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LABA/LAMA fixed-dose combinations versus LAMA monotherapy in the prevention of COPD exacerbations: a systematic review and meta-analysis.

ABSTRACT:

Background

Long-acting muscarinic antagonist (LAMA) monotherapy is recommended for chronic obstructive pulmonary disease (COPD) patients with high risk of exacerbations. It is unclear whether long-acting β2-agonist (LABA)/LAMA fixed-dose combinations (FDCs) are more effective than LAMAs alone in preventing exacerbations. The aim of this study was to systematically review the literature to investigate whether LABA/LAMA FDCs are more effective than LAMA monotherapy in preventing exacerbations.

Methods

We searched several databases and manufacturers' websites to identify relevant randomized clinical trials comparing LABA/LAMA FDC treatment with LAMAs alone ⩾24 weeks. Outcomes of interest were time to first exacerbation and rates of moderate to severe, severe and all exacerbations.

Results

We included 10 trials in 9 articles from 2013 to 2018 with a total of 19,369 patients for analysis in this study. Compared with LAMA monotherapy, LABA/LAMA FDCs demonstrated similar efficacy in terms of time to first exacerbation [hazard ratio, 0.96; 95% confidence interval (CI) 0.79-1.18; p = 0.71], moderate to severe exacerbations [risk ratio (RR), 0.96; 95% CI 0.90-1.03; p = 0.28], severe exacerbations (RR, 0.92; 95% CI 0.81-1.03; p = 0.15), and a marginal superiority in terms of all exacerbations (RR, 0.92; 95% CI 0.86-1.00; p = 0.04). The incidence of all exacerbation events was lower in the LABA/LAMA FDC group for the COPD patients with a history of previous exacerbations and those with a longer treatment period (52-64 weeks).

Conclusion

This study provides evidence that LABA/LAMA FDCs are marginally superior in the prevention of all exacerbations compared with LAMA monotherapy in patients with COPD. The reviews of this paper are available via the supplemental material section.

SUBMITTER: Chen CY

PROVIDER: S-EPMC7350046 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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LABA/LAMA fixed-dose combinations <i>versus</i> LAMA monotherapy in the prevention of COPD exacerbations: a systematic review and meta-analysis.

Chen Ching-Yi CY Chen Wang-Chun WC Huang Chi-Hsien CH Hsiang Yi-Ping YP Sheu Chau-Chyun CC Chen Yung-Che YC Lin Meng-Chih MC Chu Kuo-An KA Lee Cheng-Hung CH Wei Yu-Feng YF

Therapeutic advances in respiratory disease 20200101

<h4>Background</h4>Long-acting muscarinic antagonist (LAMA) monotherapy is recommended for chronic obstructive pulmonary disease (COPD) patients with high risk of exacerbations. It is unclear whether long-acting β2-agonist (LABA)/LAMA fixed-dose combinations (FDCs) are more effective than LAMAs alone in preventing exacerbations. The aim of this study was to systematically review the literature to investigate whether LABA/LAMA FDCs are more effective than LAMA monotherapy in preventing exacerbati ...[more]

PMID: 32643547

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Project description:ObjectivesThe aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD.Materials and methodsA systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George's Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated.ResultsIn total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents.ConclusionEvidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety.

Project description:ObjectiveThis study aimed to quantitatively compare the efficacy and safety of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for the treatment of stable chronic obstructive pulmonary disease (COPD), especially in terms of their loss of efficacy in lung function.MethodsRandomized controlled clinical trials of LABA/LAMA FDCs for the treatment of stable COPD were comprehensively searched for in public databases. Pharmacodynamic models were established to describe the time course of the primary outcome [trough forced expiratory volume in the first second (FEV1)]. Secondary outcomes [COPD exacerbations, St. George's Respiratory Questionnaire (SGRQ), Transition Dyspnoea Index (TDI), and rescue medication use] and safety outcomes [mortality, serious adverse events (SAEs), and withdrawals due to adverse events (AEs)] were also compared via a meta-analysis.ResultsA total of 22 studies involving 16,486 participants were included in this study. The results showed that in terms of primary outcome (change from baseline in trough FEV1), the efficacy of vilanterol/umeclidinium was the highest, while the efficacy of formoterol/aclidinium was the lowest, with a maximum effect value (Emax) of 0.185 L [95% confidence interval (CI): 0.173-0.197 L] and 0.119 L (95% CI: 0.103-0.135 L), respectively. The efficacy of other drugs, such as formoterol/glycopyrronium, indacaterol/glycopyrronium, and olodaterol/tiotropium, were comparable, and their Emax values were 0.150-0.177 L. Except for vilanterol/umeclidinium, the other four LABA/LAMA FDCs showed a certain degree of loss of efficacy. Compared with the efficacy at 2 days, the trough FEV1 (L) relative to baseline at 24 weeks decreased by 0.029-0.041 L. In terms of secondary outcomes, the efficacy of different LABA/LAMA FDCs was similar in TDI and rescue medication use. However, formoterol/aclidinium was better in preventing the COPD exacerbations, while vilanterol/umeclidinium was the best in terms of SGRQ. In addition, different LABA/LAMA FDCs and placebo had similar safety outcomes.ConclusionThe present findings may provide necessary quantitative information for COPD medication guidelines.

Project description:BackgroundLABA (long-acting β2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings.Objective and methodsThe main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented.ResultsIn total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%.ConclusionIn summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.

Project description:BackgroundRecently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial.MethodsWe searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest.ResultsWe identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64-0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18-0.48) and mortality (odds ratio 0.66, 95% CI 0.50-0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16-2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference.ConclusionTriple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations.Clinical trial registrationPROSPERO; CRD42020191978.

Project description:INTRODUCTION:Comparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic obstructive pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler). METHODS:We conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ≥8-week duration in adults aged ≥40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV1) and on St George's Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework. RESULTS:Data from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV1, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV1 but suggested little potential for differences in patient-reported outcomes. CONCLUSION:LAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings. FUNDING:GSK.