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Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

ABSTRACT: Bronchodilators are mainstay for the symptomatic treatment of chronic obstructive pulmonary disease (COPD) and the introduction of long-acting bronchodilators has led to an improvement in the maintenance treatment of this disease. Various clinical trials have evaluated the effects of fixed dose long-acting ?2-agonists (LABA)/long-acting anti-muscarinics (LAMA) combinations and documented greater improvements in spirometry but such improvements do not always translate to greater improvements in symptom scores or reduction in the rates of exacerbation compared with a single component drug. An analysis of whether this significantly greater change in spirometry with combination therapy is additive or synergistic was undertaken and is the subject of this review. Bronchodilators are not disease modifiers and whilst glucocorticosteroids have been shown to reduce rates of exacerbation in moderate to severe COPD, the increase risk of pneumonia and bone fractures is a motivation enough to warrant developing novel anti-inflammatory and disease-modifying drugs and with the expectation of positive outcomes.

SUBMITTER: Spina D

PROVIDER: S-EPMC4629759 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

Spina Domenico D

European clinical respiratory journal 20150316

Bronchodilators are mainstay for the symptomatic treatment of chronic obstructive pulmonary disease (COPD) and the introduction of long-acting bronchodilators has led to an improvement in the maintenance treatment of this disease. Various clinical trials have evaluated the effects of fixed dose long-acting β2-agonists (LABA)/long-acting anti-muscarinics (LAMA) combinations and documented greater improvements in spirometry but such improvements do not always translate to greater improvements in s ...[more]

PMID: 26557255

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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: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:Background:This literature review assessed comparative efficacy and safety of long-acting muscarinic antagonist/long-acting ?2-agonist (LAMA/LABA) fixed-dose combinations (FDCs) in patients with COPD and moderate-to-very severe airflow limitation, using evidence from direct (head-to-head) and indirect treatment comparisons. Methods:Two systematic literature reviews were conducted to identify direct comparisons (head-to-head randomized controlled trials [RCTs]) and indirect comparisons (network meta-analyses [NMAs]; indirect treatment comparisons; meta-analyses) in patients with COPD with moderate-to-very severe airflow limitation. Study/Analysis characteristics, eligibility criteria, patient characteristics, and overall conclusions were extracted from relevant publications. The review of indirect comparisons focused on NMAs reporting efficacy outcomes at 12 and 24 weeks of treatment (established durations of symptomatic studies in COPD recommended by regulators). Results:Direct comparisons: Four RCTs that provided head-to-head comparisons of LAMA/LABA FDCs were identified, and these varied in their study design, included patient population and reported endpoints. While some differences in lung function outcomes were noted, where assessed, LAMA/LABA FDCs had comparable efficacy in improving symptoms, health status, exacerbations, and comparable safety profiles. However, the differences in study methodology and patient characteristics between these studies made it difficult to draw generalizable conclusions regarding the comparative effectiveness of LAMA/LABA FDCs from the direct comparisons alone. Indirect comparisons: Six NMAs were identified that reported indirect comparisons between LAMA/LABA FDCs; five of these were within the pre-defined scope of this review. Although the scope of each NMA varied, all five concluded that LAMA/LABA FDCs were generally comparable in terms of lung function improvements, patient-reported outcomes, and safety (where assessed). Conclusion:Although there were some inconsistencies between the outcomes of RCTs and NMAs for lung function, the totality of lung function, symptoms, exacerbations, and safety data suggests that currently available LAMA/LABA FDCs have comparable efficacy and safety in patients with COPD and moderate-to-very severe airflow limitation.

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.

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Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

Publications

Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

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