Triple therapy in the management of chronic obstructive pulmonary disease: systematic review and meta-analysis

Abstract

ObjectiveTo compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease (COPD).DesignSystematic review and meta-analysis of randomised controlled trials.Data sourcesPubMed, Embase, Cochrane databases, and clinical trial registries searched from inception to April 2018.Eligibility criteriaRandomised controlled trials comparing triple therapy with dual therapy or monotherapy in patients with COPD were eligible. Efficacy and safety outcomes of interest were also available.Data extraction and synthesisData were collected independently. Meta-analyses were conducted to calculate rate ratios, hazard ratios, risk ratios, and mean differences with 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations assessment, development, and evaluation).Results21 trials (19 publications) were included. Triple therapy consisted of a long acting muscarinic antagonist (LAMA), long acting β agonist (LABA), and inhaled corticosteroid (ICS). Triple therapy was associated with a significantly reduced rate of moderate or severe exacerbations compared with LAMA monotherapy (rate ratio 0.71, 95% confidence interval 0.60 to 0.85), LAMA and LABA (0.78, 0.70 to 0.88), and ICS and LABA (0.77, 0.66 to 0.91). Trough forced expiratory volume in 1 second (FEV1) and quality of life were favourable with triple therapy. The overall safety profile of triple therapy is reassuring, but pneumonia was significantly higher with triple therapy than with dual therapy of LAMA and LABA (relative risk 1.53, 95% confidence interval 1.25 to 1.87).ConclusionsUse of triple therapy resulted in a lower rate of moderate or severe exacerbations of COPD, better lung function, and better health related quality of life than dual therapy or monotherapy in patients with advanced COPD.Study registrationProspero CRD42018077033.

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: Synergy of triple combination therapy on human airway smooth muscle ex vivo

“…The triple beclomethasone/formoterol/glycopyrronium 100:6:12.5 combination reduced by '0.5-1 logarithm the concentrations of monocomponents required to produce the same bronchorelaxant effect induced by the dual beclomethasone/formoterol 100:6 combination in human isolated airways, as previously reported (Calzetta, Matera, Facciolo, et al, 2018). Indeed, this finding further supports the superiority of triple therapy compared to single and dual therapy to improve pulmonary function of patients affected by asthma and stable COPD, as recently demonstrated by high-quality meta-analyses (Calzetta et al, 2019;Cazzola et al, 2018;Sobieraj et al, 2018;Zheng et al, 2018). However, further pharmacological investigations are needed to adequately quantify the possible synergistic effect of adding a LAMA to an ICS/LABA combination, but this was outside the scope of this study.…”

“…The last Global Initiative for Asthma report (GINA, ) and Global Initiative for Chronic Obstructive Lung Disease (GOLD 2019) recommend to combine an ICS with a LABA and a LAMA to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). The recent quantitative syntheses of data extracted from pivotal clinical trials carried out in asthmatic and COPD patients suggest that administering ICS/LABA/LAMA as fixed‐dose combinations may lead to clinical benefits when compared with single and dual combination therapy, namely, LAMA administered as monocomponent and ICS/LABA or LABA/LAMA combinations (Calzetta, Cazzola, Matera, & Rogliani, ; Cazzola, Rogliani, Calzetta, & Matera, ; Sobieraj et al, ; Zheng et al, ).…”

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

“…[17][18][19][20][21][22][23][24] In a systematic review and meta-analysis, Zheng and colleagues reported that the combination of LAMA, LABA, and ICS in patients with advanced COPD demonstrated better lung function and health-related quality of life, and lower rates of moderate or severe exacerbation of COPD than dual therapy or monotherapy. 25 Our results further support the effectiveness of combining LAMA with ICS/LABA. The effect observed with revefenacin for nebulization in our studies is also consistent with those from a subgroup analysis of patients from GOLDEN trials receiving nebulized LAMA glycopyrrolate in addition to ICS/LABA.…”

Triple therapy for COPD: a crude analysis from a systematic review of the evidence

“…In the case of triple therapies in COPD, recent meta-analyses have shown efficacy endpoints of fixed triple therapies combining the results in one single analysis. [7][8][9] In this analysis we aimed to perform a description of raw data on the efficacy and safety of FDC triple therapies in a systematic way in order to provide clinicians with a joint global view on the efficacy and safety profiles for each combination. In combination, this analysis and the previously published metaanalyses, constitute a thorough analysis of triple therapies in COPD.…”