Bronchodilator Combinations

There is a strong rationale for combining β2-agonists and muscarinic antagonists due to their differing mechanisms of action.6 

  • LABAs bind to β2 receptors, promoting release of cAMP and thereby stimulating relaxation of bronchial smooth muscle.
  • Blocking M2 and M3 receptors with a muscarinic antagonist prevents acetylcholine from promoting muscle contraction and allows cyclic adenosine monophosphate (cAMP) to promote relaxation.

The nature of the interaction between the β2-adrenergic and muscarinic systems is not yet fully understood, but there is enough evidence to suggest that combining β2-agonists and muscarinic antagonists is pharmacologically useful for two reasons:57,58,59

  • β-2-agonists decrease the release of acetylcholine through the modulation of cholinergic neurotransmission by pre-junctional β2-adrenoceptors. β2-agonists may, therefore, amplify the bronchial smooth muscle relaxation induced by the muscarinic antagonist.
  • Muscarinic antagonists can reduce bronchoconstrictor effects of acetylcholine, whose release has been modified by the β2-agonist, and thereby amplify the bronchodilation elicited by the β2-agonist through the direct stimulation of smooth muscle β2-adrenoceptors.

Combining bronchodilators of different pharmacologic classes may improve efficacy and decrease the risk of side effects, compared with an increased dose of a single bronchodilator.1

The current GOLD strategy document notes that combinations of β2-agonists and muscarinic antagonists improve lung function, symptoms and exacerbation rates versus monotherapy.1

Combination of short-acting bronchodilators (SAMA+SABA)

The clinical effects of the combination of ipratropium and salbutamol have been investigated in a small number of studies. ‘The COMBIVENT Inhalation Solution Study Group’ demonstrated a superior response for the combination in terms of bronchodilator responses (as shown by increases in FEV1) compared with the two drugs singly.60 However, other parameters, such as dyspnoea and HRQoL, were unchanged.60

  • Another study showed that the combination resulted in significantly greater improvements in lung function compared with salbutamol alone but again, improvements in other parameters were only small or non-significant.61
  • A third study showed that when delivered via the Respimat® device, the combination was non-inferior to delivery via an older chlorofluorocarbon (CFC)-propelled MDI.62 Delivery via the Respimat® also provided superior bronchodilation to that of ipratropium alone.

Combination of long-acting bronchodilators (LABA+LAMA)

A review of studies in patients with COPD indicated that LABA+LAMA combinations resulted in greater improvements in lung function and patient-centred outcomes such as dyspnea, symptoms, rescue medication use and HRQoL, compared with monotherapies.63,64

LABA+LAMA combinations are superior to monotherapies with respect to improvements in lung function (measured by FEV1), and while improvements in patient-reported outcomes are also apparent with combination LABA+LAMA compared with monotherapy agents, treatment differences may be more modest.65 The combination of LABA+LAMA is also superior to the combination of LABA+inhaled corticosteroid (ICS) in its effect on lung function, symptoms and exacerbations.66,67,68,69

Fixed-dose LABA/LAMA combination therapies currently approved for maintenance treatment of patients with COPD are summarised here.70,71,72,73,74,75,76,77 

Combination therapies approved for the maintenance treatment of patients with COPD:

  • Indacaterol/glycopyrronium 110/50 µg once daily: a fixed-dose LABA/LAMA combination approved in Europe and Japan;70 indacaterol/glycopyrronium also approved in the US as a twice-daily (27.5/15.6 µg) LABA/LAMA treatment71
  • Umeclidinium/vilanterol 62.5/25 µg once daily: a fixed-dose combination of a LAMA and a LABA, approved in the USA and Europe72,73
  • Aclidinium/formoterol 400/12 µg twice daily: a fixed-dose combination of a LAMA and a LABA approved in Europe74
  • Tiotropium/olodaterol 2.5/2.5 µg two puffs once daily: fixed-dose combination of a LAMA and a LABA approved in Europe and the USA75,76
  • Glycopyrrolate/formoterol (GFF) 9/4.8 µg two inhalations twice daily: a fixed-dose combination of a LAMA and LABA approved in the USA77

Evidence for efficacy and safety of the approved combination therapies for the maintenance of treatment of patients with COPD is summarized below:

  • Indacaterol/glycopyrronium (IND/GLY)
    • IND/GLY (metered dose: 110 µg indacaterol/50 µg glycopyrronium; delivered dose: 85 µg indacaterol/43 µg glycopyrronium) is administered once a day and its effects last for 24 hours.70
    • IND/GLY once daily is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.70
    • IND/GLY improves lung function (mean FEV1) compared with placebo, its monocomponents and standard-of-care treatments tiotropium and salmeterol/fluticasone (SFC).67,69,78 
    • IND/GLY also significantly improved dyspnoea (measured by TDI or Self-Administered Computerized TDI) compared with placebo, tiotropium and SFC,67,78,79 and HRQoL (measured by SGRQ) compared with placebo, glycopyrronium, tiotropium and SFC.67,68,69,78
    • Over 64 weeks, IND/GLY reduced the rate of moderate-to-severe exacerbations compared with glycopyrronium, and reduced the rate of all exacerbations and mild exacerbations compared with glycopyrronium and tiotropium.68 Additionally, IND/GLY reduced the rate of exacerbations (all, moderate or severe) compared with SFC in patients with ≥1 exacerbation in the previous year.69
    • IND/GLY is generally well tolerated and has no additional safety signals compared with monotherapies and placebo.78,80
  • Umeclidinium/vilanterol combination (UMEC/VI)
    • Once-daily UMEC/VI (metered dose: 62.5 µg umeclidinium/25 µg vilanterol; delivered dose: 55 µg umeclidinium/22 µg vilanterol) is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.72
    • In a systematic review of 11 trials, UMEC/VI provided superior improvements in lung function compared with 
    • In the same analysis, UMEC/VI was also more likely to demonstrate a clinically important improvement in TDI (dyspnoea) and significantly reduced the risk of COPD exacerbations compared with its monotherapies.81
    • Umeclidinium/vilanterol combination has a similar tolerability and safety profile as the monotherapies, tiotropium and SFC.81,82
  • Aclidinium/formoterol combination (ACL/FORM)
    • ACL/FORM (metered dose: 400 µg aclidinium/12 µg formoterol; delivered dose: 340 µg aclidinium/12 µg formoterol) is administered twice a day and its effects following each dose last for 12 hours.74
    • ACL/FORM twice daily is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.74
    • In pivotal trials, ACL/FORM was associated with significant improvements in lung function compared with one or both of its monotherapies.83,84
    • ACL/FORM has also been shown to improve lung function (peak FEV1) compared with SFC.85
    • In a pre-specified analysis of pooled data from two 24-week pivotal studies, ACL/FORM significantly improved dyspnoea (TDI focal score) compared with placebo and both monocomponents over 24 weeks.86 Improvements were also reported for overall symptom severity compared with either monotherapy, and exacerbations compared with placebo and aclidinium.
    • Long-term data indicate that ACL/FORM is well tolerated.87
  • Tiotropium/olodaterol combination (TIO/OLO)
    • TIO/OLO (delivered dose: 2.5 µg tiotropium/2.5 µg olodaterol) is administered as two inhalations once a day and its effects last for 24 hours.75
    • TIO/OLO once daily is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.75
    • TIO/OLO improves lung function (trough FEV1 and FEV1 AUC0–3h) compared with the component monotherapies administered alone;88 this combination is also associated with significant improvements in FEV1 AUC0–12 compared with SFC.89
    • Improvements in dyspnoea and rescue medication use have been reported for TIO/OLO compared with its component monotherapies;88 furthermore, TIO/OLO significantly improved health status (SGRQ) compared with placebo.90
  • Glycopyrrolate/formoterol (GFF)
    • GFF (9 µg glycopyrrolate/4.8 µg formoterol) is administered as two inhalations twice daily and is indicated (in the USA) as maintenance treatment of airflow obstruction in patients with COPD.77
    • Pooled data from the two pivotal Phase III trials of 3699 patients with COPD showed that GFF demonstrated improvements versus placebo and its monocomponents in lung function (morning pre-dose trough FEV1) at 24 weeks.91
    • In addition, GFF provided improvements in health status (SGRQ) compared with placebo and glycopyrrolate as well as less rescue medication.91