very severe COPD, with a mean post bronchodilator FEV1 <50% predicted (45% and 44%, respectively). All the other trials evaluating LABA/LAMA FDCs selected for this meta-analysis reported a mean post bronchodilator FEV1 ≥50% predicted. Patients with very severe COPD could have had a smaller FEV1 improvement if compared to patients with less severe COPD. Furthermore, across the 6 combinations analyzed for the risk of AECOPD, glycopyrronium/indacaterol significantly (P<0.05) reduced the exacerbation risk of 26%, compared to fluticasone propionate/salmeterol, and of 25% compared to aclidinium/formoterol, resulting the most effective combination in the SUCRA analysis. On the other hand, the LABA/LAMA FDCs glycopyrrolate/formoterol was the least effective treatment to reduce the risk of AECOPD. At present, no MCID has been validated for the risk of AECOPD due to the impossibility to use clinical anchor-based approaches.40 A number of factor could explain the different risk of AECOPD observed across the investigated LABA/LAMA FDCs, such as optimization of lung mechanics, degree of synergy between components, pulmonary concentration of treatment, and
effects
of
ventilation
improvement.
In
the
CLAIM
study,
glycopyrronium/indacaterol improved pulmonary ventilation and ventilation 13
homogeneity in COPD patients, compared to placebo [41]. Lung ventilation improvements obtained by treatments could vary greatly across LABA/LAMA FDCs as it depends on components, device performance and resistance, peak inspiratory flow rate achieved by COPD patients, dimension of drug particles, frequency of critical errors. These discrepancies should be analyzed for the evaluation of other potential effects of bronchodilators on exacerbation prevention. In support of this statement, Chapin et al [42] recently reported that incorporation of umeclidinium/vilanterol into the standard COPD protocol as replacement of the previous regimen (tiotropium + formoterol), led to an increased 30-day readmission rates (24.1% in post-intervention group vs. 10.8% in pre-intervention group, P=0.049) that was no longer statistically significant after adjustment for severity of illness and complications or comorbidities. With regard to lung function, LABA/LAMA FDCs led to a greater improvement also
in
peak
FEV1,
compared
to
ICS/LABA
FDCs.
In
particular,
glycopyrronium/indacaterol and tiotropium/olodaterol significantly (P<0.05) increased peak FEV1 compared to fluticasone proprionate/salmeterol. The analysis of the other secondary endpoints (SGRQ, TDI and use of rescue medication) did not detect any statistically significant difference between the selected combinations. A limited power to detect statistically significant differences could be one of the reasons behind this result. In keeping with other outcomes of this network meta-analysis, glycopyrronium/indacaterol showed the highest probability of being the best treatment for dyspnea improvement. On the other hand, surprisingly, umeclidinium/vilanterol was not superior to ICS/LABA FDCs in TDI. Given the dual bronchodilation and the beneficial effect of this 14
LABA/LAMA combination on lung function, this result probably requires further investigations of the mechanism involved in dyspnea reduction and perception. For the correct management of COPD, the GOLD documents classified patients into 4 groups (from A to D) depending on the burden of symptoms and exacerbations (GOLD 2013 and GOLD 2017). The GOLD 2017 document generally recommends LABA/LAMA FDCs over ICS/LABA FDCs for patients belonging to groups B, C and D [43]. If patients in D group have high blood eosinophil counts (≥300 cells/µL), the recent 2019 GOLD report indicates that ICS/LABA FDCs may be preferred as initial treatment [43, 44]. However, considering the increased risk of pneumonia observed in association with ICS [45, 31], a careful evaluation of the risk-benefit profile should be carried out before using ICS/LABA FDCs as first choice in COPD patients. In addition, in case of inappropriate treatment with ICS or in case of lack of response or side effects from the ICS/LABA combination treatment, GOLD 2019 report [1] suggest to switch from ICS/LABA FDCs to LABA/LAMA FDCs. A recent Cochrane systematic review reported that LABA/LAMA are associated with fewer exacerbations, larger improvement of FEV1, reduced risk of pneumonia, and more frequent SGRQ total score improvements, compared to ICS/LABA FDCs [46]. In line with GOLD recommendations and Cochrane systematic review data, the results of our network meta-analysis indicated that LABA/LAMA FDCs are more effective than ICS/LABA FDCs to improve lung function and decrease the risk of exacerbations. Across the investigated LABA/LAMA combinations, subgroup analysis of the data collected in the Cochrane systematic review [46] suggested that glycopyrronium/indacaterol can have better therapeutic effect on exacerbations
15
prevention when compared with other LABA/LAMAs FDC. Accordingly, the GOLD 2019 report suggests to consider switching inhaler device or molecules in case of persisting dyspnea, acknowledging that a different impact could be expected from treatments within the same class, at least in individual patients. In agreement, our network meta-analysis highlights that dual therapies belonging to the same class could have different clinical efficacy. This network meta-analysis provides useful information on the effects of different dual treatments for moderate-to-severe COPD patients. However this study suffered from some limitations, such as the quality of evidence between some of the indirect comparisons and the patient characteristics of the selected RCTs. In any case the baseline characteristics of the patients were homogeneous at the least by a functional viewpoint (post bronchodilator FEV1: median 50.0% predicted, lower quartile 47.25% predicted, upper quartile 51.75% predicted). Unfortunately, no subset analysis was performed on the severity of disease in agreement with the baseline risk of AECOPD: clustering the RCTs with respect to the rate of AECOPD (≥1 AECOPD per year vs. <1 AECOPD per year) disconnected the nodes of the mixed treatment comparison and, thus, no full Bayesian evidence network could result. Finally, only few studies reported the level of eosinophils, therefore it was not possible to perform a network meta-analysis by considering this co-variate.
5. Conclusions This network meta-analysis provides a ranking of dual therapies efficacy on the most relevant outcomes for COPD management. LABA/LAMA FDCs have shown superiority over LABA/ICS FDCs for the majority of the evaluated outcomes.
Across
the
investigated
16
LABA/LAMA
FDCs,
glycopyrronium/indacaterol showed a consistent and robust efficacy profile. These results indicate that significant differences in the efficacy profile could be present within a defined pharmacological class of FDCs. In our opinion, recommendations should be based on evidence from a specific dual therapy rather than on the effect of a class of compounds (unless equivalence is proven by clinical evidence).
Acknowledgments The authors thank Sara Parodi, PhD, of Forum Service S.r.l for providing medical writing support, which was funded by Novartis Farma SpA (Origgio, Italy).
Funding The authors received no specific funding for this work
Author contributions LC and PR completed the literature search, assessed eligibility of studies for inclusion and were all directly involved in the acquisition of data for the Article. LC designed the statistical analyses in consultation with all the other authors. Statistical analyses were done by LC. LC and PR wrote the first draft of the Article, in consultation with all the other authors for data interpretation. All authors revised the Article critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the Article in ensuring that questions related to the accuracy or integrity of any part of the Article were appropriately investigated and resolved.
Declaration of Interest
17
LC has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support from AstraZeneca, a research grant partially funded by Chiesi Farmaceutici, Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to ABC Farmaceutici, Recipharm, Zambon, Verona Pharma and Ockham Biotech. His department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. FDM reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from GSK, personal fees from Chiesi, personal fees from Zambon, grants and personal fees from Novartis, personal fees from Guidotti/Malesci, grants and personal fees from AZ, personal fees from Menarini, personal fees from Mundipharma, personal fees from TEVA, personal fees from Almiral. FB has received speaker or consultant honoraria or research funding from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Guidotti, Insmed, Malesci, Menarini, Mundifarma, Novartis, Pfizer, Teva, Valeas, and Zambon. MC has participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon; is or has been a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon; and his department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon.
18
SC Novartis, Chiesi, GSK, Boheringer Ingelheim, Astra Zeneca, Menarini, Guidotti-Malesci, Teva CM received honoraria for lectures and/or advisory boards from Novartis, GSK, AstraZeneca, Boehringer Ingelheim, Menarini, Guidotti, Zambon, Chiesi AR reports support for meetings from Boeheringer Ingelhehm, and personal fees from Chiesi Pharmaceuticals, Novartis, and Boheringer Ingelheim. PR participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim,
Chiesi
Farmaceutici,
GlaxoSmithKline,
Menarini
Group,
Mundipharma and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon.
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[22] Dobler CC, Wilson ME, Murad MH. A pulmonologist's guide to understanding network meta-analysis. Eur Respir J. 2018;52. [23] Cazzola M, Calzetta L, Rogliani P, Matera MG. Tiotropium formulations and safety: a network meta-analysis. Doi: 10.1177/2042098616667304. Ther Adv Drug Saf. 2016:2042098616667304. [24] Wallace BC, Dahabreh IJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Soft. 2012;49:1-15. [25] Ferguson GT, Rabe KF, Martinez FJ, Fabbri LM, Wang C, Ichinose M, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir med. 2018;6:747-58. [26] Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. DOI: 10.1056/NEJMoa1713901. N Engl J Med. 2018. [27] Kerwin E, Ferguson GT, Sanjar S, Goodin T, Yadao A, Fogel R, et al. Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies. Lung. 2017;195:739-47. [28] Feldman GJ, Sousa AR, Lipson DA, Tombs L, Barnes N, Riley JH, et al. Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study. Adv Ther. 2017:1-16. [29] Beeh KM, Derom E, Echave-Sustaeta J, Gronke L, Hamilton A, Zhai D, et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat((R)) is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler((R)) (ENERGITO((R)) study). Int J Chron Obstruct Pulmon Dis. 2016;11:193-205. [30] Vogelmeier C, Paggiaro PL, Dorca J, Sliwinski P, Mallet M, Kirsten AM,. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J. 2016;48:1030-9. [31] Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;374:2222-34. [32] Donohue JF, Worsley S, Zhu CQ, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respir Med. 2015;109:870-81. [33] Singh D, Worsley S, Zhu CQ, Hardaker L, Church A. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial. BMC Pulm Med. 2015;15:91.
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[34] Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang L, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:1015-26 [35] Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D, Kampschulte J, et al. Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD. BMC Pulm Med. 2014;14:43. [36] Agusti A, de Teresa L, De Backer W, Zvarich MT, Locantore N, Barnes N, et al. A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD. Eur Respir J. 2014;43:763-72. [37] Vogelmeier CF, Bateman ED, Pallante J, Alagappan VK, D'Andrea P, Chen H, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir med. 2013;1:51-60. [38] Calverley PM, Kuna P, Monso E, Costantini M, Petruzzelli S, Sergio F, et al. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med. 2010;104:1858-68. [39] Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31(2):416-69. [40]
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23
Tables Table 1. Patient demographics, baseline and study characteristics.
Study and year
KRONOS, Ferguson et al., 2018 (25)
ClinicalTrials.org Identifier
NCT02497001
Duration of treatment (weeks)
24
Number of analysed patients
1,257
Drugs (doses) and regimen of administration
GLY/FOR 18/9.6 µg BID vs. BUD/FOR 320/9.6 µg BID vs. open-label BUD/FOR 400/12 µg BID
Reported variables fulfilling prespecified criteria (study duration, number of nodes)
Trough FEV1
Exacerbations
YES
YES
Main inclusion Age (years) Male (%) criteria
Post Current Smoking bronchodilator smokers history FEV1 (% (%) (pack-years) predicted)
Patient with AECOPD history (%)
AECOPD in the previous year (rate)
Jadad score
FEV1 ≥25% and ≤80% predicted
65
73
38
45
50
26
0.4
4 (3 for the open-label arm)
65
67
35
≥10
45
100
1.7
3
54
24
0.3
4
IMPACT, Lipson et al., 2018 (26)
NCT02164513
52
6,204
UMEC/VI 62.5/25 µg OD vs. FF/VIL 100/25 µg OD
YES
NO
a) FEV1 <50% predicted and ≥1 moderate or severe AECOPD in the previous year; b) FEV1 ≥50% and ≤80% predicted and ≥2 moderate or ≥1 severe AECOPD in the previous year
Kerwin et al., 2017 (27)
NCT02487446, NCT02487498
12
712
GLY/IND 15.6/27.5 µg BID vs. UMEC/VI 62.5/25 µg OD
YES
NO
FEV1 ≥30% and <70% predicted
64
53
57
53
Feldman et al., 2017 (28)
NCT02799784
8
236
UMEC/VI 62.5/25 µg OD vs. TIO/OLO 5/5 µg (PD)
YES
NO
FEV1 ≥50% and <70% predicted
64
60
53
50
60
17
0.2
3
ENERGITO, Beeh et al., 2016 (29)
NCT01969721
6
229
TIO/OLO 5/5 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≥30% and <80% predicted
64
65
45
39
50
NA
NA
3
AFFIRM, Vogelmeier et al., 2016 (30)
NCT01908140
24
765
ACL/FOR 400/12 µg BID vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 <80% predicted
63.4
65.1
NA
42.1
53.3
32
0.4
3
24
FLAME, Wedzicha et al., 2016 (31)
NCT01782326
52
3,192
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 ≥25% and <60% predicted; mMRC scale ≥2
65
765
40
NA
44
100
1.2
5
Donohue et al., 2015 (32)
NCT01817764, NCT01879410
12
1,403
UMEC/VIL 62.5/25 µg OD vs. FP/SAL 250/50 µg BID
YES
NO
FEV1 ≥30% and ≤70%
63
73
43
43
50
0
0
4
Singh et al. 2015 (33)
NCT01822899
12
716
UMEC/VI 62.5/25 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≥30% and ≤70% predicted
62
72
59
40
51
0
0
4
LANTERN, Zhong et al., 2015 (34)
NCT01709903
26
741
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 ≥30% and <80% predicted
65
91
26
NA
52
21
0.2
4
Singh et al., 2014 (35)
NCT01245569
12
418
FP/SAL 500/50 µg BID vs. BDP/FOR 200/12 µg BID
YES
NO
FEV1 <80% predicted
64
71
46
41
47
47
NA
3
Agustì et al., 2013 (36)
NCT01342913
12
528
FF/VIL 100/25 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≤70%
63
82
NA
≥10
48
100
0.6a
4
ILLUMINATE, Vogelmeier et al., 2013 (37)
NCT01315249
26
522
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 >40% and <80%
63
71
48
40
51
0
0
4
NCT476099
48
470
BDP/FOR 200/12 µg BID vs. BUD/FOR 400/12 µg BID
YES
YES
FEV1 >30% and <50%
63.6
80.4
37.5
37.6
42.1
100
1.7b
5
Calverley et al., 2010 (38)
a. AECOPD in the previous 3 years b. 2-12 months of screening AECOPD: acute exacerbation of COPD: ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; mMRC: modified Medical Research Council; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
25
Table 2. Relative effect estimates for each pairs of FDCs accompanied by 95% CrI and quality of evidence according to the impact on trough FEV1 (ml, lower diagonal), and risk of AECOPD (relative risk, upper diagonal). Trough FEV1
AECOPD
GLY/IND 50/110 µg OD
UMEC/VI 62.5/25 µg OD
17 (-23, 53)
◯
12 (-15, 39)
21 (-64, 106)
◯ ◯ ◯
-6 (-48, 46)
◯ ◯ ◯
GLY/IND 15.6/27.5 µg BID
5 (-81, 90)
◯ ◯ ◯
10 (-80, 97)
◯ ◯ ◯
◯ ◯
29 (-14, 74)
◯ ◯
26 (-16, 71)
Trough FEV1
31 (-7, 76)
◯ ◯
36 (1, 76)*
19 (-70, 111)
28 (-58, 114)
49 (-36, 135)
53 (-33, 142)
◯ ◯ ◯ ◯ ◯ ◯
70 (3, 126)*
44 (21, 68)*
◯ ◯ ◯
53 (-10, 109)
0.97 (0.56, ◯ 1.64)
6 (-33, 48)
◯ ◯
26 (-66, 113)
48 (-12, 106)
26 (-42, 92)
FF/VIL 100/25 µg OD
16 (-68, 10)
◯ ◯ ◯
23 (-47, 78)
◯ ◯ ◯
87 (57, 116)*
◯ ◯ ◯
◯ ◯
76 (33, 115)*
70 (49, 97)*
◯
88 (58, 121)*
71 (24, 123)*
◯
89 (7, 159)*
◯
◯
94 (7, 170)*
46 (10, 81)*
66 (-19, 156)
◯ ◯ ◯ 85 (-21, 182)
◯
46 (1, 94)*
◯ 64 (-23, 138)
40 (4, 70)*
◯
5 (-53, 57)
◯ ◯
◯
57 (-25, 130)
20 (-58, 104)
◯ ◯ Trough FEV1
*P<0.05 vs. comparator
26
0.07 (0.01, 0.35)*
0.07 (0.01, ◯ 1.29) ◯
GLY/FOR 18/9.6 µg BID
BDP/FOR 200/12 µg BID
19 (-33, 75)
◯
16 (-44, 92)
◯ ◯ ◯
◯ ◯ 22 (-62, 112)
41 (-64, 135)
◯ ◯ ◯
FP/SAL 500/50 µg BID 1 (-43, 44)
◯ ◯ ◯
◯ ◯ ◯ ◯ ◯
BDP/FOR 200/12 µg BID
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
◯ ◯
40 (-2, 81)
1.00 (0,09, ◯ 9,73)
◯ ◯
38 (-50, 125)
18 (-58, 84)
FP/SAL 250/50 µg BID 15 (-71 93)
◯ ◯ ◯
◯ ◯
ACL/FOR 400/12 µg BID
Trough FEV1
105 (23, 177)*
66 (-15, 149)
◯ ◯
◯ ◯ ◯
76 (37, 121)*
◯ ◯
FP/SAL 500/50 µg BID
TIO/OLO 5/5 µg OD
◯ ◯ ◯
56 (-14, 120)
0.74 (0.52, 0.95)*
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
◯ ◯ ◯ ◯
66 (-17, 148)
ACL/FOR 400/12 µg BID
GLY/FOR 18/9.6 µg BID
◯ ◯ ◯
48 (25, 76)*
0.75 (0.39, ◯ 1.34) ◯
AECOPD
41 (8, 75)*
GLY/IND 50/110 µg OD
Notes: Highlighted results indicate positive significant effect of treatments reported at the head of columns compared to treatments reported at the end of rows. ◯low quality, ⨁◯ ◯ ◯very low quality. GRADE Working Group grades of evidence: ⨁⨁⨁⨁ high quality, ⨁⨁⨁◯moderate quality, ⨁⨁◯ AECOPD: acute exacerbation of COPD; ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; CrI: Credible Interval; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol .
27
Table 3. SUCRA values for the impact of LABA/LAMA FDCs and ICS/LABA FDCs on the primary and secondary endpoints investigated in this network meta-analysis. Primary endpoints Treatment
Secondary endpoints SGRQ
TDI
Rescue medicatio n
0.77
0.60
0.80
0.70
0.92
0.58
0.39
0.45
0.63
NC
0.78
NC
NC
NC
NC
GLY/FOR 18/9.6 µg BID
0.02
0.74
0.92
0.70
NC
NC
TIO/OLO 5/5 µg OD
NC
0.55
0.80
NC
NC
0.29
FF/VIL 100/25 µg OD
NC
0.50
NC
0.49
NC
NC
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
0.75
0.37
0.13
0.82
NC
0.71
BDP/FOR 200/12 µg BID
0.73
0.33
0.46
0.75
0.59
0.43
FP/SAL 500/50 µg BID
0.24
0.19
0.20
0.32
0.51
0.45
FP/SAL 250/50 µg BID
NC
0.18
0.09
0.29
0.15
0.30
ACL/FOR 400/12 µg BID
0.35
0.14
0.53
0.17
0.50
NC
AECOPD
Trough FEV1
Peak FEV1
GLY/IND 50/110 µg OD
0.94
0.81
UMEC/VI 62.5/25 µg OD
NC
GLY/IND 15.6/27.5 µg BID
AECOPD: acute exacerbation of COPD; ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; ICS: inhaled corticosteroids; LABA: long-acting β 2-agonist; LAMA: long-acting muscarinic receptor antagonist; NC: not calculable; OD: once daily; SGRQ: St’ George's Respiratory Questionnaire; SUCRA: surface under the cumulative ranking curve; TDI: Transition Dyspnea Index; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
28
Figure 1. PRISMA-P flow diagram for the identification of studies included in the network metaanalysis concerning the impact of LABA/LAMA combination vs. ICS/LABA combination in COPD. COPD: chronic obstructive pulmonary disease; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic receptor antagonist; PRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols.
29
Figure 2. Area-proportional diagram displaying the network of the arms involved in the Bayesian analysis. The links between nodes indicate the direct comparisons between pairs of treatments and the thickness of lines is related with the number of COPD patients comparing pairs of treatments head-to-head. ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease. FF/VIL:
fluticasone
furoate/vilanterol;
FP/SAL:
fluticasone
propionate/salmeterol;
GLY/FOR:
glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
30
Declaration of Interest LC has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support from AstraZeneca, a research grant partially funded by Chiesi Farmaceutici, Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to ABC Farmaceutici, Recipharm, Zambon, Verona Pharma and Ockham Biotech. His department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. FDM reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from GSK, personal fees from Chiesi, personal fees from Zambon, grants and personal fees from Novartis, personal fees from Guidotti/Malesci, grants and personal fees from AZ, personal fees from Menarini, personal fees from Mundipharma, personal fees from TEVA, personal fees from Almiral. FB has received speaker or consultant honoraria or research funding from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Guidotti, Insmed, Malesci, Menarini, Mundifarma, Novartis, Pfizer, Teva, Valeas, and Zambon. MC has participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon; is or has been a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon; and his department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon. SC Novartis, Chiesi, GSK, Boheringer Ingelheim, Astra Zeneca, Menarini, GuidottiMalesci, Teva
CM received honoraria for lectures and/or advisory boards from Novartis, GSK, AstraZeneca,
Boehringer
Ingelheim,
Menarini,
Guidotti,
Zambon,
Chiesi
AR reports support for meetings from Boeheringer Ingelhehm, and personal fees from Chiesi Pharmaceuticals, Novartis, and Boheringer Ingelheim. PR participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon.
S1094-5539(19)30162-2
DOI:
https://doi.org/10.1016/j.pupt.2019.101855
Reference:
YPUPT 101855
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 3 July 2019 Revised Date:
14 October 2019
Accepted Date: 14 October 2019
Please cite this article as: Calzetta L, Di Marco F, Blasi F, Cazzola M, Centanni S, Micheletto C, Rossi A, Rogliani P, Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis, Pulmonary Pharmacology & Therapeutics (2019), doi: https://doi.org/10.1016/ j.pupt.2019.101855. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: a network meta-analysis 1
2
3
1
4
Luigino Calzetta , Fabiano Di Marco *, Francesco Blasi , Mario Cazzola , Stefano Centanni , 5
6
1
Claudio Micheletto , Andrea Rossi , Paola Rogliani
1. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy 2. Department of Health Sciences, University of Milan, Respiratory Unit ASST – Papa Giovanni XXIII Hospital, Bergamo, Italy 3. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Department of Internal Medicine, Respiratory Unit and Adult Cystic Fibrosis Center, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy 4. Department of Health Sciences, University of Milan Respiratory Unit, ASST Santi Paolo e Carlo, Milan, Italy 5. Cardio-Thoracic Department, Respiratory Unit, Integrated University Hospital, Verona, Italy 6. Respiratory Section, Department of Medicine, University of Verona, Italy
Correspondence: Fabiano Di Marco Department of Health Sciences, University of Milan, Respiratory Unit ASST – Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy Tel: +39 035 2673444 Email [email protected].
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Abstract Background: Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixeddose combinations (FDCs) and LABA/long-acting muscarinic antagonist (LAMA) FDCs are extensively used to treat chronic obstructive pulmonary disease (COPD). The aim of the present network meta-analysis was to assess the comparative efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. Methods: A network meta-analysis (≥3 nodes, Bayesian method) was performed by searching for randomized clinical trials (RCTs) that compared the impact of different LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. The primary endpoints were: the change from baseline in trough forced expiratory volume in 1 s (FEV1) and the risk of exacerbation of COPD (AECOPD). The secondary endpoints were: peak FEV1, St’ George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), and rescue medication use. Results: Data of 17,734 COPD patients were extracted from 16 RCTs. The length of treatment ranged from 6 weeks to 52 weeks. All LABA/LAMA FDCs, except aclidinium/formoterol, produced a statistically significant improvement compared to ICS/LABAs in trough FEV1. The surface under the cumulative ranking curve (SUCRA) analysis indicated that umeclidinium/vilanterol, glycopyrronium/indacaterol and glycopyrrolate/formoterol fumarate were the most effective FDCs in improving trough FEV1. Across the FDCs analyzed for the risk of AECOPD, glycopyrronium/indacaterol significantly reduced the exacerbation risk compared to fluticasone propionate/salmeterol and resulted
2
the most effective combination in the SUCRA analysis. Similar trend were also observed for the peak FEV1. No significant differences were detected across the investigated FDCs regarding SGRQ, TDI, and use of rescue medication. Conclusions: The results of this meta-analysis show that LABA/LAMA combinations are consistently more effective than ICS/LABA FDCs for most of the evaluated outcomes. However, differences have also been observed between FDCs belonging to the same class. Across the investigated LABA/LAMA FDCs, glycopyrronium/indacaterol revealed a consistent and robust efficacy profile. Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, longacting β2 agonist, long-acting muscarinic antagonist, network meta-analysis, trough forced expiratory volume in 1 s, exacerbation
3
1. Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document states that “Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disorder characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” [1]. Therapeutic strategies for COPD aim to prevent the deterioration of lung function, alleviate symptoms, and prevent exacerbations [2]. The pharmacological armamentarium of COPD include short-acting bronchodilators, long-acting bronchodilators such as muscarinic antagonists (LAMA) and longacting β-agonists (LABA), and inhaled corticosteroids (ICS) [3]. The international GOLD document suggests as initial strategy the use of a single bronchodilator and, in case of persistent symptoms and/or exacerbations, they recommend to escalate to a dual therapy with LABA/LAMA fixed-dose combinations (FDCs) or ICS/LABA FDCs (in case of high blood eosinophil count) [1, 4]. For patients treated with a dual therapy who continue to experience severe symptom burden and frequent exacerbations, the same document suggests to consider switching inhaler device or molecules or to step up to triple therapy (ICS/LABA/LAMA) in case of high blood eosinophil count [1, 4]. Given the variety of available pharmacologic treatments for COPD, the choice of appropriate dual therapy is crucial to reduce the frequency and severity of symptoms and possible complications, and to establish the next therapy. Despite international recommendations and recent evidence supporting the efficacy of bronchodilators (as monotherapy or in combination) in the early 4
stage of the disease, ICS/LABA are often inappropriately prescribed as initial therapy, leading to the inevitable drift to triple therapy and overuse of ICS [5]. Symptomatic patients with a history of frequent exacerbations (moderate-tosevere COPD) have been suggested as the appropriate candidates for regular ICS treatment in addition to long acting bronchodilators [6]. So far, several randomized controlled trials (RCTs) have evaluated the efficacy of dual therapy strategies for the maintenance treatment of COPD [7-9], however studies evaluating the most effective combination of drugs, including newer agents in different doses, have not been conducted yet. The aim of the present network meta-analysis is to compare the efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. In particular, this study aimed to compare and rank LABA/LAMA FDCs and ICS/LABA FDCs on trough forced expiratory volume in 1 s (FEV1) and risk of acute exacerbation of COPD (AECOPD).
2. Materials and methods 2.1. Search strategy This network meta-analysis has been registered in PROSPERO (registration number: CRD42018093075), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [10]. The PRISMA flow diagram is reported in Figure 1. This quantitative synthesis satisfied all the recommended items reported by the PRISMA-P checklist (Table S1) [10].
5
Two reviewers performed a comprehensive literature search for randomized controlled trials (RCTs) evaluating the effects of LABA/LAMA FDCs vs. ICS/LABA FDCs in COPD patients. The PICO (Patient problem, Intervention, Comparison, and Outcome) framework was used to develop the literature search strategy, as previously described [11]. Namely, the "Patient problem” included
subject
affected
by
COPD;
the
“Intervention”
regarded
the
administration of LABA/LAMA FDC therapy; the “Comparison” was performed with regard to ICS/LABA FDC therapy; the “Outcomes” were lung function, risk of acute exacerbation of COPD (AECOPD), health-related quality of life (HRQoL), dyspnea, and rescue medication. The terms “COPD” or “chronic obstructive pulmonary disease” were searched for the patient problem; the terms “aclidinium AND formoterol” OR “glycopyrronium AND formoterol” OR “glycopyrrolate AND formoterol” OR “glycopyrronium AND indacaterol” “glycopyrrolate AND indacaterol” OR “tiotropium AND olodaterol” OR “umeclidinium AND vilanterol” were searched for
the
intervention;
the
terms
“fluticasone
AND
salmeterol”
OR
“beclomethasone AND formoterol” OR “budesonide AND formoterol” OR “fluticasone AND vilanterol” were searched for the comparison. The literature search was performed in Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Embase, EU Clinical Trials Register, Google Scholar, MEDLINE, Scopus, and Web of Science databases in order to provide for relevant studies lasting ≥6 weeks and available up to October 30, 2018. No language restriction was applied. Literature search results were uploaded to Eppi-Reviewer 4 (EPPI-Centre Software. London, UK), a web-based software program for managing and 6
analysing data in literature reviews that facilitates collaboration across reviewers during the study selection process. 2.2. Study selection High quality RCTs involving COPD patients that directly compared LABA/LAMA FDCs vs. ICS/LABA FDCs, different LABA/LAMA FDCs or different ICS/LABA FDC each other, were included in this network meta-analysis. Two reviewers independently checked the relevant studies identified from literature searches obtained from the already mentioned databases. The studies were selected in agreement with the above-mentioned criteria, and any difference in opinion about eligibility was resolved by consensus. 2.3. Quality score, risk of bias and evidence profile The Jadad score, with a scale ranging from 1 to 5 (score of 5 being the best quality), was used to assess the quality of the RCTs concerning the likelihood of biases related to randomization, double blinding, withdrawals and dropouts [12]. A Jadad score ≥3 was defined to identify high-quality studies. Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus. The risk of bias was assessed via the consistency/inconsistency analysis to check whether the outcomes resulting from the consistency and inconsistency models fit adequately with the line of equality, as previously described [13]. Furthermore, the inconsistency of evidence was also assessed by quantifying the inconsistency factor, indicating whether one of the treatment had a different effect when it was compared with the others [14]. The quality of the evidence was assessed for primary endpoints in agreement with the Grading of
7
Recommendations Assessment, Development, and Evaluation (GRADE) system [15]. 2.4. Data extraction Data from included RCTs were extracted and checked for study characteristics and duration, treatments, main inclusion criteria, age, gender, smoking habit, lung function, AECOPD, HRQoL, dyspnea, rescue medication and Jadad score. Due to the complexity of this meta-analysis, data have been extracted in agreement with DECiMAL recommendations [16]. 2.5. Endpoints The primary endpoints of this meta-analysis were the impact of LABA/LAMA FDCs on the change from baseline in trough forced expiratory volume in 1 s (FEV1) (study duration ≥6 weeks) and the risk of AECOPD (study duration ≥24 weeks), compared to ICS/LABA FDCs. The secondary endpoints were the impact of LABA/LAMA FDCs on peak FEV1, St’ George's Respiratory Questionnaire
(SGRQ),
Transition
Dyspnea
Index
(TDI),
and
rescue
medication, compared to ICS/LABA FDCs. 2.6. Data analysis The network meta-analysis was performed to determine the impact of LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. A full Bayesian evidence network including at least three nodes was used (chains: 4; initial values scaling: 2.5; tuning iterations: 20.000; simulation iterations: 50.000; tuning interval: 10). The convergence diagnostics for consistency and inconsistency were assessed via the Brooks-Gelman-Rubin
8
method, as previously described [17]. Results of the network meta-analysis were expressed as relative effect (RE) and 95% credible interval (95%CrI). The follow-up duration could not be consistent across the RCTs included in this meta-analysis. Therefore, dichotomous have been normalized as a function of person-time (namely person-half year) [18]. This method, supported by the Cochrane Collaboration and successfully used in recent meta-analyses [14, 1921] involves the conversion of the measures into a common metric (events per person-time) prior to meta-analyze the data, leading to improved estimates of effect, precision, and clinical interpretability of results [19, 20]. The probability that each intervention arm was the most effective was calculated by counting the proportion of iterations of the chain in which each intervention arm had the highest mean difference. The surface under the cumulative ranking curve (SUCRA), representing the summary of these probabilities, was also calculated [22]. The SUCRA is 1 when a treatment is considered to be the best, and 0 when a treatment is considered to be the worst [23]. The SUCRA analysis was performed to rank the efficacy of each FDC included in the network metaanalysis. OpenMetaAnalyst software [24] was used for performing the meta-analysis, GraphPad Prism (CA, US) software to graph the data, and GRADEpro GDT to assess the quality of evidence [15]. The statistical significance was assessed for P<0.05.
3. Results 3.1. Study characteristics
9
Data obtained from 17,734 COPD patients (42.9% treated with LABA/LAMA FDC, 57.1% treated with ICS/LABA FDC) were selected from 14 studies (25-38) including 16 RCTs published between 2010 and 2018. The relevant studies and patients’ characteristics are described in Table 1, and Figure 2 shows the network across the treatments involved in the Bayesian analysis. All the RCTs included in this meta-analysis were published as full-text papers and had a Jadad score ≥3. The length of treatment ranged from 6 weeks to 52 weeks. 3.2. Primary endpoints The change from baseline in trough FEV1 induced by the investigated FDCs is reported in Table 2 (lower diagonal). The network meta-analysis indicated that the LABA/LAMA FDCs, but not aclidinium/formoterol 400/12 µg BID, generally produced a statistically significant (P<0.05) improvement in trough FEV1 compared to ICS/LABA FDCs. In particular, umeclidinium/vilanterol 62.5/25 µg OD, glycopyrronium/indacaterol 50/110 µg OD, glycopyrronium/indacaterol 15.6/27.5 µg BID, and tiotropium/olodaterol 5/5 µg OD were significantly (P<0.05) more effective than fluticasone propionate/salmeterol 500/50 µg BID. The SUCRA analysis shown in Table 3 indicated that umeclidinium/vilanterol 62/25
µg
OD,
glycopyrronium/indacaterol
50/110
µg
OD
and
glycopyrronium/indacaterol 15.6/27.5 µg BID were the most effective FDCs (upper quartile in the SUCRA ranking); followed by glycopyrrolate/formoterol 18/9.6 µg BID, tiotropium/olodaterol 5/5 µg OD, fluticasone furoate/vilanterol 100/25 µg OD, budesonide/formoterol 400/12 µg BID and beclomethasone dipropionate/formoterol 200/12 µg BID (second and third quartile in the SUCRA ranking); followed by fluticasone propionate/salmeterol 500/50 µg BID,
10
fluticasone propionate/salmeterol 250/50 µg BID, and aclidinium/formoterol 400/12 µg BID (lower quartile in the SUCRA ranking). Not all the FDCs included in this meta-analysis permitted a network including at least three nodes with respect to the impact of AECOPD. It was possible to create two group of Bayesian evidence, as shown in Table 2 (upper diagonal). Across the investigated FDCs, only glycopyrronium/indacaterol 50/110 µg OD significantly (P<0.05) protected against the risk of AECOPD compared to ICS/LABA FDCs. Conversely, glycopyrrolate/formoterol 18/9.6 µg BID was significantly (P<0.05) less effective than a ICS/LABA FDC in reducing the risk of AECOPD. The SUCRA analysis showed that glycopyrronium/indacaterol 50/110 µg OD was the best treatment to reduce the risk of AECOPD (upper quartile in the SUCRA ranking); followed by budesonide/formoterol 400/12 µg BID and beclomethasone dipropionate/formoterol 200/12 µg BID (third quartile in the SUCRA ranking); followed by aclidinium/formoterol 400/12 µg BID (second quartile in the SUCRA ranking); followed by fluticasone propionate/salmeterol 500/50 µg BID and glycopyrrolate/formoterol 18/9.6 µg BID (lower quartile in the SUCRA ranking) (Table 3). 3.3. Secondary endpoints Across the investigated FDCs, only glycopyrronium/indacaterol 50/110 µg OD, tiotropium/olodaterol 5/5 µg OD, and glycopyrrolate/formoterol 18/9.6 µg BID significantly (P<0.05) improved peak FEV1 compared to ICS/LABA FDCs (Table S2). No significant differences were detected across the investigated FDCs with respect to the change from baseline in SGRQ, TDI, and use of rescue medication (Table S3-S6). Specific SUCRA analysis of secondary endpoints is reported on Table 3. 11
3.4. Bias and quality of evidence The inconsistency factor resulting from the network meta-analysis was not significant (P>0.05), and the overall consistency/inconsistency analysis indicated that all points fit adequately with the line of equality (trough FEV1: R2 0.98, slope 0.99 and 95%CI 0.96 – 1.04; AECOPD: R2 0.99, slope 1.01 and 95%CI 0.97 – 1.05). Detailed quality of evidence across the investigated FDCs is shown in Table 2.
4. Discussion The results of this network meta-analysis demonstrate that LABA/LAMA FDCs are consistently superior to ICS/LABA FDCs for most of the evaluated outcomes. However, not all LABA/LAMA FDCs were more beneficial compared to LABA/ICS FDCs. In fact, differences have also been observed between FDCs
belonging
to
the
same
class.
Umeclidinium/vilanterol
and
glycopyrronium/indacaterol significantly improved (P<0.05) trough FEV1, compared to fluticasone propionate/salmeterol or fluticasone furoate/vilanterol. However, the differences in trough FEV1 were generally <100 mL, namely the minimal clinical important difference (MCID) for trough FEV1 that has been proposed so far, in the comparison with placebo, based on clinical anchoring to endpoints such as exacerbations, perception of dyspnea, and decline in lung function, but not survival [39, 40]. Across the investigated LABA/LAMA combinations, umeclidinium/vilanterol and glycopyrronium/indacaterol were more effective (P<0.05) on trough FEV1 than aclidinium/formoterol, with increased trough FEV1 ranging from 94 to 105 mL. The SUCRA analysis showed that 5 LABA/LAMA FDCs out of 6 had the highest probability of being the best therapies with regard to trough FEV1 (in order, 12
umeclidium/vilanterol,
glycopyrronium/indacaterol
glycopyrronium/indacaterol
15.6/27.5
µg
BID,
50/110
µg
OD,
glycopyrrolate/formoterol
fumarate and tiotropium/olodaterol). Differences in the trough FEV1 impact across the investigated LABA/LAMA FDCs could be related to the characteristics of populations recruited in the selected trials. IMPACT [26] and FLAME [31] trials enrolled patients affected by moderate-to-very severe COPD, with a mean post bronchodilator FEV1 <50% predicted (45% and 44%, respectively). All the other trials evaluating LABA/LAMA FDCs selected for this meta-analysis reported a mean post bronchodilator FEV1 ≥50% predicted. Patients with very severe COPD could have had a smaller FEV1 improvement if compared to patients with less severe COPD. Furthermore, across the 6 combinations analyzed for the risk of AECOPD, glycopyrronium/indacaterol significantly (P<0.05) reduced the exacerbation risk of 26%, compared to fluticasone propionate/salmeterol, and of 25% compared to aclidinium/formoterol, resulting the most effective combination in the SUCRA analysis. On the other hand, the LABA/LAMA FDCs glycopyrrolate/formoterol was the least effective treatment to reduce the risk of AECOPD. At present, no MCID has been validated for the risk of AECOPD due to the impossibility to use clinical anchor-based approaches.40 A number of factor could explain the different risk of AECOPD observed across the investigated LABA/LAMA FDCs, such as optimization of lung mechanics, degree of synergy between components, pulmonary concentration of treatment, and
effects
of
ventilation
improvement.
In
the
CLAIM
study,
glycopyrronium/indacaterol improved pulmonary ventilation and ventilation 13
homogeneity in COPD patients, compared to placebo [41]. Lung ventilation improvements obtained by treatments could vary greatly across LABA/LAMA FDCs as it depends on components, device performance and resistance, peak inspiratory flow rate achieved by COPD patients, dimension of drug particles, frequency of critical errors. These discrepancies should be analyzed for the evaluation of other potential effects of bronchodilators on exacerbation prevention. In support of this statement, Chapin et al [42] recently reported that incorporation of umeclidinium/vilanterol into the standard COPD protocol as replacement of the previous regimen (tiotropium + formoterol), led to an increased 30-day readmission rates (24.1% in post-intervention group vs. 10.8% in pre-intervention group, P=0.049) that was no longer statistically significant after adjustment for severity of illness and complications or comorbidities. With regard to lung function, LABA/LAMA FDCs led to a greater improvement also
in
peak
FEV1,
compared
to
ICS/LABA
FDCs.
In
particular,
glycopyrronium/indacaterol and tiotropium/olodaterol significantly (P<0.05) increased peak FEV1 compared to fluticasone proprionate/salmeterol. The analysis of the other secondary endpoints (SGRQ, TDI and use of rescue medication) did not detect any statistically significant difference between the selected combinations. A limited power to detect statistically significant differences could be one of the reasons behind this result. In keeping with other outcomes of this network meta-analysis, glycopyrronium/indacaterol showed the highest probability of being the best treatment for dyspnea improvement. On the other hand, surprisingly, umeclidinium/vilanterol was not superior to ICS/LABA FDCs in TDI. Given the dual bronchodilation and the beneficial effect of this 14
LABA/LAMA combination on lung function, this result probably requires further investigations of the mechanism involved in dyspnea reduction and perception. For the correct management of COPD, the GOLD documents classified patients into 4 groups (from A to D) depending on the burden of symptoms and exacerbations (GOLD 2013 and GOLD 2017). The GOLD 2017 document generally recommends LABA/LAMA FDCs over ICS/LABA FDCs for patients belonging to groups B, C and D [43]. If patients in D group have high blood eosinophil counts (≥300 cells/µL), the recent 2019 GOLD report indicates that ICS/LABA FDCs may be preferred as initial treatment [43, 44]. However, considering the increased risk of pneumonia observed in association with ICS [45, 31], a careful evaluation of the risk-benefit profile should be carried out before using ICS/LABA FDCs as first choice in COPD patients. In addition, in case of inappropriate treatment with ICS or in case of lack of response or side effects from the ICS/LABA combination treatment, GOLD 2019 report [1] suggest to switch from ICS/LABA FDCs to LABA/LAMA FDCs. A recent Cochrane systematic review reported that LABA/LAMA are associated with fewer exacerbations, larger improvement of FEV1, reduced risk of pneumonia, and more frequent SGRQ total score improvements, compared to ICS/LABA FDCs [46]. In line with GOLD recommendations and Cochrane systematic review data, the results of our network meta-analysis indicated that LABA/LAMA FDCs are more effective than ICS/LABA FDCs to improve lung function and decrease the risk of exacerbations. Across the investigated LABA/LAMA combinations, subgroup analysis of the data collected in the Cochrane systematic review [46] suggested that glycopyrronium/indacaterol can have better therapeutic effect on exacerbations
15
prevention when compared with other LABA/LAMAs FDC. Accordingly, the GOLD 2019 report suggests to consider switching inhaler device or molecules in case of persisting dyspnea, acknowledging that a different impact could be expected from treatments within the same class, at least in individual patients. In agreement, our network meta-analysis highlights that dual therapies belonging to the same class could have different clinical efficacy. This network meta-analysis provides useful information on the effects of different dual treatments for moderate-to-severe COPD patients. However this study suffered from some limitations, such as the quality of evidence between some of the indirect comparisons and the patient characteristics of the selected RCTs. In any case the baseline characteristics of the patients were homogeneous at the least by a functional viewpoint (post bronchodilator FEV1: median 50.0% predicted, lower quartile 47.25% predicted, upper quartile 51.75% predicted). Unfortunately, no subset analysis was performed on the severity of disease in agreement with the baseline risk of AECOPD: clustering the RCTs with respect to the rate of AECOPD (≥1 AECOPD per year vs. <1 AECOPD per year) disconnected the nodes of the mixed treatment comparison and, thus, no full Bayesian evidence network could result. Finally, only few studies reported the level of eosinophils, therefore it was not possible to perform a network meta-analysis by considering this co-variate.
5. Conclusions This network meta-analysis provides a ranking of dual therapies efficacy on the most relevant outcomes for COPD management. LABA/LAMA FDCs have shown superiority over LABA/ICS FDCs for the majority of the evaluated outcomes.
Across
the
investigated
16
LABA/LAMA
FDCs,
glycopyrronium/indacaterol showed a consistent and robust efficacy profile. These results indicate that significant differences in the efficacy profile could be present within a defined pharmacological class of FDCs. In our opinion, recommendations should be based on evidence from a specific dual therapy rather than on the effect of a class of compounds (unless equivalence is proven by clinical evidence).
Acknowledgments The authors thank Sara Parodi, PhD, of Forum Service S.r.l for providing medical writing support, which was funded by Novartis Farma SpA (Origgio, Italy).
Funding The authors received no specific funding for this work
Author contributions LC and PR completed the literature search, assessed eligibility of studies for inclusion and were all directly involved in the acquisition of data for the Article. LC designed the statistical analyses in consultation with all the other authors. Statistical analyses were done by LC. LC and PR wrote the first draft of the Article, in consultation with all the other authors for data interpretation. All authors revised the Article critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the Article in ensuring that questions related to the accuracy or integrity of any part of the Article were appropriately investigated and resolved.
Declaration of Interest
17
LC has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support from AstraZeneca, a research grant partially funded by Chiesi Farmaceutici, Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to ABC Farmaceutici, Recipharm, Zambon, Verona Pharma and Ockham Biotech. His department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. FDM reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from GSK, personal fees from Chiesi, personal fees from Zambon, grants and personal fees from Novartis, personal fees from Guidotti/Malesci, grants and personal fees from AZ, personal fees from Menarini, personal fees from Mundipharma, personal fees from TEVA, personal fees from Almiral. FB has received speaker or consultant honoraria or research funding from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Guidotti, Insmed, Malesci, Menarini, Mundifarma, Novartis, Pfizer, Teva, Valeas, and Zambon. MC has participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon; is or has been a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon; and his department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon.
18
SC Novartis, Chiesi, GSK, Boheringer Ingelheim, Astra Zeneca, Menarini, Guidotti-Malesci, Teva CM received honoraria for lectures and/or advisory boards from Novartis, GSK, AstraZeneca, Boehringer Ingelheim, Menarini, Guidotti, Zambon, Chiesi AR reports support for meetings from Boeheringer Ingelhehm, and personal fees from Chiesi Pharmaceuticals, Novartis, and Boheringer Ingelheim. PR participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim,
Chiesi
Farmaceutici,
GlaxoSmithKline,
Menarini
Group,
Mundipharma and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon.
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[22] Dobler CC, Wilson ME, Murad MH. A pulmonologist's guide to understanding network meta-analysis. Eur Respir J. 2018;52. [23] Cazzola M, Calzetta L, Rogliani P, Matera MG. Tiotropium formulations and safety: a network meta-analysis. Doi: 10.1177/2042098616667304. Ther Adv Drug Saf. 2016:2042098616667304. [24] Wallace BC, Dahabreh IJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Soft. 2012;49:1-15. [25] Ferguson GT, Rabe KF, Martinez FJ, Fabbri LM, Wang C, Ichinose M, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir med. 2018;6:747-58. [26] Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. DOI: 10.1056/NEJMoa1713901. N Engl J Med. 2018. [27] Kerwin E, Ferguson GT, Sanjar S, Goodin T, Yadao A, Fogel R, et al. Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies. Lung. 2017;195:739-47. [28] Feldman GJ, Sousa AR, Lipson DA, Tombs L, Barnes N, Riley JH, et al. Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study. Adv Ther. 2017:1-16. [29] Beeh KM, Derom E, Echave-Sustaeta J, Gronke L, Hamilton A, Zhai D, et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat((R)) is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler((R)) (ENERGITO((R)) study). Int J Chron Obstruct Pulmon Dis. 2016;11:193-205. [30] Vogelmeier C, Paggiaro PL, Dorca J, Sliwinski P, Mallet M, Kirsten AM,. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J. 2016;48:1030-9. [31] Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;374:2222-34. [32] Donohue JF, Worsley S, Zhu CQ, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respir Med. 2015;109:870-81. [33] Singh D, Worsley S, Zhu CQ, Hardaker L, Church A. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial. BMC Pulm Med. 2015;15:91.
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[34] Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang L, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:1015-26 [35] Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D, Kampschulte J, et al. Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD. BMC Pulm Med. 2014;14:43. [36] Agusti A, de Teresa L, De Backer W, Zvarich MT, Locantore N, Barnes N, et al. A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD. Eur Respir J. 2014;43:763-72. [37] Vogelmeier CF, Bateman ED, Pallante J, Alagappan VK, D'Andrea P, Chen H, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir med. 2013;1:51-60. [38] Calverley PM, Kuna P, Monso E, Costantini M, Petruzzelli S, Sergio F, et al. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med. 2010;104:1858-68. [39] Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31(2):416-69. [40]
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23
Tables Table 1. Patient demographics, baseline and study characteristics.
Study and year
KRONOS, Ferguson et al., 2018 (25)
ClinicalTrials.org Identifier
NCT02497001
Duration of treatment (weeks)
24
Number of analysed patients
1,257
Drugs (doses) and regimen of administration
GLY/FOR 18/9.6 µg BID vs. BUD/FOR 320/9.6 µg BID vs. open-label BUD/FOR 400/12 µg BID
Reported variables fulfilling prespecified criteria (study duration, number of nodes)
Trough FEV1
Exacerbations
YES
YES
Main inclusion Age (years) Male (%) criteria
Post Current Smoking bronchodilator smokers history FEV1 (% (%) (pack-years) predicted)
Patient with AECOPD history (%)
AECOPD in the previous year (rate)
Jadad score
FEV1 ≥25% and ≤80% predicted
65
73
38
45
50
26
0.4
4 (3 for the open-label arm)
65
67
35
≥10
45
100
1.7
3
54
24
0.3
4
IMPACT, Lipson et al., 2018 (26)
NCT02164513
52
6,204
UMEC/VI 62.5/25 µg OD vs. FF/VIL 100/25 µg OD
YES
NO
a) FEV1 <50% predicted and ≥1 moderate or severe AECOPD in the previous year; b) FEV1 ≥50% and ≤80% predicted and ≥2 moderate or ≥1 severe AECOPD in the previous year
Kerwin et al., 2017 (27)
NCT02487446, NCT02487498
12
712
GLY/IND 15.6/27.5 µg BID vs. UMEC/VI 62.5/25 µg OD
YES
NO
FEV1 ≥30% and <70% predicted
64
53
57
53
Feldman et al., 2017 (28)
NCT02799784
8
236
UMEC/VI 62.5/25 µg OD vs. TIO/OLO 5/5 µg (PD)
YES
NO
FEV1 ≥50% and <70% predicted
64
60
53
50
60
17
0.2
3
ENERGITO, Beeh et al., 2016 (29)
NCT01969721
6
229
TIO/OLO 5/5 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≥30% and <80% predicted
64
65
45
39
50
NA
NA
3
AFFIRM, Vogelmeier et al., 2016 (30)
NCT01908140
24
765
ACL/FOR 400/12 µg BID vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 <80% predicted
63.4
65.1
NA
42.1
53.3
32
0.4
3
24
FLAME, Wedzicha et al., 2016 (31)
NCT01782326
52
3,192
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 ≥25% and <60% predicted; mMRC scale ≥2
65
765
40
NA
44
100
1.2
5
Donohue et al., 2015 (32)
NCT01817764, NCT01879410
12
1,403
UMEC/VIL 62.5/25 µg OD vs. FP/SAL 250/50 µg BID
YES
NO
FEV1 ≥30% and ≤70%
63
73
43
43
50
0
0
4
Singh et al. 2015 (33)
NCT01822899
12
716
UMEC/VI 62.5/25 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≥30% and ≤70% predicted
62
72
59
40
51
0
0
4
LANTERN, Zhong et al., 2015 (34)
NCT01709903
26
741
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 ≥30% and <80% predicted
65
91
26
NA
52
21
0.2
4
Singh et al., 2014 (35)
NCT01245569
12
418
FP/SAL 500/50 µg BID vs. BDP/FOR 200/12 µg BID
YES
NO
FEV1 <80% predicted
64
71
46
41
47
47
NA
3
Agustì et al., 2013 (36)
NCT01342913
12
528
FF/VIL 100/25 µg OD vs. FP/SAL 500/50 µg BID
YES
NO
FEV1 ≤70%
63
82
NA
≥10
48
100
0.6a
4
ILLUMINATE, Vogelmeier et al., 2013 (37)
NCT01315249
26
522
GLY/IND 50/110 µg OD vs. FP/SAL 500/50 µg BID
YES
YES
FEV1 >40% and <80%
63
71
48
40
51
0
0
4
NCT476099
48
470
BDP/FOR 200/12 µg BID vs. BUD/FOR 400/12 µg BID
YES
YES
FEV1 >30% and <50%
63.6
80.4
37.5
37.6
42.1
100
1.7b
5
Calverley et al., 2010 (38)
a. AECOPD in the previous 3 years b. 2-12 months of screening AECOPD: acute exacerbation of COPD: ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; mMRC: modified Medical Research Council; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
25
Table 2. Relative effect estimates for each pairs of FDCs accompanied by 95% CrI and quality of evidence according to the impact on trough FEV1 (ml, lower diagonal), and risk of AECOPD (relative risk, upper diagonal). Trough FEV1
AECOPD
GLY/IND 50/110 µg OD
UMEC/VI 62.5/25 µg OD
17 (-23, 53)
◯
12 (-15, 39)
21 (-64, 106)
◯ ◯ ◯
-6 (-48, 46)
◯ ◯ ◯
GLY/IND 15.6/27.5 µg BID
5 (-81, 90)
◯ ◯ ◯
10 (-80, 97)
◯ ◯ ◯
◯ ◯
29 (-14, 74)
◯ ◯
26 (-16, 71)
Trough FEV1
31 (-7, 76)
◯ ◯
36 (1, 76)*
19 (-70, 111)
28 (-58, 114)
49 (-36, 135)
53 (-33, 142)
◯ ◯ ◯ ◯ ◯ ◯
70 (3, 126)*
44 (21, 68)*
◯ ◯ ◯
53 (-10, 109)
0.97 (0.56, ◯ 1.64)
6 (-33, 48)
◯ ◯
26 (-66, 113)
48 (-12, 106)
26 (-42, 92)
FF/VIL 100/25 µg OD
16 (-68, 10)
◯ ◯ ◯
23 (-47, 78)
◯ ◯ ◯
87 (57, 116)*
◯ ◯ ◯
◯ ◯
76 (33, 115)*
70 (49, 97)*
◯
88 (58, 121)*
71 (24, 123)*
◯
89 (7, 159)*
◯
◯
94 (7, 170)*
46 (10, 81)*
66 (-19, 156)
◯ ◯ ◯ 85 (-21, 182)
◯
46 (1, 94)*
◯ 64 (-23, 138)
40 (4, 70)*
◯
5 (-53, 57)
◯ ◯
◯
57 (-25, 130)
20 (-58, 104)
◯ ◯ Trough FEV1
*P<0.05 vs. comparator
26
0.07 (0.01, 0.35)*
0.07 (0.01, ◯ 1.29) ◯
GLY/FOR 18/9.6 µg BID
BDP/FOR 200/12 µg BID
19 (-33, 75)
◯
16 (-44, 92)
◯ ◯ ◯
◯ ◯ 22 (-62, 112)
41 (-64, 135)
◯ ◯ ◯
FP/SAL 500/50 µg BID 1 (-43, 44)
◯ ◯ ◯
◯ ◯ ◯ ◯ ◯
BDP/FOR 200/12 µg BID
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
◯ ◯
40 (-2, 81)
1.00 (0,09, ◯ 9,73)
◯ ◯
38 (-50, 125)
18 (-58, 84)
FP/SAL 250/50 µg BID 15 (-71 93)
◯ ◯ ◯
◯ ◯
ACL/FOR 400/12 µg BID
Trough FEV1
105 (23, 177)*
66 (-15, 149)
◯ ◯
◯ ◯ ◯
76 (37, 121)*
◯ ◯
FP/SAL 500/50 µg BID
TIO/OLO 5/5 µg OD
◯ ◯ ◯
56 (-14, 120)
0.74 (0.52, 0.95)*
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
◯ ◯ ◯ ◯
66 (-17, 148)
ACL/FOR 400/12 µg BID
GLY/FOR 18/9.6 µg BID
◯ ◯ ◯
48 (25, 76)*
0.75 (0.39, ◯ 1.34) ◯
AECOPD
41 (8, 75)*
GLY/IND 50/110 µg OD
Notes: Highlighted results indicate positive significant effect of treatments reported at the head of columns compared to treatments reported at the end of rows. ◯low quality, ⨁◯ ◯ ◯very low quality. GRADE Working Group grades of evidence: ⨁⨁⨁⨁ high quality, ⨁⨁⨁◯moderate quality, ⨁⨁◯ AECOPD: acute exacerbation of COPD; ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; CrI: Credible Interval; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol .
27
Table 3. SUCRA values for the impact of LABA/LAMA FDCs and ICS/LABA FDCs on the primary and secondary endpoints investigated in this network meta-analysis. Primary endpoints Treatment
Secondary endpoints SGRQ
TDI
Rescue medicatio n
0.77
0.60
0.80
0.70
0.92
0.58
0.39
0.45
0.63
NC
0.78
NC
NC
NC
NC
GLY/FOR 18/9.6 µg BID
0.02
0.74
0.92
0.70
NC
NC
TIO/OLO 5/5 µg OD
NC
0.55
0.80
NC
NC
0.29
FF/VIL 100/25 µg OD
NC
0.50
NC
0.49
NC
NC
BUD/FOR 320/9.6 µg or BUD/FOR 400/12 µg BID
0.75
0.37
0.13
0.82
NC
0.71
BDP/FOR 200/12 µg BID
0.73
0.33
0.46
0.75
0.59
0.43
FP/SAL 500/50 µg BID
0.24
0.19
0.20
0.32
0.51
0.45
FP/SAL 250/50 µg BID
NC
0.18
0.09
0.29
0.15
0.30
ACL/FOR 400/12 µg BID
0.35
0.14
0.53
0.17
0.50
NC
AECOPD
Trough FEV1
Peak FEV1
GLY/IND 50/110 µg OD
0.94
0.81
UMEC/VI 62.5/25 µg OD
NC
GLY/IND 15.6/27.5 µg BID
AECOPD: acute exacerbation of COPD; ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 second; FF/VIL: fluticasone furoate/vilanterol; FP/SAL: fluticasone propionate/salmeterol; GLY/FOR: glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; ICS: inhaled corticosteroids; LABA: long-acting β 2-agonist; LAMA: long-acting muscarinic receptor antagonist; NC: not calculable; OD: once daily; SGRQ: St’ George's Respiratory Questionnaire; SUCRA: surface under the cumulative ranking curve; TDI: Transition Dyspnea Index; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
28
Figure 1. PRISMA-P flow diagram for the identification of studies included in the network metaanalysis concerning the impact of LABA/LAMA combination vs. ICS/LABA combination in COPD. COPD: chronic obstructive pulmonary disease; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic receptor antagonist; PRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols.
29
Figure 2. Area-proportional diagram displaying the network of the arms involved in the Bayesian analysis. The links between nodes indicate the direct comparisons between pairs of treatments and the thickness of lines is related with the number of COPD patients comparing pairs of treatments head-to-head. ACL/FOR: aclidinium bromide/formoterol fumarate; BDP/FOR: beclomethasone dipropionate/formoterol fumarate; BID: bis in die; BUD/FOR: budesonide/formoterol fumarate; COPD: chronic obstructive pulmonary disease. FF/VIL:
fluticasone
furoate/vilanterol;
FP/SAL:
fluticasone
propionate/salmeterol;
GLY/FOR:
glycopyrrolate/formoterol fumarate; GLY/IND: glycopyrronium bromide/indacaterol; OD: once daily; TIO/OLO: tiotropium bromide/olodaterol; UMEC/VI: umeclidinium bromide/vilanterol.
30
Declaration of Interest LC has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support from AstraZeneca, a research grant partially funded by Chiesi Farmaceutici, Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to ABC Farmaceutici, Recipharm, Zambon, Verona Pharma and Ockham Biotech. His department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. FDM reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from GSK, personal fees from Chiesi, personal fees from Zambon, grants and personal fees from Novartis, personal fees from Guidotti/Malesci, grants and personal fees from AZ, personal fees from Menarini, personal fees from Mundipharma, personal fees from TEVA, personal fees from Almiral. FB has received speaker or consultant honoraria or research funding from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Guidotti, Insmed, Malesci, Menarini, Mundifarma, Novartis, Pfizer, Teva, Valeas, and Zambon. MC has participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon; is or has been a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon; and his department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon. SC Novartis, Chiesi, GSK, Boheringer Ingelheim, Astra Zeneca, Menarini, GuidottiMalesci, Teva
CM received honoraria for lectures and/or advisory boards from Novartis, GSK, AstraZeneca,
Boehringer
Ingelheim,
Menarini,
Guidotti,
Zambon,
Chiesi
AR reports support for meetings from Boeheringer Ingelhehm, and personal fees from Chiesi Pharmaceuticals, Novartis, and Boheringer Ingelheim. PR participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon.