Dual bronchodilation in COPD: lung function and patient-reported outcomes – a review

Introduction

Appropriate pharmacological management of COPD involves treatment with inhaled bronchodilators to reduce airflow limitation and hyperinflation. Most patient groups identified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy can be managed using long-acting inhaled bronchodilators (long-acting muscarinic antagonists [LAMAs] and long-acting β₂-agonists [LABAs]), with or without inhaled corticosteroids.¹ Fixed dose combinations (FDCs) provide potent bronchodilation versus single agents,² with some advantage in terms of convenience and simplicity compared with combinations administered via separate inhalers. Beta agonists (BAs) and muscarinic antagonists (MAs) target different pathways to promote smooth-muscle relaxation and inhibit pulmonary constriction. Combining bronchodilators with different modes of action appears to be additive, providing greater efficacy versus component monotherapies.³ Randomized controlled trials (RCTs) of LABA–LAMA combinations via separate inhalers have generally shown improved lung function versus component monotherapies.^4–12

COPD is characterized by persistent airflow limitation, with forced expiratory volume in 1 second (FEV₁) to forced vital capacity ratio and percentage predicted FEV₁ widely used as pathophysiological markers.¹ However, COPD is multidimensional, with pulmonary, extrapulmonary, and systemic effects. Outcomes in addition to FEV₁ are needed to assess disease burden and treatment efficacy.¹³ Spirometry is central to COPD diagnosis, but does not measure COPD burden in terms of health status.¹⁴ Additionally, spirometry is not always performed, and symptoms and exacerbation history can play important roles in treatment initiation and management.¹⁵ It is therefore important that spirometry is accompanied by assessments using patient-reported outcome (PRO) measures, such as breathlessness, physical functioning, and health status.¹⁴ Minimal clinically important differences (MCIDs) for these assessments and other COPD outcomes have been reviewed by Jones et al.¹⁴ Although a few studies and reports have examined associations between improved lung function (mainly FEV₁) and PROs in COPD,^16–21 the relationship between these efficacy measures is often weak, particularly for LAMAs and LABA–LAMA combinations. Here, we examine the evidence for the use of FDC bronchodilators in COPD, assess effects on PROs, and evaluate relationships between PROs and changes in lung function.

Materials and methods

This systematic literature search (not registered) was performed in accordance with the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).²² The literature search identified primary, English-language, RCT publications of fixed-combination bronchodilators reporting treatment effects on lung function and/or PROs in comparison with placebo, bronchodilator monotherapy, or inhaled corticosteroid–LABA combinations in patients with COPD (Table S1). Data sources included a ProQuest search of Biosis, Biosis previews, Embase and Medline databases (January 1, 2006 to July 31, 2014), and abstracts from principal respiratory congresses (January 1, 2009 to May 20, 2015; Table S2). These selected search dates ensured that all relevant publications on fixed-combination bronchodilators were captured. Following the publication-database searches and during preparation of this manuscript (August 2015 onward), additional relevant articles became available, and thus these were added to the literature-search results.

All search results were extracted and gathered by a single party. Titles and abstracts were then scrutinized in parallel by two independent reviewers, and papers were categorized as relevant (where both reviewers categorized a paper as “relevant”), not relevant (where both reviewers judged a paper as “not relevant”), or potentially relevant (where one reviewer judged a paper as “relevant” and the other judged the same paper as “not relevant”). Irrelevant publications/studies comprised review papers, unapproved treatment doses, nonclinical trials, incorrect drug, or incorrect disease. Conflicting results were resolved by a third reviewer, who provided input as to whether the abstract was of potential relevance based on the same criteria as the first reviewers. To reduce the risk of omitting relevant studies/papers, all relevant and potentially relevant results were subsequently reviewed by the authors, who had the final decision regarding which publications to take to the next review level. Where relevance was not discernible from abstracts, full copies of author-confirmed relevant/potentially relevant articles were further assessed by two reviewers and conflicts resolved by a third reviewer. Data from the literature describing treatment differences with the FDC and comparator are summarized – according to end point – using least-squares mean (LSM) and 95% confidence interval (95% CI), odds ratio (OR), rate ratio, or hazard ratio (HR).

Results

Systematic literature-search results

The searches yielded 729 records, from which 35 primary publications were relevant (Figure 1). Literature searches were supplemented with information from ClinicalTrials.gov, and author expertise/knowledge (eg, if authors were aware that important publications were missing from search results).²³ Between the time of the predefined search end (July 2014 for published manuscripts and May 2015 for congress abstracts) and the drafting of this manuscript (August 2015 onwards), additional FDC studies were being published, and are thus included in this review.^23–34

Figure 1 Flowchart of systematic literature search. Notes: Reasons for exclusion comprised: not a primary publication or not containing novel data from clinical studies, non-COPD study, data not from a randomized clinical study, medication not combination LABA–LAMA bronchodilator treatment, and unapproved dose for a licensed combination therapy. Abbreviations: LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist.

Trials of fixed-dose dual-combination bronchodilators

FDC bronchodilators approved or in advanced clinical development for COPD include: indacaterol–glycopyrronium once daily (OD; QVA149; Ultibro^® Breezhaler^®; Novartis International AG, Basel, Switzerland), umeclidinium–vilanterol 110/50 μg OD (Laventair/Anoro^® Ellipta^®; GlaxoSmithKline PLC, London, UK), tiotropium–olodaterol OD (Spiolto^® Respimat^®; Boehringer Ingelheim, Ingelheim, Germany), aclidinium–formoterol twice daily (bis in die [BID]; Duaklir^® Genuair^®; AstraZeneca PLC, London, UK) and glycopyrrolate–formoterol (PT003; AstraZeneca).

Indacaterol–glycopyrronium OD is approved in >70 countries. Of 13 large Phase III trials of indacaterol–glycopyrronium, publications are available for ten (SHINE, ILLUMINATE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, BEACON, LANTERN, QUANTIFY, and FLAME), all of which report lung function and PRO data and are included in this review (Table 1).^{2,24–26,35–40} These active-comparator and placebo-controlled trials ranged from 3 to 64 weeks in duration.

Table 1 Clinical trials of FDC bronchodilator therapies evaluating treatment effects on lung function and/or patient-reported outcome Notes: Treatment was once daily unless stated otherwise. aPatients randomized to treatment; binvestigator-blinded only; cinclusion criteria: FEV1 ≤70% predicted and FEV1/FVC 0.7. Abbreviations: ACL–FORM, aclidinium–formoterol; AUC0–4 h, area under the (plasma concentration–time) curve from 0 to 4 hours; AUC0–12 h, area under the (plasma concentration–time) curve from 0 to 12 hours; AUC0–24 h, area under the (plasma concentration–time) curve from 0 to 24 hours; B, blinded; BID, bis in die (twice daily); CAT, COPD Assessment Test; DB, double-blind; DD, double-dummy; DPI, dry-powder inhaler; E-RS, Evaluating Respiratory Symptoms; EXACT, EXAcerbations of COPD Tool; FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; GFF, glycopyrrolate–formoterol fumarate; GOLD, Global Initiative For Chronic Obstructive Lung Disease; HCRU, health care-resource utilization; IC, inspiratory capacity; IN, incomplete; IND–GLY, indacaterol–glycopyrronium; MC, multicenter; MDI, metered-dose inhaler; mMRC, modified Medical Research Council; NI, noninferiority; NR, not reported; OL, open-label; PEFR, peak expiratory flow rate; R, randomized; SFC, salmeterol–fluticasone combination; SOBDA, Shortness Of Breath with Daily Activity; SGRQ-C, St George’s Respiratory Questionnaire – COPD; TD, triple-dummy; TDI-SAC, transition dyspnea index – self-administered, computerized; TIO–OLO, tiotropium–olodaterol; UMEC–VI, umeclidinium–vilanterol; XO, crossover.

Umeclidinium–vilanterol 62.5/25 μg OD is approved in the US and EU (higher doses are not reviewed here). Findings from 12 Phase III trials had been reported in publications or conference abstracts at the time of the literature search, including: five 24-week studies,^23,32,41 seven 12-week studies,^27,33,42,43 and one 52-week safety study (125/25 μg).⁴⁵ Lung-function and PRO data have been fully reported for six of the eight trials listed in Table 1.^23,27,32,41

Tiotropium–olodaterol (5/5 μg; lower doses are not reviewed) OD has been approved in more than 20 European countries, the US, Canada, and Australia since May 2015. Results from two 1-year studies with tiotropium–olodaterol 5/5 μg (included in this review; Table 1) have been reported and include data on lung function and health status versus the monocomponents.³⁰ Results from an additional Phase III trial evaluating lung function and volume (VIVACITO) have been published (Table 1),³¹ two Phase III trials have been presented as abstracts,^34,45 one further Phase III study has been completed (ClinicalTrials.gov NCT01536262) and four are ongoing (ClinicalTrials.gov NCT02006732, NCT01964352, NCT01969721, and NCT02085161).

Aclidinium–formoterol (400/12 μg BID) is approved in the EU. Findings from two of four Phase III trials have been fully reported comparing the combination therapy versus monocomponents or placebo, and are included in this paper (Table 1).^28,29,46 Results from a 24-week Phase III study comparing aclidinium–formoterol with salmeterol–fluticasone combination (SFC) BID had been published in abstract form at the time of the literature search.⁴⁷ For glycopyrrolate–formoterol (in late-stage development), only Phase II congress abstracts are available.^48–50 Three Phase III studies are ongoing (ClinicalTrials.gov NCT01854645, NCT01854658, and NCT01970878).

In this review, we focus on the 23 aforementioned published Phase III RCTs and listed in Table 1 (supplemented with results presented at major respiratory congresses, where applicable): ten with indacaterol–glycopyrronium OD, eight with umeclidinium–vilanterol OD, three with tiotropium–olodaterol OD, and two with aclidinium–formoterol BID. The remaining primary publications from the literature search were excluded, due to duplicate publications of the same results (eg, where a primary publication superseded several congress abstracts).

Patient population and study design

Patient populations, inclusion criteria, treatment blinding, and other characteristics differed between trials (Table 1). The majority of indacaterol–glycopyrronium OD studies enrolled symptomatic patients with moderate-to-severe airflow limitation (GOLD 2008, 2009, or 2010 classification), except for SPARK and FLAME, which enrolled patients with severe-to-very-severe or moderate-to-very-severe disease, respectively, and one or more exacerbations in the past year.^{2,24,26,35–40} The eight umeclidinium–vilanterol OD trials enrolled patients with moderate-to-severe or moderate-to-very-severe COPD who were symptomatic.^23,27,32,41 Patients in the tiotropium–olodaterol OD studies had moderate-to-very-severe COPD.^30,31 The aclidinium–formoterol BID studies were conducted in patients with moderate-to-severe COPD.^28,29

Lung function

Across eight trials (3–64 weeks), indacaterol–glycopyrronium OD provided significant LSM treatment differences in trough FEV₁ of 60–80 mL versus tiotropium 18 μg, 70–80 mL versus indacaterol 150 μg or glycopyrronium 50 μg alone, 68 mL versus tiotropium + formoterol 18/12 μg, 62–72 mL versus SFC 50/500 μg BID, and 189–200 mL versus placebo (Table 2).^{2,24–26,35,36,39,40} Preliminary data suggest that the extent of FEV₁ improvement may vary: in a post hoc analysis of SHINE, data from patients in the spirometry subset who received indacaterol–glycopyrronium OD (n=399) showed that 39.8% had an increase in FEV₁ of ≥200 mL between baseline and week 26, 23.8% achieved ≥300 mL, and 13.1% had an increase of ≥400 mL.⁵¹

Table 2 Lung function: margin of efficacy of fixed combinations versus comparators in fully published studies Notes: Treatment once daily unless stated otherwise. aSignificant treatment difference; bFEV1 AUC0–4 h; cdose not approved for use (ACL–FORM, dose not approved in EU); destimated from figure. Abbreviations: ACL–FORM, aclidinium–formoterol; AUC0–3 h, area under the plasma concentration-time curve from 0 to 3 hours; AUC0–4 h, area under the (plasma concentration–time) curve from 0 to 4 hours; AUC0–12 h, area under the (plasma concentration–time) curve from 0 to 12 hours; AUC0–24 h, area under the (plasma concentration–time) curve from 0 to 24 hours; BID, bis in die (twice daily); CI, confidence interval; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FRC, functional residual capacity; IC, inspiratory capacity; IND–GLY, indacaterol–glycopyrronium; LSM, least-squares mean; NR, not reported; NS, not significant; OD, once daily; OL, open-label; SFC, salmeterol/fluticasone combination; TIO–OLO, tiotropium–olodaterol; UMEC–VI, umeclidinium–vilanterol.

In three Phase III studies, LSM treatment differences in trough-FEV₁ change from baseline to week 24 with umeclidinium–vilanterol 62.5/25 μg OD were 60–112 mL versus tiotropium 18 μg, 52 mL versus umeclidinium 62.5 μg, 22 mL versus umeclidinium 125 μg (not statistically significant), 90–95 mL versus vilanterol 25 μg, and 167 mL versus placebo.^23,32,41 In two 12-week studies, umeclidinium–vilanterol 62.5/25 μg produced greater increases in trough FEV₁ versus individual components.³³ In another two 12-week studies, umeclidinium–vilanterol 62.5/25 μg resulted in significant improvements in FEV₁ 0–24 hours and trough FEV₁ compared with 50/250 μg BID.²⁷

At week 24 of the two 1-year studies, tiotropium–olodaterol 5/5 μg OD increased trough FEV₁ by 82–88 mL versus olodaterol 5 μg and by 50–71 mL versus tiotropium 5 μg.³⁰ A 6-week incomplete crossover study showed improvements in 24-hour lung function with tiotropium–olodaterol 5/5 μg versus components or placebo.³¹

Aclidinium–formoterol (400/12 μg BID) increased week 24 trough FEV₁ significantly versus placebo (143 mL) and formoterol (85 mL) in the ACLIFORM study, but the smaller difference (~25 mL) versus aclidinium BID was not statistically significant.²⁸ Similar results were observed in the AUGMENT trial, with a significant difference for the combination versus formoterol (45 mL), but not aclidinium (28 mL).²⁹

Symptoms

Improvements in dyspnea and other symptoms were seen with fixed-dose LABA–LAMA therapies versus monotherapies and for indacaterol–glycopyrronium OD versus SFC BID. (Table 3, Figure 2).^{2,24,25,38,39} Indacaterol–glycopyrronium significantly improved transition dyspnea index (TDI) scores in SHINE and ILLUMINATE versus placebo, open-label tiotropium, and SFC.^2,39 In BLAZE, indacaterol–glycopyrronium significantly improved self-administered computerized total TDI score versus placebo (LSM treatment difference 1.37, P<0.001) and blinded tiotropium (LSM treatment difference: 0.49, P=0.021).³⁸ The proportion of patients achieving the MCID (≥1-point) for TDI score was also significantly increased versus blinded tiotropium in BLAZE (OR 1.78, P<0.05) and versus SFC in ILLUMINATE (OR 1.56, P<0.05; Figure 2).^2,39 In QUANTIFY, a similar reduction in dyspnea was observed with indacaterol–glycopyrronium versus tiotropium + formoterol, and significantly more patients achieved clinically relevant improvements in TDI total score with indacaterol–glycopyrronium (49.6%) versus tiotropium + formoterol (42.4%, P=0.033).²⁵

Table 3 Symptoms: margin of efficacy of fixed combinations versus comparators in published studies Notes: Treatment once daily unless stated otherwise. aTDI responders had improvement ≥1 unit in TDI score. bSignificant treatment difference. Significant treatment difference versus cindacaterol, dglycopyrronium or etiotropium (values NR). fDose not approved for use (ACL–FORM, dose not approved in EU). gValues in parentheses are differences expressed in percentage points (not percentage differences). Abbreviations: ACL–FORM, aclidinium–formoterol; BID, bis in die (twice daily); CI, confidence interval; E-RS, Evaluating Respiratory Symptoms; IND–GLY, indacaterol–glycopyrronium; LSM, least-squares mean; NR, not reported; NS, not significant; OR, odds ratio; SAC, self-administered, computerized; SFC, salmeterol–fluticasone combination; SGRQ-C, St George’s Respiratory Questionnaire – COPD; TIO–OLO, tiotropium–olodaterol; TDI, transition dyspnea index; UMEC–VI, umeclidinium–vilanterol.

Figure 2 Differences between monotherapy and combination bronchodilators or placebo in TDI patient-response rates in published studies. Notes: (A) Indacaterol–glycopyrronium; (B) umeclidinium–vilanterol 62.5/25 μg; (C) aclidinium–formoterol 400/12 μg BID. TDI response was defined as improvement of ≥1 unit in TDI score. All treatments were once daily unless stated otherwise. *Significant treatment difference. aBateman et al;2 bself-administered computerized TDI;38 cVogelmeier et al;39 dBuhl et al;25 eDonohue et al;41 fDecramer et al;23 gSingh et al;28 hD’Urzo et al.29 Abbreviations: BID, bis in die (twice daily); SFC, salmeterol–fluticasone propionate; TDI, transition dyspnea index.

In LANTERN, a comparable improvement with indacaterol–glycopyrronium OD and SFC BID was demonstrated for TDI focal score and St George’s Respiratory Questionnaire (SGRQ) total score from baseline after 26 weeks; the percentage of patients achieving the MCID for both end points was higher with indacaterol–glycopyrronium versus SFC.²⁴ Compared with its component monotherapies, indacaterol–glycopyrronium was associated with numerical improvements in TDI score and percentage of TDI responders at week 26 in SHINE.² At week 12, improvement in TDI score with indacaterol–glycopyrronium was significantly greater than with glycopyrronium (LSM treatment difference 0.41, P=0.03).

Three indacaterol–glycopyrronium OD studies evaluated patient-diary data and reported significantly improved symptom scores versus indacaterol, glycopyrronium, tiotropium, or placebo (Table 3).^2,36,38 In the shorter BRIGHT trial, change in mean daily symptom score from baseline to week 3 was numerically greater for indacaterol–glycopyrronium versus tiotropium and placebo.³⁵ In ILLUMINATE, differences in scores for most symptoms were comparable for indacaterol–glycopyrronium and SFC BID.³⁹

In three 24-week studies, umeclidinium–vilanterol 62.5/25 μg OD significantly improved TDI focal and Shortness of Breath with Daily Activity (SOBDA) scores versus placebo, with numerical improvements versus monocomponents and tiotropium.^23,41 The proportion of patients achieving the MCID for TDI score was significantly increased in patients receiving umeclidinium–vilanterol versus placebo (OR 2, P<0.001) and vilanterol (OR 1.4, P<0.05)⁴¹ in one study (Figure 2).²³ LSM changes from baseline to week 24 in SOBDA scores were clinically significant (≥0.1 unit) for umeclidinium–vilanterol, vilanterol 25 μg, umeclidinium 62.5 and 125 μg, and tiotropium 18 μg.^23,41 SOBDA responder rates were reported for one trial, and were significantly higher for umeclidinium–vilanterol (OR 1.8, P<0.01) and its monocomponents (umeclidinium 52.5 μg OR 1.7, P<0.01; vilanterol 25 μg OR 1.6, P<0.05) versus placebo. In two 12-week studies, there was no significant difference in TDI focal scores between umeclidinium–vilanterol 62.5/25 μg and salmeterol–fluticasone propionate 50/250 μg.²⁷ Exercise-associated dyspnea (Borg) was reduced with umeclidinium–vilanterol 62.5/25 μg compared with placebo in one of two studies; active–placebo differences were not significant for the individual components.³³ In combined results from two 1-year studies, tiotropium–olodaterol OD increased TDI total score versus monocomponents (week 24) by approximately 0.4 points with the higher dose and by a similar margin (0.3–0.4 points) with the lower dose.³⁰

Symptoms were evaluated using a number of end points in the two 24-week aclidinium–formoterol BID studies.^28,29 For TDI total score, aclidinium–formoterol 400/12 μg BID achieved a significant, >1-point improvement versus placebo (and a higher proportion of TDI responders), but the differences versus the monotherapies were not significant. For Evaluating Respiratory Symptoms (E-RS) score, the combination was significantly better than placebo (both studies) and the monotherapies (one study). Aclidinium–formoterol 400/12 μg improved nighttime symptom scores versus placebo (one study) or aclidinium BID (one study); early morning symptom scores were improved versus placebo and aclidinium (both studies), assessed by questionnaires for both.^28,29

Rescue-medication use

Rescue-medication usage provides a surrogate measure of symptom control, and was reported in most of the published indacaterol–glycopyrronium OD and umeclidinium–vilanterol OD Phase III trials (Table 4). Indacaterol–glycopyrronium treatment consistently led to significantly less rescue-medication use per day than LABA or LAMA monotherapy or LABA–inhaled corticosteroids in each trial with active comparators.^{2,26,35,38–40} In LANTERN, rescue-medication use was comparable between the indacaterol–glycopyrronium and SFC BID groups.²⁴ Daily rescue-medication use was similar or numerically slightly lower with umeclidinium–vilanterol versus either umeclidinium or vilanterol monotherapy, significantly lower versus tiotropium in two of three trials, and significantly lower versus SFC in one of two trials.^{23,27,32,33,41} Rescue-medication use remained at approximately two puffs/day with tiotropium–olodaterol OD over the course of 52 weeks; at the end of the studies, this was 0.3–0.4 puffs/day less than with olodaterol and 0.7–0.8 puffs/day less than with tiotropium.³⁰ In the two 24-week studies with aclidinium–formoterol 400/12 μg BID, rescue-medication use was significantly lower compared with placebo and aclidinium BID, but not compared with formoterol.^28,29

Table 4 Rescue-medication use: margin of efficacy of fixed combinations versus comparators in published studies Notes: Treatment once daily unless stated otherwise. aSignificant treatment difference; bdose not approved for use; cestimated from figure. Statistical analysis not reported. Abbreviations: ACL–FORM, aclidinium–formoterol; BID, bis in die (twice daily); CI, confidence interval; IND–GLY, indacaterol–glycopyrronium; LSM, least-squares mean; NR, not reported; NS, not significant; OL, open-label; SFC, salmeterol–fluticasone combination; TIO–OLO, tiotropium–olodaterol; UMEC–VI, umeclidinium–vilanterol.

Exacerbations

The effects of FDC therapy on exacerbation rates and time to first exacerbation are summarized in Table 5.

Table 5 Exacerbations: margin of efficacy of fixed combinations versus comparators in published studies that included exacerbations as an efficacy outcome Notes: Treatment once daily unless stated otherwise. aSignificant treatment difference; bdata reported for all exacerbations; cincludes only severe exacerbations requiring hospitalization/emergency room treatment for ≥24 hours; ddose not approved for use (ACL–FORM dose not approved in EU); ethe EXACT instrument assesses patients’ breathlessness, cough and sputum, chest symptoms, difficulty bringing up sputum, feeling tired or weak, sleep disturbance, and feeling scared or worried about their condition with a 14-item questionnaire. Abbreviations: ACL–FORM, aclidinium–formoterol; BID, bis in die (twice daily); CI, confidence interval; EXACT, EXAcerbations of COPD Tool; HCRU, health care-resource utilization; HR, hazard ratio; IND–GLY, indacaterol–glycopyrronium; NR, not reported; OL, open-label; RR, rate ratio; TIO–OLO, tiotropium–olodaterol; UMEC–VI, umeclidinium–vilanterol.

The effect of indacaterol–glycopyrronium OD on exacerbation rate was examined as the primary end point in both SPARK and FLAME, and exacerbation rates have also been reported from ILLUMINATE, LANTERN, and QUANTIFY.^{24–26,39,40,52} In SPARK, indacaterol–glycopyrronium significantly reduced rates of moderate-to-severe (primary end point, rate ratio 0.88; P=0.038) and all exacerbations (LSM treatment difference 0.85, P<0.01) versus glycopyrronium.⁴⁰ Compared with open-label tiotropium, rates of moderate-to-severe exacerbations were 10% lower with indacaterol–glycopyrronium (P=0.096), and rates of all exacerbations were 14% lower (P<0.01). In comparison with SFC BID in a post hoc analysis of data from ILLUMINATE, rates of moderate-to-severe exacerbations (rate ratio 0.8, not significant [NS]) and all exacerbations (rate ratio 0.69, NS) were numerically lower with indacaterol–glycopyrronium.⁵² In LANTERN, indacaterol–glycopyrronium significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.²⁴ Furthermore, in the recent FLAME study, indacaterol–glycopyrronium significantly reduced the rates of all exacerbations (primary end point) by 11% (P=0.003) and of moderate-to-severe exacerbations by 17% (P<0.001) compared with SFC; findings were consistently in favor of indacaterol–glycopyrronium when patients were analyzed according to their baseline disease characteristics, including baseline eosinophil count (<2% or ≥2%).²⁶ This study also found that compared with SFC, indacaterol–glycopyrronium was associated with longer times to first exacerbation, representing reduced risks of 16% for all exacerbations (P<0.001), 22% for moderate-to-severe exacerbations (P<0.001), and 19% for severe exacerbations (P=0.046). Finally, QUANTIFY showed a comparable percentage of patients experiencing at least one moderate or severe exacerbation and a comparable time to first moderate or severe exacerbation between the two treatment groups (indacaterol–glycopyrronium vs tiotropium + formoterol).²⁵

Currently, there are no studies evaluating exacerbation risk as a primary end point in patients receiving umeclidinium–vilanterol OD. The data available from analysis of secondary end points indicate that umeclidinium–vilanterol significantly increased time to first exacerbation versus placebo (HR 0.5, P<0.001),⁴¹ but not compared with vilanterol 25 μg (HR 0.7, NS) or umeclidinium 125 μg (HR 1, NS).²³

Time to first exacerbation was comparable for combination therapy versus tiotropium alone in two trials²³ and significantly greater in a third study (HR 0.5, P=0.044).³² In the combined results of the two 52-week studies with tiotropium–olodaterol OD, there was only a “trend” for improvement in exacerbations with both doses of the combination versus the monotherapy components.³⁰ Over the 24 weeks of the ACLIFORM study, using the health care resource-utilization definition of exacerbations, aclidinium–formoterol BID 400/12 μg was not significantly different from placebo or its separate components; with the EXACT (EXAcerbations of COPD Tool) definition, a significant difference was demonstrated versus placebo, but not compared with the components.²⁸

Exacerbations were not reported as an efficacy outcome in the AUGMENT study.²⁹

Health status

Indacaterol–glycopyrronium OD significantly improved health status, assessed using the SGRQ (Table 6). In SPARK, indacaterol–glycopyrronium improved SGRQ total score versus glycopyrronium (all P<0.01) and open-label tiotropium (all P<0.05; 12–64 weeks).⁴⁰ In SHINE, improvement in SGRQ with indacaterol–glycopyrronium was superior to open-label tiotropium (P=0.009) and placebo (P=0.002) and comparable to component monotherapies.² In a 26-week study, indacaterol–glycopyrronium and SFC BID provided similar improvements in health status.³⁹ However, in FLAME, significant improvements over time in SGRQ total score were observed for indacaterol–glycopyrronium compared with SFC, with treatment differences that ranged from −1.2 points to −1.8 points over the time points measured between weeks 12 and 52 (all P<0.01).²⁶ The SGRQ responder rate for the MCID (reduction of ≤4 units from baseline)⁵³ was also significantly greater with indacaterol–glycopyrronium versus SFC in FLAME (OR 1.3, P<0.001)²⁶ and versus glycopyrronium (OR 1.62, P=0.00013) and open-label tiotropium (OR 1.48, P=0.0017) at all time points except week 64 in SPARK.⁴⁰ In QUANTIFY, indacaterol–glycopyrronium was noninferior to tiotropium + formoterol for improvement in SGRQ score; the percentage of patients achieving a MCID was significantly in favor of indacaterol–glycopyrronium (50.1% vs 42.5%, P=0.038) in the per-protocol set.²⁵ Similarly, in LANTERN comparable improvements with indacaterol–glycopyrronium versus SFC were observed for all SGRQ analyses (weeks 12 and 26).²⁴

Table 6 Health status: margin of efficacy of fixed combinations versus comparators in published studies Notes: Treatment once daily unless stated otherwise. SGRQ response = SGRQ total score ≤4 units versus baseline. aSignificant treatment difference; brange of LSM differences in scores for weeks 12, 24, 38, 52, and 64 (95% CI not reported); cdifferences in LSM change from baseline to week 24; ddose not approved for use (ACL–FORM dose not approved in EU); e95% CI not reported; fOR not reported. Abbreviations: ACL–FORM, aclidinium–formoterol; BID, bis in die (twice daily); CI, confidence interval; IND–GLY, indacaterol–glycopyrronium; LSM, least-squares mean; NR, not reported; OL, open-label; OR, odds ratio; SFC, salmeterol–fluticasone combination; SGRQ, St George’s Respiratory Questionnaire; TIO–OLO, tiotropium–olodaterol; UMEC–VI, umeclidinium–vilanterol.

Significant improvements in SGRQ total score mean change from baseline (P≤0.001) and percentages of SGRQ responders (OR 2, P≤0.001) were reported for umeclidinium–vilanterol 62.5/25 μg OD versus placebo in three 24-week studies.⁴¹ Across three of four trials, health-status improvement was not significantly different for umeclidinium–vilanterol versus monotherapy with tiotropium, vilanterol, or umeclidinium (SGRQ total scores or percentage of SGRQ responders).^23,41 The fourth trial reported significant improvement in SGRQ total score from baseline (P<0.006) and percentage of SGRQ responders (OR 1.4, P=0.022) for umeclidinium–vilanterol versus tiotropium.³² Improvements in SGRQ from baseline were not significantly different between umeclidinium–vilanterol 62.5/25 μg and salmeterol–fluticasone propionate 50/250 μg in two 12-week studies.²⁷

In combined results from two 1-year studies, tiotropium–olodaterol 5/5 μg OD significantly improved SGRQ total score at week 24 by 1.2 and 1.7 units versus its respective components. Proportions of SGRQ responders were significantly increased for all the combination-versus-component comparisons, apart from tiotropium–olodaterol 2.5/5 μg versus tiotropium 2.5 μg. In the 24-week ACLIFORM and AUGMENT studies, aclidinium–formoterol BID improved SGRQ total score and percentage of responders significantly compared with placebo in one study, but did not achieve significant differences against its components in either study.^28,29

Safety

To date, the most extensive safety data available for FDC bronchodilators comes from indacaterol–glycopyrronium OD trials. Overall, indacaterol–glycopyrronium was well tolerated across the studies, and had a similar safety profile to placebo in individual trials and analyses of pooled data.^{2,36,39,40,54–56} The incidence of adverse events (AEs) and serious AEs (SAEs) reported with indacaterol–glycopyrronium treatment was comparable to that of placebo, indacaterol, glycopyrronium, tiotropium (± formoterol) or SFC BID.^{2,24–26,36,39,40} Interestingly, the FLAME trial reported a significant reduction in the incidence of pneumonia with indacaterol–glycopyrronium compared with SFC (3.2% vs 4.8%, respectively; P=0.02).²⁶ In an analysis of pooled data from 11,404 patients, the HR for indacaterol–glycopyrronium versus placebo showed no significant increase in the overall risk for death (HR [95% CI] 0.93 [0.34–2.54]), cardiocerebrovascular events (0.6 [0.29–1.24]), major adverse cardiovascular events (MACEs; 1.04 [0.45–2.42]), pneumonia (1.1 [0.54–2.25]), COPD exacerbations (0.6 [0.4–0.91]), or atrial flutter/fibrillation (1.03 [0.49–2.18]).⁵⁴

Over 24 weeks, umeclidinium–vilanterol 62.5/25 μg OD was well tolerated, and the incidence of AEs and serious AEs was similar for combination therapy versus placebo and monocomponents.^41,57 The rate of class-effect AEs associated with anticholinergic (eg, dry mouth) and BA (eg, tachycardia) agents was similar to that observed for placebo.^41,57 In two 12-week studies, umeclidinium–vilanterol 62.5/25 μg and SFC 250/50 μg were both well tolerated and had similar AE profiles.²⁷ In a pooled analysis of data from eight trials of umeclidinium–vilanterol 62.5/25 μg and 125/25 μg, no increased risk of MACE was observed with active treatment versus placebo.⁵⁸ Small numerical imbalances in cardiac ischemia were reported in some studies, but not others. As the imbalances were not dose-related, they were not considered drug-related. The incidence of cardiovascular AEs of special interest was comparable for umeclidinium–vilanterol, monocomponents, and placebo.

In the two 1-year tiotropium–olodaterol OD studies, the frequency of AEs was largely comparable between the combination- and individual component-treatment groups. The rates of MACE and cardiac events did not differ significantly between the combination and the individual component groups.³⁰ Similarly, AE reporting (including MACE and Holter monitoring) in the two aclidinium–formoterol BID studies was generally comparable across all treatment groups.^28,29

In a 2013 preliminary report from a retrospective cohort study of mortality in more than 5,000 patients with COPD, LAMA–LABA combination therapy reduced both all-cause (HR 0.53 [95% CI 0.34–0.84]) and cardiovascular mortality (HR 0.39 [95% CI 0.17–0.9]).⁵⁹ Reductions in both mortality types were also observed with LAMA–LABA–inhaled corticosteroids, LABA–inhaled corticosteroids, and LAMA-only treatment.

Discussion

We identified 23 published Phase III RCTs of FDC bronchodilators in COPD. The data demonstrated that fixed-dose LAMA–LABA combinations significantly improved lung function compared with component monotherapies or single agents.^{2,23,30–32,35,36,39–41} Indacaterol–glycopyrronium OD, umeclidinium–vilanterol OD, and tiotropium–olodaterol OD also provided significant improvements over component monotherapies and/or tiotropium in several PROs.^{2,23,30,32,35,38,40,41} Compared with its components, aclidinium–formoterol BID improved symptoms (one study),²⁸ but did not improve health status.^28,29 Indacaterol–glycopyrronium and umeclidinium–vilanterol significantly improved lung function compared with SFC BID.^26,27,39 Indacaterol–glycopyrronium also improved exacerbation rates in LANTERN and FLAME (Table 6), reduced dyspnea in ILLUMINATE, and led to reductions in use of rescue medication in ILLUMINATE and FLAME compared with SFC.^24,26,27,39 The safety profiles of the FDC agents were similar to placebo and incidence of pneumonia significantly reduced with indacaterol–glycopyrronium versus SFC in FLAME.^{2,23,26,30,32,36,39–41,54,56}

Several studies have examined the relationship between improvements in lung function following LABA or LAMA monotherapy and improvements in other outcomes, such as SGRQ total score, TDI, exacerbation rate, and rescue-medication use. However, although significant or clinically relevant correlations appear at group levels, they tend to be only moderate, weak, or too weak to be useful at individual levels.^16–19,21 This may be because some patients have very poor health despite only mild lung-function impairments or vice versa.¹⁷ Indeed, the health impact of COPD is not necessarily mediated entirely through expiratory airflow limitation; a better correlate may instead be exercise performance.¹⁷ The analyzed studies may also have been too short in duration to capture meaningful changes in exacerbations or health status, and only a few studies were available for some outcomes.¹⁸ Finally, the Hawthorne effect may also have played a role, as changes in FEV₁ of 0 still resulted in a 2.5-point reduction in SGRQ score in some cases.¹⁸

Likewise, in trials of combination-bronchodilator therapy versus components, improvement in FEV₁ was not always mirrored by improved PROs. For example, significant improvement in dyspnea for umeclidinium–vilanterol OD versus monocomponents occurred only for vilanterol (in one of three trials), despite improvements in FEV₁.^23,41 Possible reasons for this include insufficient sensitivity/specificity in instruments assessing PROs. Additionally, such measurements as inspiratory capacity may be more strongly related to dyspnea and COPD pathophysiology than FEV₁.⁶⁰ Therefore, it may be useful to examine correlations between other outcomes instead, in larger sample sizes or longer-duration studies. Findings may still be somewhat limited though, as these end points are often only secondary, meaning power may be lacking.

Patient-selection criteria represent an important limitation of RCTs. Most trials recruit subjects from highly selective populations likely to represent less than 5% of “real-life” patients. As such, the extrapolation of RCT data is limited.⁶¹ Populations are generally chosen to demonstrate the primary end point (usually lung function). Clinical trial participants tend to be less symptomatic than general patient populations, and clinical trials may exclude patients likely to benefit the most from treatment (as a maximum level of benefit may be reached sooner). Additionally, the most symptomatic patients in control arms may discontinue study treatment to obtain greater symptom relief. In contrast, real-life studies are likely to involve broader populations and treat each study arm to a similar level. Roche et al suggested a new framework to categorize the approach taken in clinical trials from highly controlled efficacy RCT management to usual clinical care.⁶¹ The positioning of studies on this scale can be useful as a descriptive classification.⁶¹ Future COPD trials may need to include more real-life patient populations and ecology of care. In addition, composite end points, such as lack of exacerbations and improved health status, may provide greater insight into the true benefits of treatment.

Additional studies of fixed-combination bronchodilators are needed to characterize further the relationship between FEV₁ and PROs with these agents, as well as defining optimal strategies for their use in clinical practice. Should therapy be initiated with a single bronchodilator and then stepped up to a LABA–LAMA combination and/or triple therapy with LABA–LAMA plus another agent as needed, or should treatment commence with a LABA–LAMA in certain patients?

In conclusion, our review of a systematic literature search indicates that fixed-dose LABA–LAMA combinations significantly improved lung function compared with their component monotherapies. In general, LABA–LAMA combinations also improved other outcomes, including symptoms and health status, compared with the monotherapies, although some discrepancies between lung function and PROs were apparent. Further research is needed to explore the relationship between lung-function outcomes and PROs in patients receiving LABA–LAMA combinations.

Acknowledgments

The authors were assisted in the preparation of the manuscript by Molly Heitz and Sarah Filcek, professional medical writers at CircleScience, an Ashfield company, part of UDG Healthcare PLC. Medical writing support was funded by Novartis Pharma AG (Basel, Switzerland).

Author contributions

All authors contributed to the concept and objectives of the review and provided guidance on the literature search, presentation, and discussion of the findings, as well as critically reviewing the article. In addition, all authors reviewed and approved the final manuscript.

Disclosure

AØ has received payment for lectures/speaking from Boehringer Ingelheim, GlaxoSmithKline, Meda, Sandoz, and Pfizer. He has advisory board membership with Boehringer Ingelheim, Novartis and Teva. DP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from UK National Health Service, British Lung Foundation, Aerocrine, AKL Ltd, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Pfizer, Respiratory Effectiveness Group, Takeda, Teva Pharmaceuticals, Zentiva, and Theravance; payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, Takeda, and Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma and Teva Pharmaceuticals; payment for the development of educational materials from Novartis and Mundipharma; payment for travel/accommodation/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, Teva Pharmaceuticals, and AstraZeneca; funding for patient enrolment or completion of research from Chiesi, Teva Pharmaceuticals, Zentiva, and Novartis; stock/stock options from AKL Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd, UK and 74% of Observational and Pragmatic Research Institute Pte Ltd, Singapore; and is peer reviewer for grant committees of the Medical Research Council, Efficacy and Mechanism Evaluation programme, and HTA. Neither MT nor any member of his close family has any shares in pharmaceutical companies. In the last 3 years, he has received honoraria for speaking at sponsored meetings or satellite symposia at conferences from the following companies marketing respiratory and allergy products: Aerocrine, AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline and Teva. MT has received honoraria for attending advisory panels with Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, and Novartis. He has received sponsorship to attend international scientific meetings from AstraZeneca, GlaxoSmithKline, and Mundipharma; and has received funding for research projects from Almirall and GlaxoSmithKline. Neither TW nor his close family members have any shares in pharmaceutical companies. In the last 3 years, TW has received honoraria for speaking at sponsored meetings or satellite symposia at conferences from the following companies marketing respiratory and allergy products: Almirall, Astra Zeneca, Boehringer Ingelheim, Chiesi, Mundipharma, Novartis, GlaxoSmithKline, and Teva. He has received honoraria for attending advisory panels with Astra Zeneca, Boehringer Ingelheim, Chiesi, MSD, and Novartis, as well as receiving funding for research projects from Novartis. The authors report no other conflicts of interest in this work.

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Supplementary materials

Table S1 Search strategy and results for published manuscripts and congress abstracts Notes: aDuplicate citations removed from result count; bresult count includes duplicate citations. ProQuest search, including Biosis, Biosis previews, Embase, and Medline databases. Searches were limited to publications from January 1, 2006 to July 31, 2014 and English-language articles. Abbreviations: EXACT, EXAcerbations of COPD Tool; EXPLODE, terms indexed as subterms included; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; MeSH, Medical Subject Headings.

Table S2 Congress abstract search strategy and results Note: Available abstracts from January 1, 2009 to May 20, 2015 were included in the literature search.