A Network Meta-Analysis of Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting β₂-Agonist (LABA) Combinations in COPD

Bronchodilators, particularly long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists (LABAs), have become the mainstay of pharmacological therapy for chronic obstructive pulmonary disease (COPD) [1‐3]. Despite the well-demonstrated utility of LABAs [4‐7] and LAMAs [8‐11] as maintenance therapy, a high number of patients with moderate or severe COPD receiving LABA or LAMA monotherapy can fail to achieve adequate control of symptoms [12]. A combination of a LAMA and a LABA maintenance therapy is a logical therapeutic option to improve symptom control for such patients [13]. In the last decade, multiple randomized controlled trials (RCTs) have reported that improvements in lung function and patient-reported outcomes (PROs) can be achieved with LAMA + LABA combinations compared with the component monotherapies for patients with stable COPD, with no differences in safety [14‐20].

LAMA + LABA combinations can be administered as open dual combinations (using separate prescribed inhalers for each bronchodilator) and fixed-dose combinations (FDCs; use of a single inhaler delivering a fixed dose of each bronchodilator). Several options are available within each class; in the last few years, several FDC LAMA/LABA therapies have been approved as once-daily (OD) or twice-daily (BID) maintenance therapies for COPD, including glycopyrronium/indacaterol (GLY/IND) 110/50 mcg OD (outside the USA) [21] and 27.5/15.6 mcg BID (USA only) [22], umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg OD [23, 24], aclidinium/formoterol (ACL/FOR) 400/12 mcg BID [25], and tiotropium/olodaterol (TIO/OLO) 5/5 mcg OD [26, 27]. With the increasing range of LAMA + LABA therapies that have become available, it is desirable to assess their comparative efficacies and characteristics. Limited data are currently available from direct comparisons between FDC LAMA/LABA therapies or of FDC therapies with open dual LAMA + LABA combinations. There is therefore a need to synthesize the available data from RCTs to enable comparisons to be made between therapies.

The aim of this Bayesian network meta-analysis (NMA) was to compare the efficacy of available FDC and open dual LAMA + LABA bronchodilators in patients with moderate-to-very-severe COPD, based on a systematic literature review (SLR) up to October 2015. The NMA reported here contains a further 18 trials that were not previously available in an earlier NMA based on the literature up to the end of 2014 [28]. A novel aspect of this NMA compared with other NMAs in the area is the potential to examine differences in efficacy between FDCs and open dual LAMA + LABA combinations, and between once- and twice-daily therapies. An added feature was to explore subgroup analyses where possible to observe the impact of severity of lung function impairment and use of concurrent inhaled corticosteroids (ICS) across different trials on the relative efficacies of bronchodilators.

In this study, the relative efficacy of LAMA + LABA combination bronchodilators was evaluated in patients with moderate-to-very-severe COPD using data from 44 RCTs on four outcomes of interest reported at 12 and/or 24 weeks after randomization: trough FEV₁, SGRQ total score, TDI focal score, and daily rescue medication use. These outcomes were selected in accordance with the bulk of available data for RCTs involving dual bronchodilators.

Clinically relevant improvements were observed versus placebo over the 12- and/or 24-week time frame in trough FEV₁ (improvements of ≥100 mL [39]), SGRQ total score (improvements of ≥4 units [40]), and TDI focal score (improvements of ≥1 unit [43]) with all FDC therapies, with the exception of TIO/OLO and ACL/FOR, both of which failed to show clinically relevant improvements in SGRQ total score at 24 weeks. Although no MCID has been established for rescue medication use, improvements were observed with all FDCs versus placebo at 12 and 24 weeks, with probabilities of improved outcomes of ≥92%. With open dual combinations of TIO with LABA therapies, improvements were observed versus placebo in all outcomes, but while improvements in trough FEV₁ were clinically relevant, the magnitudes of treatment benefits for the PROs of SGRQ total score and TDI focal score were often below clinically relevant thresholds. These results are not surprising given the historical emphasis on improving lung function in the development of therapies for COPD [45]. The findings suggest that there may be a greater likelihood of a clinically important patient response with FDC bronchodilators compared with open dual regimens, particularly when comparing once- versus twice-daily treatments. To the best of our knowledge, comparative outcomes between FDCs and open dual combinations have not been assessed in other NMAs, and direct evidence in support of this claim is available from only one 6-month RCT that reported improvements in pre-bronchodilator FEV₁ and forced vital capacity, and a significantly higher percentage of patients achieving a clinically relevant improvement in TDI, using GLY/IND 110/50 compared with TIO 18 + FOR 12 [46].

Once-daily FDCs showed consistent improvements versus TIO monotherapy in lung function, HRQoL, and rescue medication use after 12 and 24 weeks of treatment, with probabilities of better outcomes of ≥87% in all cases. However, less certainty of improvement was apparent with FDCs or open dual combinations containing FOR or SAL taken twice daily. When the TDI focal score was examined, improvements were observed with all FDCs versus TIO at 12 and 24 weeks, with probabilities of improvement of ≥85%, while the probability of improvement using open dual combinations was lower (16–65%). In contrast to improvements in trough FEV₁ and SGRQ total score, no potential for efficacy differences emerged between once- or twice-daily regimens for the TDI assessments. The improvements observed using LAMA + LABA combination therapy compared with TIO monotherapy are consistent with results from several RCTs which directly compared various LAMA + LABA therapies with TIO [14‐20]. This observation is therefore not unexpected and could be attributed to the direct agonist effect of the added LABA, as well as possible synergistic effects [13]. Some RCTs have reported improved lung function outcomes using LAMA + LABA therapies compared with LABA monotherapy; [15‐17] these findings are consistent with the conclusions of two recent NMAs, which performed slightly different analyses to that presented in this study [47, 48].

It was notable that for most dual bronchodilators assessed at both time points, a greater magnitude of benefit in TDI focal score and SGRQ total score was observed at 12 compared with 24 weeks, but this diminution of response with time was not consistently observed for FEV₁ and rescue medication use. This result may indicate that some PROs may be more subject to recall bias, as patients are required to recall their previous state in order to estimate changes [49], making them potentially less effective in discriminating between different active therapies over time, and suggests that shorter assessments may be more reliable for within-class comparisons. However, alternative approaches, such as comparing responder rates between two regimens, which has previously identified efficacy differences between dual bronchodilators, may be equally valid [46].

In this study, improvements in SGRQ total score and TDI focal score were never greater than the proposed MCIDs of 4 units [40] and 1 unit [43], respectively, when comparisons were made between active regimens. This finding highlights that dual combination therapy was associated with an incremental efficacy gain in PROs compared with standard of care monotherapy, a finding concordant with that reported in other meta-analyses comparing FDCs with their individual component LAMA or LABAs [47, 48]. By contrast, the magnitude of lung function benefit using FDCs compared with placebo was often twofold higher than that seen with TIO monotherapy. The current NMA identified a potential gradient of effectiveness emerging between the once-daily FDCs and those including twice-daily LABAs, particularly with regards to improvements in trough FEV₁: at 12 weeks, GLY/IND and UMEC/VI demonstrated the greatest improvements, followed by TIO + IND, while improvements with ACL/FOR, TIO/OLO, TIO + OLO, and TIO 18 + FOR 10 were lower; at 24 weeks, UMEC/VI demonstrated the greatest improvement, followed by GLY/IND, then TIO/OLO, with ACL/FOR and the open dual combinations showing lower improvements. However, further trials are required to confirm these findings. Head-to-head trials of FDCs with results yet to be reported include two trials comparing GLY/IND with UMEC/VI (NCT02487446 and NCT02487498) and one trial comparing UMEC/VI with TIO/OLO (NCT02799784).

It is worth noting that the effectiveness of an inhaled therapy could potentially be affected by the delivery device used [50]. While several inhaler types are available, dry powder inhalers (DPIs) have become increasingly common for COPD therapies due to their multiple advantages over the more traditional pressurized metered-dose inhalers (pMDIs) [51]. However, different classes of DPIs are available, with ongoing debate about their relative advantages [51]. Of the therapies assessed in this NMA, most were delivered by either single-dose DPIs (TIO 18, IND, FOR 12, and the combined therapy GLY/IND) or multi-dose DPIs (FOR 10 and the combined therapies ACL/FOR and UMEC/VI). The exceptions were SAL, which was delivered by a pMDI, and TIO 5, OLO, and TIO/OLO, which were delivered by soft mist inhalers [52]. However, as the majority (40/44) of the studies included in the NMA were blinded, it is unlikely that these differences in inhaler type would be reflected in the results. Currently, while several studies have identified patient preferences between different inhaler types [53‐55], there is limited evidence to demonstrate any differences in efficacy outcomes [56, 57]. Further research is therefore required to inform optimal device design, improve compliance, reduce handling errors and, ultimately, improve outcomes.

This NMA is an updated extension of our previous NMA comparing the efficacy of UMEC/VI with other dual bronchodilators, TIO, or placebo [28]. The previous review included 26 RCTs of ≥10 weeks’ duration, published in English up to April 2014. The expanded inclusion criteria in this update allowed the inclusion of a further 18 RCTs and enabled analysis of additional combination bronchodilators (TIO + OLO, TIO/OLO, GLY/IND 27.5/15.6, and ACL/FOR); also, TIO 5 was not included as a comparator in the previous analysis. However, the principal observation of similar efficacy between available combination bronchodilators with regards to PROs remained the same for both analyses. Improvements in trough FEV₁ using different combination therapies were less similar; here, the magnitude of some of the differences between therapies were beyond accepted non-inferiority margins used for within-class comparisons (≥50 mL or ≥50% of the proposed MCID [8, 58]). Scenario analysis separating TIO 18 and TIO 5 showed that the addition of TIO 5 to the analysis had a negligible effect on measured outcomes. In this updated NMA we also performed subgroup analysis to examine potential confounding due to disease severity and concurrent therapy. The results highlight some additional differences in the magnitudes of improvements in lung function between therapies in patient subgroups with differing capacities for bronchodilation.

Two other recent NMAs have examined the comparative effects of available FDCs on lung function and PROs; neither included open dual combination therapies [48, 59]. The NMA by Schlueter et al. included 27 RCTs of ≥20 weeks’ duration, published up to September 2014, and assessed outcomes at 24 and 48 weeks [59]. RCTs were excluded based on concomitant treatments, and meta-regression rather than subgroup analysis was performed to assess the effects of baseline disease severity and concomitant ICS use on outcomes [59]. The NMA by Calzetta et al. included 22 RCTs of ≥3 months’ duration, published up to October 2015, and assessed outcomes for FDC LAMA/LABA combinations versus their component monotherapies when they were reported for each study; RCTs without comparisons of the dual therapy to a component monotherapy were excluded [48]. Despite the differences in inclusion criteria and analysis methods, the results obtained in both NMAs were consistent with those for the current analysis. Both NMAs assessed differences in SGRQ total score and TDI focal score using the percentage of responders, rather than the calculated differences in scores as in the present NMA; however, in accordance with our results, neither study reported any significant difference in these outcomes between FDCs [48, 59]. Both previous NMAs reported differences between the FDCs for trough FEV₁. Schlueter et al. reported improvements with TIO/OLO, GLY/IND 110/50, and UMEC/VI above those seen with ACL/FOR that were of similar magnitudes to the improvements observed in the present study at the same time point (approximately 24 weeks) [59]. Calzetta et al. reported a similar potential gradient of effectiveness to that presented here, with UMEC/VI and GLY/IND 27.5/15.6 demonstrating the greatest improvements, followed by GLY/IND 110/50, TIO/OLO, then ACL/FOR [48].

A potential limitation of this and other NMAs of FDC bronchodilators is the low number of studies involving some treatments and the scarcity of direct comparisons of these with other active treatments. In particular, of the FDCs, only two studies presenting data for ACL/FOR were eligible for inclusion; both of these were ‘large’ trials (each with >300 patients receiving ACL/FOR [41, 42], considerably greater than the previously proposed cut-off for large trials of 100 patients [60]), thereby reducing the likelihood of any distortion of results due to a small study effect [61]. However, the heterogeneity of the studies included in this NMA was not assessed, so the extent of distortion is not known. Additionally, comparisons in this study were frequently calculated indirectly, so there is some uncertainty in the estimated efficacies. As with all meta-analyses, the potential influence of confounders constitutes a limitation. Due to the low number of studies involved, meta-regression to adjust for any confounders was infeasible, so subgroup analysis was performed. The greatest improvements in lung function were observed in non-ICS users and patients with moderate disease for all combination therapies versus placebo. However, it is still unclear whether any greater magnitude of difference in lung function between the therapies in these subgroups is likely to be matched by clinically important changes in PROs. Another limitation of this study is that the outcomes analyzed were restricted to those investigated in multiple RCTs of 12 or 24 weeks’ duration; other relevant endpoints that have been less commonly or inconsistently reported, such as exacerbation rate or time to first event in patients of varying exacerbation risk, were excluded.

In an indirect treatment comparison using a Bayesian NMA, most but not all dual combination therapies showed improved outcomes versus placebo and versus TIO monotherapy at 12 and/or 24 weeks. The likelihood of improved outcomes appeared to be greater with FDCs compared with open dual combinations. The relative probabilities of improvement between available FDCs suggested broadly similar efficacy when assessed using the PROs of SGRQ total score, TDI focal score, and rescue medication use, while some differences between bronchodilators were observed for objective assessments using trough FEV₁. While head-to-head RCTs would be required to provide robust evidence of efficacy differences between LAMA + LABA bronchodilators, indirect comparisons such as the present NMA allow the existing volume of RCT data to be employed to generate data which may be of use to healthcare payers and providers.