Introduction
Evolving COPD guidelines
Long-acting bronchodilators: the cornerstone of COPD maintenance therapy
Patient group | 1st choice | 2nd choice | Alternative |
---|---|---|---|
A: GOLD 1-2 | Short-acting anticholinergic prn OR SABA prn | LAMA OR LABA OR SABA and short-acting anticholinergic | Theophylline |
Low risk of exacerbation, less symptoms | |||
B: GOLD 1-2 | LAMA OR LABA | LAMA and LABA | SABA and/or short-acting anticholinergic |
Low risk of exacerbation, more symptoms | Theophylline | ||
C: GOLD 3-4 | ICS + LABA OR LAMA | LAMA and LABA OR LAMA and PDE-4 inhibitor OR LABA and PDE-4 inhibitor | SABA and/or short-acting anticholinergic |
High risk of exacerbation, less symptoms | Theophylline | ||
D: GOLD 3-4 | ICS + LABA and/or LAMA | ICS and LABA and LAMA OR ICS + LABA and PDE-4 inhibitor OR LAMA and LABA OR LAMA and PDE-4 inhibitor | Carbocysteine |
High risk of exacerbation, more symptoms | SABA and/or short-acting anticholinergic | ||
Theophylline |
Therapy | LABA/LAMA | Manufacturer | Dosage | Time to onset | Trough FEV1(difference from placebo) |
---|---|---|---|---|---|
Formoterol | LABA | Mercka | Twice daily | 5 min [26] | 50–90 mL [26] |
4.5 μg (MDI) and 12 μg (DPI) | |||||
Indacaterol | LABA | Novartis | Once daily 150 and 300 μg (EU) (DPI) [20] | 5 min [22] | 130–180 mL (p < 0.001) [22] |
Indacaterol | LABA | Novartis | Once daily 75 μg (US) (DPI) [21] | 5 min [22] | |
Olodaterol | LABA | Boehringer Ingelheim | Once daily 5 and 10 μg (Respimat®) | Not available | 61–132 mL (p < 0.01) [24] |
Vilanterol | LABA | GSK | Once daily 25 and 50 μg (DPI) | Median 6 min [25] | 137–165 mL (p < 0.001) [25] |
Aclidinium | LAMA | Almirall/Forest Laboratories | Twice daily 200–400 μg (DPI) | 86–124 mL (p < 0.0001) [29] | |
Glycopyrronium | LAMA | Novartis | Once daily 50 μg (DPI) | ||
Glycopyrrolate | LAMA | Pearl Therapeutics | Twice daily 36 μg (MDI) | 5 min [19] | Statistically superior to placebo (p < 0.0001) [31] |
GSK233705 | LAMA | GSK | Twice daily 200 μg | Not available | 130 mL (p < 0.001) [32] |
Tiotropium | LAMA | Boehringer Ingelheim | Once daily 18 μg (DPI) and 5 μg (via SMI) | 15 min [18] | 120–150 mL (p < 0.001) [18] |
Umeclidinium (GSK573719) | LAMA | GSK | Once daily | Not available | Not available |
Combination bronchodilation: rationale
Combination bronchodilation: existing evidence and ongoing studies
Short-acting muscarinic antagonist plus short-acting β2-agonist
Free combinations of LAMA plus LABA
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 |
Fixed-dose combinations (FDCs)
LAMA | LABA | Trial numbers | Summary of ongoing Phase II/III studies |
---|---|---|---|
Aclidinium | Formoterol | NCT01572792, NCT0143797, NCT01462942, NCT01437540, NCT01049360 | 4 Phase III studies and 1 Phase II study, examining the long-term efficacy and safety of 2 different doses of aclidinium + formoterol vs monotherapy with either component and placebo |
Glycopyrrolate | Formoterol | NCT01587079, NCT01587079 | 2 Phase II studies (both recently completed), examining efficacy of the combination vs the monotherapy components and tiotropium |
Glycopyrronium | Indacaterol | NCT01120691 (SPARK), NCT01202188 (GLEAM) (pivotal studies, both completed), NCT0171251, NCT01604278, NCT01727141, NCT01529632, NCT01709903 | 2 recently completed pivotal Phase III studies investigating efficacy and safety, exacerbations, exercise, and TDI, and 5 ongoing Phase III studies, examining safety and efficacy of combination vs placebo, monotherapy components, and salmeterol/fluticasone |
Tiotropium | Olodaterol | NCT01431274, NCT01431287 (pivotal studies), NCT01525615, NCT01533922, NCT01533935, NCT01559116, NCT01536262 | 7 Phase III studies, investigating efficacy and safety of combination vs monotherapy components and effects on exercise |
Umeclidinium (GSK573719) | Vilanterol | NCT01313637, NCT01316900, NCT01316913, NCT01313650 (pivotal studies, recently completed), NCT01716520, NCT01491802 | 6 Phase III studies (4 recently completed, 2 ongoing), focused primarily on efficacy, with other studies examining AE incidence, exercise endurance time, and exertional dyspnea |
Delivery devices
Type of delivery device | Description | Advantages | Disadvantages | Combination products in development |
---|---|---|---|---|
pMDI | Drug is dissolved in propellant (generally HFA). When activated, a valve system releases a metered volume of propellant containing the medication | Can be more cost-effective than DPIs [84] | Pearl inhaler for glycopyrrolate + formoterol (Pearl Therapeutics) [86] | |
High fine-particle fraction, leading to better peripheral lung deposition | Evidence suggests fewer patients use pMDIs correctly without teaching [84] | |||
Breath-actuated DPIs require no hand-lung coordination | ||||
DPI | Drug is delivered in powder form on inspiration by the patient; de-aggregation of the powder and generation of the aerosol provided by the patient’s inspiratory effort | Activated by inhalation, avoiding synchronization issues [84] | Can be more expensive vs MDIs [84] | Breezhaler® for indacaterol + glycopyrronium (single-dose, Novartis) [87] |
Evidence suggests more patients have an accurate inhaler technique with DPIs without teaching [84] | Errors in inhaler technique can still occur [92] | Ellipta® Vilanterol (single-dose, GSK) | ||
Pressair® for aclidinium (multi-dose, Almirall) [88] | ||||
Soft Mist™ Inhaler | Less clinical experience with this device; more safety data are required | Respimat® for tiotropium + olodaterol (Boehringer Ingelheim) [85] |
Consideration of potential adverse effects of LAMA/LABA combinations
Emerging therapeutic approaches
Triple therapy
Dual muscarinic antagonist-β2-agonists (MABAs)
Novel bronchodilators
Conclusions
Mean monthly patient volumea | |||
---|---|---|---|
Regimen | Total COPD | COPD only | COPD + asthma |
Tiotropium monotherapy | 310,423 | 279,530 | 30,893 |
ICS/LABA | 451,019 | 360,760 | 90,259 |
LABA + LAMA | 5,888 | 5,479 | 410 |
Tiotropium + ICS/LABA | 193,137 | 170,063 | 23,074 |