Systematic review and network meta-analysis of the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in comparison with other long-acting muscarinic antagonist/long-acting β₂-agonist fixed-dose combinations in COPD

Abstract

Background: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 μg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA). Methods: A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks’ duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies. Results: In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV1 [trough, peak, and area under the curve (AUC)0–4], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case. Conclusions: GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.

<p>Efficacy and Safety of LAMA/LABA Fixed-Dose Combination Therapies in Chronic Obstructive Pulmonary Disease: A Systematic Review of Direct and Indirect Treatment Comparisons</p>

“…Full details of the search strategy (including search terms) have been published previously. 15 Databases evaluated included MEDLINE, MEDLINE In-Process, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). Bibliographic screening of any relevant reviews published in the English language was conducted to validate the searches and ensure the inclusion of all relevant evidence.…”

“…Following the literature review, a total of six NMAs were identified that provided indirect comparisons of LAMA/ LABA FDCs ( Figure 2); however, one of these was out of the pre-defined scope of this review as it included studies of short duration (3 and 6 weeks) and did not specifically report outcomes at or over 12 or 24 weeks. 21 All NMAs included RCTs conducted in adult patients with stable, moderate-to-very severe airflow obstruction, 15,[22][23][24][25] The NMA by Aziz et al included only parallel-group RCTs. 22 The NMAs by Siddiqui et al, 15 Sion et al, 23 Schlueter et al, 24 and Huisman et al 25 did not have any restriction on the design of the RCTs as both cross-over and parallel studies were included ( Table 3).…”

“…The scope of each NMA varied (Table 3). For example, the NMAs by Aziz et al, 22 Sion et al, 23 and Huisman et al 25 included RCTs with durations of ≥8 weeks, ≥10 weeks, and ≥12 weeks, respectively, whereas the NMA by Schlueter et al 24 15 and Schleuter et al 24 NMAs focused on the comparative efficacy of LAMA/LABA FDCs. The most recently published NMAs included a wider variety of LAMA/LABA FDCs compared with earlier NMA publications, due to the availability of new combinations.…”

“…The most recently published NMAs included a wider variety of LAMA/LABA FDCs compared with earlier NMA publications, due to the availability of new combinations. In four NMAs, the comparators of interest were any of the listed interventions and placebo, whereas in the NMA by Siddiqui et al, 15 only RCTs evaluating LAMA/ LABA FDCs were included. All of the NMAs attempted to identify treatment effect modifiers (ie, patient characteristics that may impact the effectiveness of treatment) across the included RCTs, and three NMAs (Siddiqui et al, 15 Sion et al, 23 and Schlueter et al 24 ) reported differences in the distribution of treatment effect modifiers across studies.…”

“…In four NMAs, the comparators of interest were any of the listed interventions and placebo, whereas in the NMA by Siddiqui et al, 15 only RCTs evaluating LAMA/ LABA FDCs were included. All of the NMAs attempted to identify treatment effect modifiers (ie, patient characteristics that may impact the effectiveness of treatment) across the included RCTs, and three NMAs (Siddiqui et al, 15 Sion et al, 23 and Schlueter et al 24 ) reported differences in the distribution of treatment effect modifiers across studies. Schlueter et al 24 performed meta-regression to adjust for baseline disease severity and concomitant ICS use, whereas Sion et al 23 performed subgroup analyses to control for severity of lung function impairment and baseline ICS use.…”