Table 3 LABA and LAMA combinations: current evidence

Beier et al. [61]

Larger mean increases from baseline trough FEV₁ vs placebo with 20 μg GSK233705 + salmeterol (203 mL) and 50 μg GSK233705 + salmeterol (215 mL) vs monotherapy with tiotropium (101 mL) or salmeterol (118 mL)

Tashkin et al. [60]

Greater improvement in FEV₁ AUC_0-24 from baseline with combination (0.22 L) vs monotherapy with either arformoterol (0.10 L) or tiotropium (0.08 L); p < 0.001

Greater improvement in TDI with combination (3.1) vs monotherapy with either arformoterol (2.3; CI 0.03, 1.70) or tiotropium (1.8; CI 0.50, 2.20)

Hanania et al. [65]

FEV₁ AUC_0-3 greater with combination (1.57 L) vs tiotropium alone (1.38 L); p < 0.0001

Reduced use of rescue medication vs tiotropium alone; p < 0.05

Tashkin et al. [56]

Greater FEV₁ AUC_0-3 with combination (1.52 L) vs tiotropium alone (1.34 L); p < 0.0001

Greater improvement in TDI with combination than tiotropium alone (2.30 vs 0.16; mean difference of 1.80); 95% CI 0.86, 2.74, p < 0.0002

Tashkin et al. [55]

Greater improvement in FEV₁ AUC_0-4 from baseline with combination (0.34 L) vs tiotropium alone (0.17 L); p < 0.001

Dyspnea significantly improved with combination at week 8 (1.86) vs tiotropium alone (1.01); p = 0.013

Reduced use of rescue medication vs tiotropium alone; p < 0.04

Terzano et al. [66]

Greater improvement in FEV₁ with combination vs tiotropium alone at day 30 (0.16 L); p = 0.0001

Improvement in dyspnea with combinations (2.32-2.61) vs tiotropium alone (1.0); p < 0.05

Lower rescue medication use with combinations (0.71-0.80 puffs/day) vs tiotropium alone (2.14 puffs/day); p < 0.05

van Noord et al. [47]

Greater average improvement in FEV₁ AUC_0-24 0.16-0.20 L with combinations vs 0.08 L with tiotropium alone; p < 0.05

Lower rescue medication use with combinations vs tiotropium alone; p < 0.01 (daily rescue medication use with tiotropium + formoterol QD or BID) and p < 0.05 (tiotropium + formoterol BID)

van Noord et al. [49]

Average improvement in daytime (0.234 L) and night-time FEV₁ (0.086 L) with combination vs monotherapy with tiotropium (p ≤ 0.001) or formoterol (p ≤ 0.01)

Lower rescue medication use with combination (1.81 puffs/day) vs monotherapies (2.37-2.41 puffs/day); p < 0.01

Vogelmeier et al. [54]

Improvement in FEV₁ 2 h post-dose after 24 weeks with combination vs formoterol alone (p = 0.044)

Mahler et al. [50]

Greater increase in trough FEV₁ from baseline with combination: 70–80 mL difference vs tiotropium alone (p < 0.001)

Improved trough IC with combination vs tiotropium alone: 100–130 mL; p < 0.01

Less use of albuterol as rescue medication with combination: reduction of 0.8–1.3 puffs/day from baseline vs tiotropium alone

Aaron et al. [48]

No statistical improvement in lung function or hospitalization rates with combination compared to tiotropium monotherapy

van Noord et al. [59]

Improved average FEV₁ (0–24 h) with combination (0.142 L) vs monotherapy with either tiotropium (0.07 L) or salmeterol (0.045 L); p < 0.0001

Combination associated with clinically relevant improvements in TDI focal score (p < 0.001)

Reisner et al. [53]

Increase in FEV₁ AUC_0–12 on day 7 with combination compared to monotherapy with either of the components, tiotropium, and placebo (p < 0.0001)

Reisner et al. [52]

Higher morning pre-trough and peak IC with combination vs placebo (p < 0.0005 and p < 0.005, respectively) or tiotropium monotherapy (p < 0.05 for all comparisons)

Reisner et al. [62]

Similar metabolic and cardiac safety profile to tiotropium

van Noord et al. [58]

Improved trough FEV₁ with combination: 0.226 L difference in trough FEV₁ vs placebo (p < 0.001)

Greater peak FEV₁ with combination (1.709 L) vs 300 μg indacaterol (1.579 L) and 600 μg indacaterol (1.573 L); p < 0.0001 for both comparisons

Van de Maele et al. [57]

Increased trough FEV₁ with combination (1.61 L) vs indacaterol monotherapy 300 μg (1.46 L); p < 0.05

Bateman et al. [68]

Improved trough FEV₁ with combination vs placebo (0.20 L mean difference), indacaterol (0.07 L), glycopyrronium (0.09 L), and tiotropium (0.08 L) monotherapy; p < 0.001

Improved TDI score with combination vs placebo (mean difference 1.09); p < 0.001 and tiotropium (0.51 mean difference); p < 0.05

Improved SGRQ score with combination vs tiotropium (-2.13 mean difference); p < 0.05

Reduced use of rescue medication with combination vs monotherapies (-0.30 to -0.54 mean difference); p < 0.05

Vogelmeier et al. [69]

Improvement in trough FEV₁ with combination vs salmeterol/fluticasone (mean difference 0.103 L); p < 0.0001

Improvements in TDI score with combination vs salmeterol/fluticasone (mean difference 0.76); p = 0.003

Lower use of rescue medication with combination vs salmeterol/fluticasone (-0.39 puffs/day); p = 0.019)

Dahl et al. [67]

Combination increased FEV₁ and FVC vs placebo over a 52-week period; p < 0.001

Maltais et al. [51]

Higher peak FEV₁ for all doses of combination investigated vs tiotropium alone (p ≤ 0.05); higher trough FEV₁ response with tiotropium + olodaterol 5/10 μg vs tiotropium alone (p = 0.034)

Aalbers et al. [64]

Significant improvements in FEV₁ for all doses of combination vs olodaterol alone, with evidence of a dose-dependent response

Feldman et al. [63]

Adverse-event rate of 26%, with no single adverse event reported in >1 patient

Combination similar to placebo in terms of cardiac parameters

Greater change from baseline in trough FEV₁ and FEV₁ from 0–6 h post-dose with combination vs placebo