TABLE 1

Summary of studies comparing the efficacy of long-acting muscarinic antagonist/long-acting β2-agonist with monotherapy in maintenance-naïve patients with COPD#

First author [Ref.]StudyLung functionSymptoms/disease impactRisk of a CID event or exacerbation
Zheng [59]Post hoc analysis of two phase III PINNACLE studies: GLY/FOR, GLY, FOR or placebo for 24 weeks
MN patients had no LABD in the 30 days prior to screening
FEV1 mean change from baseline treatment difference: GLY/FOR versus GLY 73 mL; versus FOR 56 mL; versus placebo 152 mL; all p<0.0001SGRQ mean change from baseline treatment difference (95% CI): GLY/FOR versus GLY −0.39 (−1.92–1.14), p=0.6179; versus FOR 0.81 (−0.69–2.31), p=0.2903; versus placebo −1.75 (−3.71–0.22), p=0.0810)
Rescue medication mean change from baseline treatment difference puffs/day (95% CI): GLY/FOR versus GLY −0.2 (−0.6–0.2), p=0.2740; versus −0.2 (−0.5–0.2), p=0.3845 versus placebo −0.9 (−1.4– −0.5), p<0.0001)
CID % risk reduction: GLY/FOR versus GLY 21%, p=0.0018; versus FOR 17%, p=0.0157; versus placebo 43%, p<0.0001
Naya [60]Post hoc analysis of two replicate RCTs: UMEC/VI, UMEC, VI and placebo for 24 weeks in exacerbation-free patientsTrough FEV1 LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus: UMEC 60 (14–106) mL, p=0.011; versus VI 72 (27–117) mL, p=0.010; versus placebo 209 (159–260) mL, p<0.001Moderate/severe exacerbation % risk reduction (95% CI): UMEC/VI versus: UMEC 51 (−8–77)%, p=0.076; versus VI 60 (16–81)%, p=0.016; versus placebo 62 (15–83)%, p=0.018
Muro [61]Post hoc pooled analysis of ARISE, SHINE and SPARK trials: IND/GLY versus TIO and GLY over 24 weeks in MN patientsTrough FEV1 mean (95% CI) change from baseline treatment difference: IND/GLY versus TIO 86 (54–118) mL; versus GLY 80 (47–112) mLTDI focal score mean (95% CI) change from baseline treatment difference: IND/GLY versus TIO 0.634 (−0.012–1.281); versus GLY 0.286 (-0.345–0.918)
SGRQ total score mean (95% CI) change from baseline treatment difference: IND/GLY versus TIO −1.808 (−3.783–0.168); versus GLY −0.809 (−2.829–1.210)
Rescue medication use mean (95% CI) change from baseline puffs/day treatment difference: IND/GLY −0.531 (−0.869– −0.192); versus GLY −0.499 (−0.849– −0.150)
Takahashi [65]Prospective study: TIO/OLO versus TIO for 12 weeks in MN patientsFEV1 mean (95% CI) change from baseline treatment difference: TIO/OLO versus TIO 139 (53–225) mL; p=0.002
IC mean (95% CI) change from baseline treatment difference: TIO/OLO versus TIO 115 (−40–267) mL; p=0.13
FVC mean (95% CI) change from baseline treatment difference: TIO/OLO versus TIO 55 (−93–202) mL; p=0.46
TDI focal score mean (95% CI) change from baseline treatment difference: TIO/OLO versus TIO 0.9 (0.2–1.8); p=0.02
Physical activity change in duration (95% CI) at ≥2.0 METs from baseline treatment difference: TIO/OLO versus TIO 2.5 (−19.0–24.0) min; p=0.82
Bjermer (unpublished data)Pre-specified prospective analysis of EMAX: UMEC/VI versus UMEC and SAL over 24 weeks MN and MT patientsTrough FEV1 LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC 44 (1–87) mL, p=0.045; versus SAL 128 (85–171) mL, p<0.001
Trough FVC LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC 82 (15–148) mL, p=0.016; versus SAL 177 (110–243) mL, p<0.001
Trough IC LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC 29 (−37–94) mL, p=0.388; versus SAL 71 (6–136) mL, p=0.032
TDI focal score LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC −0.37 (−0.21–0.96), p=0.210; versus SAL 0.47 (−0.10–1.05), p=0.108
E-RS total score LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC −0.26 (−1.04–0.53), p=0.524; versus SAL −0.58 (−1.36–0.20), p=0.148
SGRQ total score LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus UMEC 0.30 (−2.00–2.60), p=0.797; versus SAL −1.12 (−3.40–1.17), p=0.338
CAT total score LS mean (95% CI) change from baseline treatment difference UMEC/VI versus UMEC −0.3 (−1.4–0.8), p=0.599; versus SAL −1.0 (−2.1–0.1), p=0.067
Rescue medication use LS mean (95% CI) change from baseline puffs/day treatment difference UMEC/VI versus UMEC −0.44 (−0.73– −0.16), p=0.002; versus SAL −0.37 (−0.66– −0.09), p=0.010
Rescue medication use LS mean (95% CI) % rescue medication-free days treatment difference UMEC/VI versus UMEC 10.6 (4.9–16.3), p<0.001; versus SAL 8.3 (2.6–14.0), p=0.005
CID (exacerbation, FEV1, SGRQ) HR (95% CI): UMEC/VI versus UMEC 1.16 (0.88–1.52), p=0.292; versus SAL 0.78 (0.60–1.00), p=0.048
CID (exacerbation, FEV1, CAT) HR (95% CI): UMEC/VI versus UMEC 0.90 (0.69–1.18), p=0.454; versus SAL 0.70 (0.54–0.90), p=0.006
CID (exacerbation, SGRQ, CAT, TDI) HR (95% CI): UMEC/VI versus UMEC 0.84 (0.67–1.06), p=0.144; versus SAL 0.80 (0.64–1.00), p=0.052
Singh [63]Post hoc analysis of ACL/FOR and AUGMENT RCTs: ACL/FOR versus ACL, FOR and placebo over 24 weeks
MN patients
Trough FEV1 mean change from baseline treatment difference: ACL/FOR versus ACL 14 mL, ns; versus FOR 57 mL, p<0.01; versus placebo 134 mL, p<0.001TDI focal score mean (95% CI) change from baseline treatment difference: ACL/FOR versus ACL 1.166, p<0.001; versus FOR 0.0916, p<0.01; versus placebo 1.535, p<0.001
E-RS total score mean (95% CI) change from baseline treatment difference: ACL/FOR versus ACL −0.818, p<0.05; versus FOR −0.827, p<0.05; versus placebo −1.445, p<0.001
SGRQ total score mean (95% CI) change from baseline treatment difference: ACL/FOR versus ACL −3.1, p<0.01; versus FOR −2.3, p<0.05; versus placebo −5.3, p<0.001
Maleki-Yazdi [45]Pooled analysis of three 24-week studies; UMEC/VI versus TIO in MN patientsTrough FEV1 LS mean (95% CI) change from baseline treatment difference: UMEC/VI versus TIO 146 (102–189) mL, p<0.001SGRQ total score mean (95% CI) change from baseline treatment difference: UMEC/VI versus TIO ns
Rescue medication mean (95% CI) change from baseline puffs/day treatment difference: UMEC/VI versus TIO −0.5 (−0.9–0.0), p=0.066
Risk of a first CID HR (95% CI): UMEC/VI versus TIO 0.66 (0.51–0.85), p=0.001
Singh [58]Post hoc analysis of OTEMTO 1 and OTEMTO 2 RCTs: TIO/OLO versus TIO and placebo over 12 weeks
MN and MT subgroups
FEV1 AUC0–3 : TIO/OLO versus TIO significant improvements
Trough FEV1: TIO/OLO versus TIO ns
TDI focal score: TIO/OLO versus TIO significant improvements
SGRQ total score: TIO/OLO versus TIO significant improvements
Ferguson [64]Post hoc analysis of the two TORNADO trials: TIO/OLO versus TIO and OLO at 24 weeks
Subgroup analysis by prior bronchodilator treatment
Trough FEV1 adjusted mean±se change from baseline
GOLD 2: TIO/OLO (5/5 µg) 146±14 mL versus TIO (5 µg) 68±14 mL, significant difference
GOLD 3/4: TIO/OLO (5/5 µg) 148±14 mL versus TIO (5 µg) 79±13 mL, significant difference
Buhl [66]Post hoc analysis of four pooled studies TIO/OLO versus TIO at 12 weeks in MN patients
Subgroup analysis by GOLD stage, BDI score or baseline SGRQ total score
Trough FEV1 adjusted mean (95% CI) change from baseline treatment difference (TIO/OLO versus TIO):
GOLD 2: 56 (25–87) mL, p=0.0004
GOLD 3: 51 (11–91) mL, p=0.0122
BDI ≤6: 62 (29–95) mL, p=0.0002
BDI >6: 54 (21–86) mL, p=0.0012
SGRQ <median: 41 (8–74) mL, p=0.0138
SGRQ ≥median: 68 (35–101) mL, p<0.0001
SGRQ total score adjusted mean (95% CI) change from baseline treatment difference (TIO/OLO versus TIO):
GOLD 2: −2.02 (−3.69– −0.36), p=0.0171
GOLD 3: −1.36 (−3.85–1.13), p=0.2841
BDI ≤6: −2.41 (−4.40– −0.41), p=0.0183
BDI >6: −1.70 (−3.49–0.08), p=0.0617
SGRQ <median: −1.56 (−3.14–0.04), p=0.0562
SGRQ ≥median: −1.97 (−4.17–0.23), p=0.0786
TDI focal score adjusted mean (95% CI) change from baseline treatment difference (TIO/OLO versus TIO):
GOLD 2: 0.52 (0.10–0.94), p=0.0152
GOLD 3: 0.18 (−0.43–0.80), p=0.5628
BDI ≤6: 0.37 (−0.09–0.83), p=0.1152
BDI >6: 0.50 (0.02–0.98), p=0.0415
SGRQ <median: 0.31
(−0.14–0.77), p=0.1732
SGRQ ≥median: 0.54 (0.05–1.03), p=0.0295

CID: clinically important deterioration; GLY: glycopyrrolate; FOR: formoterol fumarate; MN: maintenance-naïve; LABD: long-acting bronchodilator; FEV1: forced expiratory volume in 1 s; SGRQ: St George's Respiratory Questionnaire; RCT: randomised controlled trial; UMEC: umeclidinium; VI: vilanterol; LS: least squares; IND: indacaterol; TIO: tiotropium; TDI: Transition Dyspnoea Index; OLO: olodaterol; IC: inspiratory capacity; FVC: forced vital capacity; METs: metabolic equivalents; SAL: salmeterol; MT: maintenance-treated; E-RS: Evaluating Respiratory Symptoms–COPD; CAT: COPD Assessment Test; ACL: aclidinium; ns: not significant; AUC0–3: area under the curve from 0–3 h; GOLD: Global Initiative for Chronic Obstructive Lung Disease; BDI: Baseline Dyspnoea Index. #: data for maintenance-treated subgroups are presented in supplementary table 1.