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Mario Cazzola - One of the best experts on this subject based on the ideXlab platform.
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Triple Therapy Versus Dual Bronchodilation and Inhaled Corticosteroids/Long-Acting β-Agonists in COPD: Accumulating Evidence from Network Meta-Analyses
Pulmonary Therapy, 2019Co-Authors: Mario Cazzola, Paola Rogliani, Luigino Calzetta, Maria Gabriella MateraAbstract:Guidelines are mainly based on evidence of well-designed randomized controlled trials (RCTs), but there are limitations to the transferability of conclusions of RCTs to usual care mainly because the patients enrolled in RCTs are selected and not representative of the population encountered in daily practice; moreover, the research environment is substantially different from that of the real world. Because of the scarcity of data generated in large unselected populations in everyday clinical practice, the possibility of using meta-analyses can be considered. Recently, several meta-analyses have attempted to clarify the role of triple therapy containing a long-acting β-agonist (LABA), a long-acting muscarinic antagonist (Lama) and an inhaled corticosteroid (ICS) delivered from a single inhaler in chronic obstructive pulmonary disease (COPD), also considering that there is a big difference in the use of triple therapy between what is recommended by COPD guidelines or strategies and the prescriptive behaviour of clinicians. Taking into account the results of the most recent meta-analyses, we believe that triple therapy provides modest clinical benefit in the general COPD population, but in patients on LABA/Lama combination therapy, who still experience acute exacerbations of COPD (AECOPDs) and have blood eosinophil counts ≥ 300 cells·μl^−1, it is of clinical relevance. On the contrary, adding a Lama to an ICS/LABA combination elicits relevant clinical benefit in the general COPD population, supporting the role of dual bronchodilation therapy for the treatment of COPD. The quantitative synthesis of the currently available clinical evidence seems to suggest that, in patients with COPD already on ICS/LABA combination, the therapy can be improved without an increase of cardiovascular severe adverse events (SAEs) when a Lama is added to the combination.
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impact of ics laba and laba Lama fdcs on functional and clinical outcomes in copd a network meta analysis
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Andrea Rossi, Mario Cazzola, Fabiano Di Marco, Francesco Blasi, Stefano Centanni, Claudio Micheletto, Paola RoglianiAbstract:Abstract Background Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixed-dose 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 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.
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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients
Advances in Therapy, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β_2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (Lama) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/Lama combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with olodaterol 5 μg is the best combination option: tiotropium/olodaterol 5/5 μg has the same efficacy profile of tiotropium/olodaterol 5/2 μg, and it is less effective than tiotropium/olodaterol 5/10 μg. Furthermore, tiotropium/olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the Lama.
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pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Barbara Rinaldi, Paola Rogliani, Mario Cazzola, Clive P. Page, Maria Gabriella MateraAbstract:: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (Lama) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the Lama tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
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adding a Lama to ics laba therapy a meta analysis of triple combination therapy in copd
Chest, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:Background Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (Lama) to ICS/LABA combination in COPD. Methods Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/Lama combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence. Results Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/Lama combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/Lama combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/Lama combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a Lama to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence). Conclusions Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a Lama is added to the combination. Trial Registry ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov .
Luigino Calzetta - One of the best experts on this subject based on the ideXlab platform.
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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients
Advances in Therapy, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β_2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (Lama) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/Lama combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with olodaterol 5 μg is the best combination option: tiotropium/olodaterol 5/5 μg has the same efficacy profile of tiotropium/olodaterol 5/2 μg, and it is less effective than tiotropium/olodaterol 5/10 μg. Furthermore, tiotropium/olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the Lama.
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Triple Therapy Versus Dual Bronchodilation and Inhaled Corticosteroids/Long-Acting β-Agonists in COPD: Accumulating Evidence from Network Meta-Analyses
Pulmonary Therapy, 2019Co-Authors: Mario Cazzola, Paola Rogliani, Luigino Calzetta, Maria Gabriella MateraAbstract:Guidelines are mainly based on evidence of well-designed randomized controlled trials (RCTs), but there are limitations to the transferability of conclusions of RCTs to usual care mainly because the patients enrolled in RCTs are selected and not representative of the population encountered in daily practice; moreover, the research environment is substantially different from that of the real world. Because of the scarcity of data generated in large unselected populations in everyday clinical practice, the possibility of using meta-analyses can be considered. Recently, several meta-analyses have attempted to clarify the role of triple therapy containing a long-acting β-agonist (LABA), a long-acting muscarinic antagonist (Lama) and an inhaled corticosteroid (ICS) delivered from a single inhaler in chronic obstructive pulmonary disease (COPD), also considering that there is a big difference in the use of triple therapy between what is recommended by COPD guidelines or strategies and the prescriptive behaviour of clinicians. Taking into account the results of the most recent meta-analyses, we believe that triple therapy provides modest clinical benefit in the general COPD population, but in patients on LABA/Lama combination therapy, who still experience acute exacerbations of COPD (AECOPDs) and have blood eosinophil counts ≥ 300 cells·μl^−1, it is of clinical relevance. On the contrary, adding a Lama to an ICS/LABA combination elicits relevant clinical benefit in the general COPD population, supporting the role of dual bronchodilation therapy for the treatment of COPD. The quantitative synthesis of the currently available clinical evidence seems to suggest that, in patients with COPD already on ICS/LABA combination, the therapy can be improved without an increase of cardiovascular severe adverse events (SAEs) when a Lama is added to the combination.
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impact of ics laba and laba Lama fdcs on functional and clinical outcomes in copd a network meta analysis
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Andrea Rossi, Mario Cazzola, Fabiano Di Marco, Francesco Blasi, Stefano Centanni, Claudio Micheletto, Paola RoglianiAbstract:Abstract Background Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixed-dose 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 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.
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pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Barbara Rinaldi, Paola Rogliani, Mario Cazzola, Clive P. Page, Maria Gabriella MateraAbstract:: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (Lama) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the Lama tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
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adding a Lama to ics laba therapy a meta analysis of triple combination therapy in copd
Chest, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:Background Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (Lama) to ICS/LABA combination in COPD. Methods Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/Lama combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence. Results Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/Lama combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/Lama combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/Lama combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a Lama to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence). Conclusions Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a Lama is added to the combination. Trial Registry ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov .
Paola Rogliani - One of the best experts on this subject based on the ideXlab platform.
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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients
Advances in Therapy, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β_2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (Lama) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/Lama combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with olodaterol 5 μg is the best combination option: tiotropium/olodaterol 5/5 μg has the same efficacy profile of tiotropium/olodaterol 5/2 μg, and it is less effective than tiotropium/olodaterol 5/10 μg. Furthermore, tiotropium/olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the Lama.
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Triple Therapy Versus Dual Bronchodilation and Inhaled Corticosteroids/Long-Acting β-Agonists in COPD: Accumulating Evidence from Network Meta-Analyses
Pulmonary Therapy, 2019Co-Authors: Mario Cazzola, Paola Rogliani, Luigino Calzetta, Maria Gabriella MateraAbstract:Guidelines are mainly based on evidence of well-designed randomized controlled trials (RCTs), but there are limitations to the transferability of conclusions of RCTs to usual care mainly because the patients enrolled in RCTs are selected and not representative of the population encountered in daily practice; moreover, the research environment is substantially different from that of the real world. Because of the scarcity of data generated in large unselected populations in everyday clinical practice, the possibility of using meta-analyses can be considered. Recently, several meta-analyses have attempted to clarify the role of triple therapy containing a long-acting β-agonist (LABA), a long-acting muscarinic antagonist (Lama) and an inhaled corticosteroid (ICS) delivered from a single inhaler in chronic obstructive pulmonary disease (COPD), also considering that there is a big difference in the use of triple therapy between what is recommended by COPD guidelines or strategies and the prescriptive behaviour of clinicians. Taking into account the results of the most recent meta-analyses, we believe that triple therapy provides modest clinical benefit in the general COPD population, but in patients on LABA/Lama combination therapy, who still experience acute exacerbations of COPD (AECOPDs) and have blood eosinophil counts ≥ 300 cells·μl^−1, it is of clinical relevance. On the contrary, adding a Lama to an ICS/LABA combination elicits relevant clinical benefit in the general COPD population, supporting the role of dual bronchodilation therapy for the treatment of COPD. The quantitative synthesis of the currently available clinical evidence seems to suggest that, in patients with COPD already on ICS/LABA combination, the therapy can be improved without an increase of cardiovascular severe adverse events (SAEs) when a Lama is added to the combination.
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impact of ics laba and laba Lama fdcs on functional and clinical outcomes in copd a network meta analysis
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Andrea Rossi, Mario Cazzola, Fabiano Di Marco, Francesco Blasi, Stefano Centanni, Claudio Micheletto, Paola RoglianiAbstract:Abstract Background Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixed-dose 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 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.
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pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Barbara Rinaldi, Paola Rogliani, Mario Cazzola, Clive P. Page, Maria Gabriella MateraAbstract:: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (Lama) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the Lama tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
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adding a Lama to ics laba therapy a meta analysis of triple combination therapy in copd
Chest, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:Background Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (Lama) to ICS/LABA combination in COPD. Methods Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/Lama combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence. Results Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/Lama combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/Lama combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/Lama combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a Lama to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence). Conclusions Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a Lama is added to the combination. Trial Registry ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov .
Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.
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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients
Advances in Therapy, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β_2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (Lama) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/Lama combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with olodaterol 5 μg is the best combination option: tiotropium/olodaterol 5/5 μg has the same efficacy profile of tiotropium/olodaterol 5/2 μg, and it is less effective than tiotropium/olodaterol 5/10 μg. Furthermore, tiotropium/olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the Lama.
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Triple Therapy Versus Dual Bronchodilation and Inhaled Corticosteroids/Long-Acting β-Agonists in COPD: Accumulating Evidence from Network Meta-Analyses
Pulmonary Therapy, 2019Co-Authors: Mario Cazzola, Paola Rogliani, Luigino Calzetta, Maria Gabriella MateraAbstract:Guidelines are mainly based on evidence of well-designed randomized controlled trials (RCTs), but there are limitations to the transferability of conclusions of RCTs to usual care mainly because the patients enrolled in RCTs are selected and not representative of the population encountered in daily practice; moreover, the research environment is substantially different from that of the real world. Because of the scarcity of data generated in large unselected populations in everyday clinical practice, the possibility of using meta-analyses can be considered. Recently, several meta-analyses have attempted to clarify the role of triple therapy containing a long-acting β-agonist (LABA), a long-acting muscarinic antagonist (Lama) and an inhaled corticosteroid (ICS) delivered from a single inhaler in chronic obstructive pulmonary disease (COPD), also considering that there is a big difference in the use of triple therapy between what is recommended by COPD guidelines or strategies and the prescriptive behaviour of clinicians. Taking into account the results of the most recent meta-analyses, we believe that triple therapy provides modest clinical benefit in the general COPD population, but in patients on LABA/Lama combination therapy, who still experience acute exacerbations of COPD (AECOPDs) and have blood eosinophil counts ≥ 300 cells·μl^−1, it is of clinical relevance. On the contrary, adding a Lama to an ICS/LABA combination elicits relevant clinical benefit in the general COPD population, supporting the role of dual bronchodilation therapy for the treatment of COPD. The quantitative synthesis of the currently available clinical evidence seems to suggest that, in patients with COPD already on ICS/LABA combination, the therapy can be improved without an increase of cardiovascular severe adverse events (SAEs) when a Lama is added to the combination.
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pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Barbara Rinaldi, Paola Rogliani, Mario Cazzola, Clive P. Page, Maria Gabriella MateraAbstract:: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (Lama) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the Lama tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
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adding a Lama to ics laba therapy a meta analysis of triple combination therapy in copd
Chest, 2019Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola, Paola RoglianiAbstract:Background Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (Lama) to ICS/LABA combination in COPD. Methods Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/Lama combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence. Results Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/Lama combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/Lama combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/Lama combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a Lama to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence). Conclusions Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a Lama is added to the combination. Trial Registry ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov .
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Pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways
Pulmonary Pharmacology & Therapeutics, 2019Co-Authors: Luigino Calzetta, Barbara Rinaldi, Paola Rogliani, Mario Cazzola, Clive P. Page, Maria Gabriella MateraAbstract:: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (Lama) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the Lama tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P
Gary T. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only Lama at Baseline: Pooled Analysis of the TONADO^® and OTEMTO^® Studies
Advances in Therapy, 2020Co-Authors: Roland Buhl, Dave Singh, Gary T. FergusonAbstract:Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (Lama) or long-acting β_2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. Methods TONADO^® 1&2 and OTEMTO^® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with Lama monotherapy at baseline who were randomised to receive either 5 µg tiotropium (Lama) or 5/5 µg tiotropium/olodaterol (Lama/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV_1), St. George’s Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Results Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV_1, − 2.675 (95% CI − 5.060, − 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV_1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P
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benefits of tiotropium olodaterol compared with tiotropium in patients with copd receiving only Lama at baseline pooled analysis of the tonado and otemto studies
Advances in Therapy, 2020Co-Authors: Roland Buhl, Dave Singh, Gary T. FergusonAbstract:INTRODUCTION The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (Lama) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. METHODS TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with Lama monotherapy at baseline who were randomised to receive either 5 µg tiotropium (Lama) or 5/5 µg tiotropium/olodaterol (Lama/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). RESULTS Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). CONCLUSION In patients with COPD receiving only Lama monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone. TRIAL REGISTRATION TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).
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Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only Lama at Baseline: Pooled Analysis of the TONADO® and OTEMTO® Studies.
Advances in therapy, 2020Co-Authors: Roland Buhl, Dave Singh, Gary T. FergusonAbstract:The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (Lama) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with Lama monotherapy at baseline who were randomised to receive either 5 µg tiotropium (Lama) or 5/5 µg tiotropium/olodaterol (Lama/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). In patients with COPD receiving only Lama monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone. TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).
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Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting β_2-Agonist (ICS/Lama/LABA) Triple Combinations in COPD: A Systematic Literatur
Advances in Therapy, 2020Co-Authors: Gary T. Ferguson, Patrick Darken, Shaila Ballal, Mohd Kashif Siddiqui, Barinder Singh, Sumeet Attri, Ulf Holmgren, Enrico NigrisAbstract:Introduction Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β_2-agonist (ICS/Lama/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual Lama/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/Lama/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). Methods A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV_1), post-dose peak FEV_1, and St. George’s Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12–24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Results Eighteen studies ( n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/Lama/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. Conclusion This NMA suggested that BGF MDI has comparable efficacy to other ICS/Lama/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.
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efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ics laba or laba subgroup analysis from phase iii trials
Therapeutic Advances in Respiratory Disease, 2020Co-Authors: Sanjay Sethi, Gary T. Ferguson, James F. Donohue, Chris N Barnes, Glenn CraterAbstract:Background:Combinations of a long-acting muscarinic receptor antagonist (Lama), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstruct...
