Quantitative analysis of efficacy and safety of LABA/LAMA fixed-dose combinations in the treatment of stable COPD

Abstract

Objective: This 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. Methods: Randomized 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. Results: A 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. Conclusion: The present findings may provide necessary quantitative information for COPD medication guidelines.

Combination Therapy for COPD: Efficacy and Prospects of Multiple Therapy

“…The reasonable principle of the combination of LABA and LAMA in the treatment of COPD is that they provide the synergistic effect of airway smooth muscle relaxation in small and mediumsized human airway. Since muscarinic M3 receptor mainly appears in the bronchus,and the density gradually decreases from segmental to sub segmental bronchus,it is missing in the parenchyma of the lung.In contrast,the effect of the β2-adrenergic receptors is to increase along the airway,the density in subsegmental bronchus,also lung parenchymawas about twice that of mAChR.The differential distribution of these receptors may finally lead to improvie the efficacy of COPD patients,thus is the basic.When using LABA and LAMA for 12 weeks,the lung function (FEV1) was significantly improved,compared with the use of the LABA alone(also 12 weeks).These effects were sustained over time.Prominent change in TDI and SGRQ scores were observed for LABA/LAMA FDCs with each comparator that was evaluated.For the reduction of the rate of acute exacerbation,only LABA/LAMA FDC indaterol/glulammonium was superior to LAMA in reducing the rate of acute exacerbation,while odaterol/tiotropium bromide and indaterol/glulammonium bromide showed the effect of improving ET and IC [10].…”

Dual bronchodilation for the treatment of COPD: From bench to bedside

“…The findings of a very recent quantitative analysis of the efficacy and safety of LABA/LAMA FDCs in the treatment of stable COPD were more comprehensive. Results from a review of 22 studies involving 16 486 participants showed that the efficacy of umeclidinium/vilanterol was found to be the best in respect of trough FEV 1 , while that of aclidinium/formoterol was the worst 53 . Aclidinium/formoterol, glycopyrronium/formoterol, glycopyrronium/indacaterol and tiotropium/olodaterol all showed a progressive reduction in their ability to improve trough FEV 1 over time, whereas there was no significant loss of efficacy after the administration of umeclidinium/vilanterol (Figure 3).…”

“…While there was a progressive loss of efficacy with aclidinium/formoterol (ACL/FOR), glycopyrronium/formoterol (GLY/FOR), glycopyrronium/indacaterol (GLY/IND) and tiotropium/olodaterol (TIO/OLO) as evidenced by the trough (pre dose) FEV 1 trend over time, this was not the case with the administration of umeclidinium/vilanterol (UMEC/VIL) (data from Gong et al, 53 modified)…”

“…While there was a progressive loss of efficacy with aclidinium/formoterol (ACL/FOR), glycopyrronium/formoterol (GLY/FOR), glycopyrronium/indacaterol (GLY/IND) and tiotropium/olodaterol (TIO/OLO) as evidenced by the trough (pre dose) FEV 1 trend over time, this was not the case with the administration of umeclidinium/vilanterol (UMEC/VIL) (data from Gong et al,53 modified) exacerbations to the extent expected compared with tiotropium alone,61 cast doubt on the ability of dual bronchodilation to influence the rate of exacerbations. Nevertheless, before any negative judgment is made on the outcome of this study, the possibility that it may have been influenced by the broad inclusion and exclusion criteria regarding baseline respiratory medication and the noninterruption of ICS before enrolment should be examined 62.…”

Kvėpavimo ir kraujotakos parametrų, fizinio krūvio tolerancijos bei širdies ir kraujagyslių sistemos saugumo įvertinimas, skiriant dviejų ilgo veikimo bronchus plečiančių vaistų derinius lėtine obstrukcine plaučių liga sergantiems pacientams

“…Vis dėlto LOPL diagnozė neretai nustatoma vėlai, jau esant sunkių, pacientą varginančių ligos simptomų, todėl tokiais atvejais netgi pradiniam gydymui turi būti skiriamas ilgo veikimo muskarino receptorių blokatoriaus (IVMB) ir ilgo veikimo β 2 agonisto (IVBA) derinys [2,19]. Atliekant klinikinius tyrimus bei įgyvendinant jų programas, įrodyta, kad IVMB / IVBA deriniai turi teigiamą poveikį plaučių funkcijos rodikliams, mažina paūmėjimų skaičių, gerina fizinio krūvio toleranciją ir gyvenimo kokybę [20][21][22]. Tačiau pastaraisiais metais daug dėmesio skiriama šių vaistų poveikio širdies ir kraujagyslių sistemai vertinimui -tiek kalbant apie jų saugumą [23][24][25], tiek apie galimą teigiamą poveikį [26,27].…”