Table 3.
LABA and LAMA combinations: current evidence
| Combination (manufacturer) | Reference | Reported results |
|---|---|---|
|
Free combinations | ||
| GSK233705: 20 or 50 μg BID; salmeterol: 50 μg BID |
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) |
| Tiotropium: 18 μg QD; arformoterol: 15 μg BID |
Tashkin et al. [60] |
Greater improvement in FEV1 AUC0-24 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) | ||
| Tiotropium: 18 μg QD; formoterol: 20 μg BID |
Hanania et al. [65] |
FEV1 AUC0-3 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 | ||
| Tiotropium: 18 μg QD; formoterol: 20 μg BID |
Tashkin et al. [56] |
Greater FEV1 AUC0-3 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 | ||
| Tiotropium: 18 μg QD; formoterol: 12 μg BID |
Tashkin et al. [55] |
Greater improvement in FEV1 AUC0-4 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 | ||
| Tiotropium: 18 μg QD; formoterol: 12 μg QD or BID |
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 | ||
| Tiotropium: 18 μg QD; formoterol: 12 μg QD or BID |
van Noord et al. [47] |
Greater average improvement in FEV1 AUC0-24 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) | ||
| Tiotropium: 18 μg QD; formoterol: 12 μg QD or 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 | ||
| Tiotropium: 18 μg QD; formoterol: 10 μg BID |
Vogelmeier et al. [54] |
Improvement in FEV1 2 h post-dose after 24 weeks with combination vs formoterol alone (p = 0.044) |
| Tiotropium: 18 μg QD; indacaterol: 150 μg QD |
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 | ||
| Tiotropium: 18 μg QD; salmeterol: 50 μg BID |
Aaron et al. [48] |
No statistical improvement in lung function or hospitalization rates with combination compared to tiotropium monotherapy |
| Tiotropium: 18 μg QD; salmeterol: 50 μg BID |
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) | ||
|
Fixed-dose combinations | ||
| Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics) |
Reisner et al. [53] |
Increase in FEV1 AUC0–12 on day 7 with combination compared to monotherapy with either of the components, tiotropium, and placebo (p < 0.0001) |
| Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics) |
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) |
| Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics) |
Reisner et al. [62] |
Similar metabolic and cardiac safety profile to tiotropium |
| Glycopyrronium: 50 μg QD; indacaterol: 300 μg QD (Novartis) |
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 | ||
| Glycopyrronium: 100 μg QD; indacaterol: 600 μg QD (Novartis) |
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 |
| Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis) |
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 | ||
| Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis) |
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) | ||
| Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis) |
Dahl et al. [67] |
Combination increased FEV1 and FVC vs placebo over a 52-week period; p < 0.001 |
| Tiotropium: 5 μg QD; olodaterol: 2, 5, and 10 μg QD (Boehringer Ingelheim) |
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) |
| Tiotropium: 1.25, 2.5, and 5 μg QD; olodaterol: 5 and 10 μg QD (Boehringer Ingelheim) |
Aalbers et al. [64] |
Significant improvements in FEV1 for all doses of combination vs olodaterol alone, with evidence of a dose-dependent response |
| Umeclidinium (GSK573719): 500 μg QD; vilanterol: 25 μg QD (GSK) |
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 | ||
PubMed and relevant respiratory congresses were searched for abstracts relating to LAMA/LABA combination therapies.
BID = twice a day; FEV1 = forced expiratory volume in 1 second; QD = once a day; AUC = area under the curve; TDI = Transition Dyspnea Index; CI = confidence interval; IC = inspiratory capacity; SGRQ = St George’s Respiratory Questionnaire.