laba lama combination in copd a meta analysis on the duration of treatment

REVIEW COPD LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment Luigino Calzetta1, Paola Rogliani1,2, Josuel Ora2, Ermanno Puxeddu1, Mario Cazzola1 and Maria Gabriella Matera3 Affiliations: 1Dept of Systems Medicine, University of Rome Tor Vergata, Rome, Italy 2Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy 3Dept of Experimental Medicine, Second University of Naples, Naples, Italy Correspondence: Luigino Calzetta, Dept of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy E-mail luigino.calzetta@uniroma2.it @ERSpublications We propose a simple and effective meta-analytic approach for exploring the impact of LABA/LAMA combinations in COPD http://ow.ly/8Zd9302154B Cite this article as: Calzetta L, Rogliani P, Ora J, et al LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment Eur Respir Rev 2017; 26: 160043 [https://doi.org/10.1183/ 16000617.0043-2016] ABSTRACT When there are no randomised clinical trials directly comparing all relevant treatment options, an indirect treatment comparison via meta-analysis of the available clinical evidence is an acceptable alternative However, meta-analyses may be very misleading if not adequately performed Here, we propose and validate a simple and effective approach to meta-analysis for exploring the effectiveness of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations in chronic obstructive pulmonary disease 14 articles with 20 329 patients (combinations n=9292; monocomponents n=11 037) were included in this study LABA/LAMA combinations were always more effective than the monocomponents in terms of the improvement in trough forced expiratory volume in s, transition dyspnoea index and St George’s Respiratory Questionnaire scores after 3, and 12 months of treatment No significant publication bias was identified Significant discrepancies with previous network meta-analyses have been found, with overall differences ranging from 26.7% to 43.3% Results from previous network meta-analyses were misleading because no adequate attention was given to formulating the review question, specifying eligibility criteria, correctly identifying studies, collecting appropriate information and deciding what it would be pharmacologically relevant to analyse The real gradient of effectiveness of LABA/LAMA fixed-dose combinations remains an unmet medical need; however, it can be investigated indirectly using a high-quality meta-analytic approach Introduction The wide availability of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the absence of head-to-head comparative randomised clinical trials (RCTs) makes difficult the choice of combination for the treatment of chronic obstructive pulmonary This article has supplementary material available from err.ersjournals.com Received: April 27 2016 | Accepted after revision: June 24 2016 Support statement: This study was supported by institutional funds (University of Rome Tor Vergata) Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com Provenance: Submitted article, peer reviewed Copyright ©ERS 2017 ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0 https://doi.org/10.1183/16000617.0043-2016 Eur Respir Rev 2017; 26: 160043 COPD | L CALZETTA ET AL disease (COPD), a heterogeneous disorder characterised by an enormous variability in drug response between phenotypes [1, 2] Some meta-analyses have been undertaken in an attempt to improve the gaps in our knowledge in this field [3–5] Since no RCTs exist that have directly compared all relevant treatment options, an indirect treatment comparison via a meta-analytic approach can be an acceptable alternative to quantifying scientific uncertainty However, only the meta-analysis published by OBA et al [4] has investigated the impact of LABA/LAMA FDCs in COPD with specific regard to the duration of treatment These authors performed a sophisticated meta-analysis [4], but we have identified several critical points in their method that have affected the results and produced quite inconsistent conclusions In particular, we strongly believe that comparing LABA/LAMA FDCs with placebo is anachronistic In fact, there is solid evidence suggesting that the so-called “dual” bronchodilator therapy has an important role in optimising bronchodilation [6–8] In any case, the effectiveness of dual bronchodilation should always be compared with at least one of the monocomponents included in the FDCs, and not with different LABAs or LAMAs [5] We also believe that the regimen of administration should be consistent between the drugs of each combination, i.e both medications should be administered once daily, for example, and not one on a once-daily and the other on a twice-daily basis [5] A correct meta-analytic approach should have both quantitative and qualitative characteristics, in order to reveal the biases, strengths and weaknesses of analysed studies [9] Although the Jadad score rates three out of 10 dimensions of RCT quality, it represents an easy, fast and objective tool for assessing the quality of RCTs, by revealing great overlap with the Cochrane Back Review Group [10] In spite of this, OBA et al [4] selected the studies to be included in their network meta-analysis according to personal opinion [4] Moreover, they omitted to examine several important outcomes after 12 months of treatment, although RCTs in which these variables were available at week 52 were included in their analysis [4] More surprising is that the flow diagram for the identification of the included studies was not reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11] We have recently performed an indirect treatment comparison of the currently approved LABA/LAMA FDCs in COPD [5], in which the variables have been meta-analysed regardless of the duration of the treatment The aim of the present meta-analysis was to explore whether the duration of treatment could in some way influence the clinical effectiveness of LABA/LAMA FDCs Therefore, we have now adequately assessed the impact of the duration of treatment with LABA/LAMA FDCs on the trough forced expiratory volume in s (FEV1), St George’s Respiratory Questionnaire (SGRQ) and transition dyspnoea index (TDI) in COPD, by extracting each variable at the end of RCTs lasting ⩾3 months and performing a high-quality meta-analysis Materials and methods Search strategy This systematic review was performed in agreement with the PRISMA statement (supplementary table S1) [12] We performed a comprehensive literature search for RCTs written in English regarding the impact of treatment with LABAs and LAMAs administered in combination in patients suffering from COPD and lasting ⩾3 months [13, 14] The terms “chronic obstructive pulmonary disease” and “COPD” were searched for the disease, the terms “LABAs” and “LAMAs” for the class of drugs, the terms “aclidinium”, “formoterol”, “glycopyrronium”, “indacaterol”, “olodaterol”, “tiotropium”, “umeclidinium” and “vilanterol” for specific compounds and the term “combination” to identify RCTs investigating combination therapy The search was performed on PubMed and Google Scholar in order to provide for relevant studies published up to April 15, 2016 [15] Further searches were performed on www.clinicaltrials.gov, the EU Clinical Trials Register and the 2015 European Respiratory Society (ERS) International Congress abstracts in order to find RCTs not yet published Citations of previous published meta-analyses and relevant reviews were checked to select further pertinent studies, if any [16–19] Study selection RCTs involving COPD patients that had received inhalant administration of LABA/LAMA combinations versus at least one monocomponent were included in the analysis Two reviewers independently examined the RCTs found from literature and databases, and any difference in opinion about eligibility was resolved by consensus https://doi.org/10.1183/16000617.0043-2016 COPD | L CALZETTA ET AL Quality score and risk of bias assessment The Jadad score, with a scale of 1–5 (score of being the best quality), was used to assess the quality of the papers concerning the likelihood of bias related with randomisation, double blinding, withdrawals and dropouts [20] Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus RCTs with Jadad score ⩾3 were included in the meta-analysis The risk of publication bias was analysed by applying Egger’s test in order to assess funnel plot symmetry through the following regression equation: SND = a + b × precision, where SND represents the standard normal deviate (treatment effect divided by its standard error), and precision represents the reciprocal of the standard error [21–24] Evidence of asymmetry from Egger’s test was considered to be significant for p50% [29] The network meta-analysis was performed using a full Bayesian evidence network (chains: 4; initial values scaling: 2.5; tuning iterations: 20 000; simulation iterations: 50 000; and tuning interval: 10), the convergence diagnostics for consistency and inconsistency was assessed using the Brooks–Gelman–Rubin method [30, 31] Results of the network meta-analysis are presented as mean difference and 95% credible level (Crl) Due to the complex evidence structure, the inconsistency of evidence has been assessed in addition to heterogeneity obtained from the pair-wise meta-analysis While heterogeneity represents between-study variation in the measured relative effect of a pair of treatments, inconsistency can only occur when one of the treatments has a different effect when it is compared with the others [31] 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, and the surface under the cumulative ranking (SUCRA), which represents the summary of these probabilities, was also calculated The SUCRA is 100% when a treatment is certain to be the best, and 0% when a treatment is certain to be the worst [32] The percentage of differences between the summary effects resulting from network meta-analysis and pair-wise meta-analysis was calculated in order to compare the results obtained from these different meta-analytic approaches In particular, Gini’s mean absolute difference (GMD) between each observation and any other observation has been calculated as previously described [33] The GMD is defined in terms of absolute deviations averaging differences between pairs of observations, as defined by the following equation: GMD = ∑|Xi−Xj|/n [33] The optimal information size was calculated as previously reported [34, 35], and the statistical significance was assessed for p