Inhaled Management of COPD

Treatment options

This section of the Learning Zone aims to provide you with information to help you decide which treatments options are suitable for your patients. Topics include:

• Goals of treatment
• Non-pharmacological intervention options
• Pharmacological intervention options
• Bronchodilators
• Muscarinic antagonists
• β₂-agonists
•  Methylxanthines
• Bronchodilator combinations
• Anti-inflammatory drugs
• Triple therapy
• Advantages of 24-hour duration of action and once-daily dosing

Goals of Treatment

Following a confirmed diagnosis of chronic obstructive pulmonary disease (COPD), effective management should be based on individualised assessment of disease in order to reduce current symptoms and future risk (Figure 1) (GOLD, 2020).¹

Patients should receive advice on healthy living, including diet and physical exercise. Furthermore, identification and reduction of exposure to risk factors, particularly smoking and other air pollutants, are important in the treatment and prevention of COPD¹.

The major treatment expectations of patients are greater symptomatic relief and mobility, faster symptomatic relief, and improvement in morning activities².

Non-pharmacological Intervention

Smoking cessation

Smoking cessation is the intervention with the greatest capacity to influence the natural history of COPD and should be considered paramount for all COPD patients, regardless of disease severity¹.

Physical activity

Daily physical activity is recommended for all patients with COPD, regardless of disease severity. As well as benefitting pulmonary rehabilitation, it also has important general health benefits, such as primary and secondary prevention of cardiovascular disease¹.

Vaccination

Depending on local policies, availability and affordability, patients with COPD should be considered for vaccination against influenza and pneumococcal infection¹.

Pulmonary rehabilitation

The main goals of pulmonary rehabilitation are to reduce symptoms, improve quality of life, and increase physical and emotional participation in day-to-day activities^3,4. All patients with COPD appear to benefit from rehabilitation and maintenance of physical activity; their exercise tolerance improves and they have less dyspnoea and fatigue⁵. The GOLD strategy document recommends pulmonary rehabilitation for patients in categories B–D¹.Pharmacological Intervention

The aims of pharmacological therapy in COPD are to:

• Reduce symptoms
• Reduce the frequency and severity of exacerbations
• Improve health status and exercise tolerance

There is no conclusive evidence to show that existing medications modify the long-term decline in lung function characteristic of COPD¹. 

Therapy for COPD falls into two main categories:

• Bronchodilators
• Anti-inflammatory drugs

These therapies may be used alone or in combination, and the choices within each class are dependent on the availability and cost of medication, and on the patient’s response¹. 

Bronchodilators

Bronchodilators relax the smooth muscle around the bronchioles, which widens airways and allows easier airflow. These drugs decrease airflow obstruction (improve emptying of the lungs), reducing hyperinflation and improving exercise performance¹. Bronchodilators are fundamental to symptom management in COPD. There are three main types of bronchodilator medication:

• Muscarinic antagonists
• β₂-agonists
• Methylxanthines

β₂-agonists and muscarinic antagonists are usually administered via inhalation, while  methylxanthines are given orally or intravenously.

The two main types of pharmacological therapies available for the management of COPD are bronchodilators and anti-inflammatory drugs. Bronchodilators are central to the symptomatic management of COPD, with β₂-agonists and muscarinic antagonists being the most widely used classes.

Muscarinic Antagonists

The binding of acetylcholine to muscarinic receptors triggers a signalling cascade that results in the contraction of smooth muscle (Figure 2). Muscarinic antagonists (also known as anticholinergics or antimuscarinics) bind to muscarinic receptors and inhibit their interaction with acetylcholine^6,7.

Early muscarinic antagonists, such as atropine and ipratropium, blocked equally M1, M2, and M3 receptors. Antagonism of the M2 receptor may diminish the bronchodilation that results from antagonism of the M1 and M3 receptors⁸. Selective receptor antagonists that preferentially block M1 and M3 receptors are therefore preferable.

By inhibiting the action of acetylcholine in the airway, muscarinic antagonists indirectly inhibit contraction of airway smooth muscle⁷. Muscarinic antagonists, such as ipratropium (available for 20 years) and tiotropium, are the most frequently prescribed inhaled medications for COPD⁹.

Muscarinic antagonists may be long acting or short acting:

• Short-acting muscarinic antagonists (SAMAs), such as ipratropium or oxitropium, have a duration of action of 6–9 hours¹.
  • Oral ipratropium has maximal effect 1‒2 hours after use, persisting for 2‒4 hours in most patients. The usual starting dose is two inhalations, four times a day. Patients may take additional inhalations as required¹⁰. 
• Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrronium, aclidinium or umeclidinium, are effective for 12–24 hours^1,11.
• Tiotropium
  • Tiotropium has a relatively slow onset of action, taking effect within 30 minutes, but the effect lasts for 24 hours. It is therefore able to maintain bronchodilation when administered once-daily¹¹.  
  • Tiotropium (metered dose: 18 µg; delivered dose: 10 µg) once-daily is indicated as a maintenance bronchodilator treatment to relieve the symptoms of patients with COPD¹¹.
  • Tiotropium improves lung function, which can be measured by the forced expiratory volume in 1 second (FEV₁) (Figure 3)¹².  
  • Tiotropium, 18 µg, has also been shown to produce improvements in health-related quality of life (HRQoL) and dyspnoea, as measured by the St George’s Respiratory Questionnaire (SGRQ) and Transition Dyspnea Index (TDI), respectively^12,13.
  • Treatment with tiotropium 18 µg once-daily has also been shown to reduce the risk of exacerbations versus salmeterol, 50 µg twice daily¹⁴.  
  • Tiotropium is generally well-tolerated^{12,13,15,16,17,18,19}.

• Glycopyrronium
  • Glycopyrronium (metered dose: 50 µg; delivered dose: 44 µg) is administered once a day and its effects last for 24 hours^1,20.
  •  Glycopyrronium, once daily, is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD²⁰.
  • Glycopyrronium improves lung function (measured by mean FEV₁) compared with placebo²¹ (Figure 4).
  • Glycopyrronium also significantly improved dyspnoea (measured by TDI) and HRQoL (measured by SGRQ) versus placebo^21,22.
  • Glycopyrronium significantly improved shortness of breath during exertion in the morning compared with placebo²³.
  • Glycopyrronium significantly prolonged the time to first moderate-to-severe exacerbation compared with placebo over 26 and 52 weeks of treatment^21,22.
  • Glycopyrronium is generally well tolerated^21,20,22.

• Aclidinium
  • Aclidinium (metered dose: 343 µg; delivered dose: 322 µg) is administered twice daily and its effects, following each dose, last for 12 hours^1,24.
  • Twice-daily aclidinium is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD²⁴.
  • Aclidinium improves lung function (measured by trough FEV₁ and FEV₁ area under the curve 0–24 hours [AUC_{0–24 hours}] to a similar degree as tiotropium (Figure 5)²⁵.
  • Aclidinium significantly improved exercise endurance time, dyspnoea (measured by TDI) and HRQoL (measured by SGRQ) versus placebo^26,27.
  • Aclidinium significantly reduced the rate of moderate-to-severe exacerbations compared with placebo (pooled data) in studies of 3–6 months' duration²⁸.
  • Aclidinium is generally well tolerated^24,26,27,29.

• Umeclidinium
  • Umeclidinium, once daily (metered dose: 62.5 µg; delivered dose 55µg), is indicated as maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD³⁰.
  • Umeclidinium improves lung function (measured by trough FEV₁, 0−6 hours weighted mean FEV₁ and peak FEV₁) compared with placebo (Figure 6)³¹.
  • Umeclidinium has been shown to improve dyspnoea and health status (measured by TDI and SGRQ, respectively) compared with placebo³¹.
  • Once-daily umeclidinium has demonstrated a reduced risk of COPD exacerbations compared with placebo³¹.
  • Umeclidinium is generally well tolerated^31,32.

β₂-agonists

β₂-adrenergic receptors are located on the airway smooth muscle of large and small airways, as well as on mast cells and post-capillary venules⁶. Adrenaline activates β₂-adrenergic receptors and leads to smooth muscle relaxation. Thus, the action of β₂-agonists, which selectively activate β₂-adrenergic receptors, directly causes bronchodilation³⁴. Two types of β₂-agonist are used in the treatment of COPD:

• Short-acting β₂-agonists (SABAs), such as salbutamol (or albuterol, the US Adopted Name), are effective for up to 12 hours; they are usually used by patients ‘on demand’ as rescue medication to relieve symptoms¹.
• Long-acting β₂-agonists (LABAs), such assalmeterol, formoterol, indacaterol, arformoterol or olodaterol, are effective for 12–24 hours; they are used as maintenance therapy, and depending on the agent, it is recommended they are used once or twice daily¹.
• Salmeterol
  • Salmeterol (metered dose: 25 µg; delivered dose: 21 µg) is administered twice daily and has a 12-hour duration of action^1,35.
  • Twice-daily treatment with salmeterol significantly improves lung function (measured by FEV₁) compared with placebo^36,37.
  • Treatment with salmeterol significantly improved dyspnoea^36,37, exercise capacity^36,7,  HRQoL (measured by SGRQ)³⁷ and exacerbations³⁸, compared with placebo.
  • Salmeterol is generally well tolerated⁷.
• Formoterol
  • Formoterol (metered and delivered dose: 12 µg) is administered twice daily and has a 12-hour duration of action; it is indicated for the relief of reversible airways obstruction in COPD patients^1,39.
  • Twice-daily treatment with formoterol significantly improves lung function compared with placebo^7,40.
  • Treatment with formoterol significantly improves dyspnoea (measured by TDI), exercise capacity and HRQoL (measured by SGRQ), compared with placebo^7,40.
  • Formoterol is generally well tolerated⁷.
• Indacaterol
  • Indacaterol (metered dose: 150 or 300 µg; delivered dose: 120 or 240 µg) has a 24-hour duration of action and is therefore suitable for once-daily dosing^1,41.
  • Indacaterol is indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD⁴¹.
  • Once-daily treatment with indacaterol significantly improves lung function (trough FEV₁) compared with placebo^37,42.
  • Treatment with indacaterol significantly improves dyspnoea (measured by TDI), health status (measured by SGRQ), exercise endurance and exacerbations, compared with placebo^37,43,44.
  • Once-daily treatment with indacaterol also significantly improves dyspnoea and health status compared with tiotropium^42,45.
  • Indacaterol is generally well tolerated⁴³.
• Arformoterol
  • Arformoterol (metered dose: 15 µg) is administered twice daily and has a 12-hour duration of action; it is indicated for the maintenance treatment of bronchoconstriction in COPD patients^46,1.
  • Twice-daily treatment with arformoterol significantly improves lung function (measured by trough FEV₁ and FEV₁ AUC_{0-12 hours}) compared with placebo^47,48.
  • Treatment with arformoterol significantly improves dyspnoea (measured by TDI) and health status (measured by SGRQ) and reduces exacerbation-related hospitalisations, compared with placebo^47,48,49.
  • Arformoterol is generally well tolerated⁴⁸.
• Olodaterol
  • Olodaterol (2.5 µg per puff) is administered once daily to a total dose of 5 µg (two puffs) and is indicated as a maintenance bronchodilator treatment in COPD patients^1,50.
  • Treatment with olodaterol improved lung function compared with placebo over 48 weeks of treatment⁵¹.
  • Treatment with olodaterol has also been shown to improve dyspnoea, health status (SGRQ total score) and exercise tolerance compared with placebo⁵¹.
  • Olodaterol is generally well tolerated and has an acceptable cardiovascular event profile⁵¹.

Methylxanthines

Xanthine derivatives, including oral methylxanthine, have been used for decades as bronchodilators and anti-inflammatory drugs. The use of methylxanthines in the treatment of COPD has declined with the introduction of the more effective and better tolerated β₂-agonists and muscarinic antagonists¹.

Theophylline is the most widely used methylxanthine in the treatment of COPD and is administered orally^1,52.

The exact mechanism of action of xanthine derivatives remains controversial, though as non-selective phosphodiesterase (PDE) inhibitors they cause bronchodilation. They may also have other non-bronchodilator actions, although the significance of these is unknown^1,52. There is limited and contradictory evidence about the effect of low-dose theophylline on exacerbation rates in COPD; the addition of theophylline to salmeterol produces a greater improvement in post-bronchodilator lung function and breathlessness than salmeterol alone¹. Higher doses of theophylline are effective bronchodilators in COPD. However, due to the potential for toxicity, inhaled bronchodilators are preferred¹.

Bronchodilator Combinations

There is a strong rationale for combining β₂-agonists and muscarinic antagonists due to their differing mechanisms of action⁷: 

• 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^53,54,55: 

• β₂-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 pharmacological classes may improve efficacy and decrease the risk of side-effects, compared with an increased dose of a single bronchodilator¹.

The current GOLD strategy document notes that combinations of β₂-agonists and muscarinic antagonists improve lung function, symptoms and exacerbation rates versus monotherapy¹.

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’ showed a superior response for the combination in terms of bronchodilator responses (as shown by increases in FEV1) compared with the two drugs singly⁵⁶. However, other parameters, such as dyspnoea and HRQoL, were unchanged.

• Another study showed that the combination resulted in significantly greater improvements in lung function compared with salbutamol alone; however, improvements in other parameters were again only small or non-significant⁵⁷.
• A third study showed that when delivered via the Respimat^® device, the combination was non-inferior to delivery via an older chlorofluorocarbon (CFC)-propelled MDI⁵⁸. Delivery via the Respimat^® also provided superior bronchodilation to 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 dyspnoea, symptoms, rescue medication use and health-related quality of life, compared with monotherapies^59,60.

LABA+LAMA combinations are superior to monotherapies with respect to improvements in lung function (measured by FEV₁). Improvements in patient-reported outcomes have also been reported with combination LABA+LAMA versus monotherapies, but the treatment differences appear to be more modest⁶¹. 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^62,63,64,65.

Fixed-dose LABA/LAMA combination therapies currently approved for maintenance treatment of patients with COPD are summarised here^{66,67,68,69,70,71,72,73}.

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 Japan⁶⁶. Indacaterol/glycopyrronium is also approved in the US as a twice-daily (27.5/15.6 µg) LABA/LAMA treatment⁶⁷.
• Umeclidinium/vilanterol, 62.5/25 µg once daily: a fixed-dose combination of a LAMA and a LABA, approved in the USA and Europe^68,69.
• Aclidinium/formoterol, 400/12 µg twice daily: a fixed-dose combination of a LAMA and a LABA approved in Europe⁷⁰.
• 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 USA^71,72. 
• Glycopyrrolate/formoterol (GFF) 9/4.8 µg two inhalations twice daily: a fixed-dose combination of a LAMA and LABA approved in the USA⁷³.

Evidence for the efficacy and safety of approved combination therapies for maintenance treatment of patients with COPD is summarised 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 hours⁶⁶.
  • IND/GLY once daily is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD⁶⁶.
  • IND/GLY improves lung function (mean FEV₁) compared with placebo, its monocomponents and standard-of-care treatments tiotropium and salmeterol/fluticasone^74,64,65.
  • IND/GLY also significantly improved dyspnoea (measured by TDI or Self-Administered Computerized TDI) compared with placebo, tiotropium and salmeterol/fluticasone^74,75,64, and HRQoL (measured by SGRQ) compared with placebo, glycopyrronium, tiotropium and salmeterol/fluticasone^62,64,65,74.
  • 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 tiotropium⁶⁵. Additionally, IND/GLY reduced the rate of exacerbations (all, moderate or severe) compared with salmeterol/fluticasone in patients with ≥1 exacerbation in the previous year⁶².
  • IND/GLY is generally well tolerated and has no additional safety signals compared with monotherapies and placebo^74,76.
• 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 COPD⁶⁸.
  • In a systematic review of 11 trials, UMEC/VI provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV₁, 60, 110, 90, and 90 mL, respectively; p< .0001)⁷⁷
  • 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 monotherapies⁷⁷.
  • Umeclidinium/vilanterol combination has a similar tolerability and safety profile as the monotherapies, tiotropium, and salmeterol/fluticasone^31,77.
• 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 hours⁷⁰.
  • ACL/FORM twice daily is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD⁷⁰.
  • In pivotal trials, ACL/FORM was associated with significant improvements in lung function compared with one or both of its monotherapies^78,79.
  • ACL/FORM has also been shown to improve lung function (peak FEV₁) compared with salmeterol/fluticason⁸⁰.
  • 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 weeks⁸¹. 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 tolerated⁸².
• 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 hours⁷¹.
  • TIO/OLO, once daily, is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD⁷¹.
  • TIO/OLO improves lung function (trough FEV₁ and FEV₁ AUC_{0–3 hours}) compared with the component monotherapies administered alone⁸³; this combination is also associated with significant improvements in FEV₁ AUC_{0–12 hours} compared with salmeterol/fluticasone⁸⁴.
  • Improvements in dyspnoea and rescue medication use have been reported for TIO/OLO compared with its component monotherapies⁸³; furthermore, TIO/OLO significantly improved health status (SGRQ) compared with placebo⁶⁰. 
• 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 COPD⁷³.
• 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 weeks⁸⁵.
• In addition, GFF provided improvements in health status (SGRQ) compared with placebo and glycopyrrolate as well as less rescue medication⁸⁵.

Anti-inflammatory Drugs

Glucocorticosteroids

The main anti-inflammatory drugs used in COPD are glucocorticosteroids (corticosteroids). However, the effects of both oral and inhaled corticosteroids are much less dramatic in COPD than in asthma¹. With the exception of a few countries, ICS are not licensed as a monotherapy in COPD; instead they are used in combination with a LABA. Corticosteroids exert their therapeutic effect by binding to glucocorticoid receptors on the bronchial epithelium^86,87. Stimulation of these receptors alters the expression of genes involved in the inflammatory response. In COPD, corticosteroids are most frequently administered by inhalation, but they can also be administered orally, intravenously or intramuscularly to treat exacerbations. 

Factors to consider when initiating ICS therapy 

GOLD 2020 lists these important factors to consider when initiating ICS treatment in combination with either one or two LABAs¹:

• Strong support: history of hospitalization (s) for COPD exacerbation despite adequate LABA maintenance therapy; ≤2 moderate COPD exacerbations annually despite adequate LABA maintenance therapy; blood eosinophil count >300 cells/μL; and history of, or concomitant, asthma
• Consider use of ICS: one moderate COPD exacerbation per year, despite adequate LABA maintenance therapy: blood eosinophils, 100‒300 cells/μL
• Against use of ICS: repeated episodes of pneumonia; blood eosinophils <100 cells/μL; history of mycobacterial infection

Blood eosinophil count as a biomarker

GOLD 2019 introduced the blood eosinophil count as a biomarker for estimating the efficacy of ICS for the prevention of exacerbations, with further information on its role in GOLD 2020. There is a continuous relationship between the blood eosinophil count and the effects of ICS (as an addition to regular maintenance therapy for COPD), with little or no treatment benefit at blood eosinophil levels of <100 cells/μL and maximum treatment benefit at an upper threshold of >300 cells/μL. These thresholds are estimated values rather than strict cut-off points, but in conjunction with a clinical assessment, they are very helpful for the clinician in knowing when to add an ICS to ongoing maintenance therapy¹.

Phosphodiesterase-4 inhibitors

PDE-4 inhibitors (PDE-4i) inhibit the breakdown of the intracellular messenger, cAMP, thereby reducing inflammation⁸⁸.

Roflumilast is the first PDE-4i to become available, having received approval in the EU, US and Canada. Roflumilast may be used to reduce exacerbations in patients with chronic bronchitis, severe and very severe COPD and frequent exacerbations that are not adequately controlled by long-acting bronchodilators¹. 

In a specific subset of patients with severe COPD, chronic bronchitis and a history of exacerbations, the frequency of COPD exacerbations was shown to be significantly reduced with roflumilast compared with placebo (Figure 7)⁸⁹. Although roflumilast has no direct bronchodilator activity, it has been shown to improve FEV₁ in patients also receiving salmeterol or tiotropium⁹⁰. More recently, in a population of patients with severe COPD, symptoms of chronic bronchitis and ≥2 exacerbations in the previous year, roflumilast, 500 μg once daily, together with an ICS and long-acting β₂-agonist significantly reduced the rate of moderate-to-severe exacerbations by 13.2% versus placebo⁹¹.

Combinations of anti-inflammatory drugs and bronchodilators

Combinations of an ICS plus a LABA have been shown to be more effective than either component alone in improving lung function, health status and reducing the frequency of COPD exacerbations in patients with moderate-to-very severe COPD. ICS/LABA combinations are recommended in patients with more severe COPD (GOLD C and D) who experience frequent exacerbations despite long-acting bronchodilator treatment¹.

In general, ICS/LABA combination products are licensed for use in moderate-to-severe COPD. Studies have shown that, in comparison with the individual components and/or placebo, combined therapy with an ICS and a LABA reduced the exacerbation rate (Figure 8) and improved health status and spirometric values³⁸.

However, because combination therapy includes an ICS component, it was also associated with a significantly greater risk of developing pneumonia compared with LABA alone or placebo (p<0.001)⁹². Evidence also points to a clear dose-response relationship, with an increased risk of pneumonia with increasing ICS dose⁹³.

ICS plus LABA is recommended for use only in patients with more severe COPD who experience frequent exacerbations despite treatment with long-acting bronchodilators. 

Evidence suggests that the combined use of an ICS and a LABA may reduce exacerbations versus monotherapy, but the risk/benefit profile limits the use of ICS to patients at high risk of exacerbation, as an alternative to recommended treatments¹.

The benefits of ICS+LABA combination products should be weighed against the increased risk of side-effects⁹⁴. There are a number of dose-related side effects associated with ICS use such as increased risk of cataracts, diabetes, pulmonary tuberculosis and pneumonia, and reduced bone density^93,95,96.

Evidence is accumulating on the potential to withdraw non-recommended ICS safely from combination therapy comprising long-acting bronchodilators⁹⁷. A real-life study in patients with moderate COPD at low risk of exacerbation found that ICS could be withdrawn without increasing the risk of exacerbations in patients who were maintained on long-acting bronchodilators⁹⁸. In patients with severe-to-very-severe COPD and at least one exacerbation in the previous 12 months, that is to say, high risk, progressive ICS withdrawal was also shown to be non-inferior to ICS continuation in terms of moderate-to-severe exacerbations⁹⁹.

Triple Therapy

Triple therapy (a combination of a long-acting muscarinic antagonist [LAMA], long-acting β₂-agonist [LABA] and ICS) is recommended as a treatment option for some symptomatic patients at high risk of exacerbation (GOLD Group D), who experience frequent exacerbations despite long-acting bronchodilator treatment or persistent symptoms/further exacerbations on ICS/LABA treatment¹. Several inhaled ICS+LABA+LAMA fixed-dose combinations, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are currently in Phase III clinical development for COPD¹⁰⁰.

The addition of a salmeterol/fluticasone or budesonide/formoterol combination to tiotropium has been shown to improve lung function and HRQoL compared with tiotropium alone^101,102. Triple therapy with fluticasone/salmeterol and tiotropium also showed greater bronchodilation than fluticasone/salmeterol¹⁰³. In a recent randomised, double-blind, parallel-group study, triple therapy with beclometasone/formoterol/glycopyrronium (via a single inhaler) was associated with significant improvements in lung function and a 23% reduction in exacerbations compared with beclometasone/formoterol treatment in patients with severe-to-very-severe airflow limitation and a history of ≥1 exacerbations. Moreover, adverse events were reported in a similar proportion of patients in each treatment group¹⁰³.

There have been relatively few studies of triple fixed-dose combination therapy for patients with COPD. Further research is required to assess the efficacy and safety of triple therapy in selected phenotypes of COPD¹⁰⁰.

Once-daily Dosing

Longer-acting inhaled therapies in COPD have been shown to be associated with higher levels of persistence (a measure of the duration of time over which a patient continues to take their medication correctly)¹⁰⁴. Furthermore, simplification of dosing regimens by reducing dosing frequency has been associated with an increase in medication adherence (compliance) in COPD¹⁰⁵. A survey of COPD and asthma patients showed that dose frequency was the most important factor for non-compliance with the treatment regimen, and 83% of patients preferred once-daily dosing¹⁰⁶. Higher compliance has been found to result in lower utilisation of hospital- and emergency room-related healthcare resources¹⁰⁷.

Guidelines

Global initiative for chronic Obstructive Lung Disease

The latest recommendations from GOLD are available from the GOLD website.

Since its first annual report in 1997, the Global initiative for chronic Obstructive Lung Disease (GOLD) has sought to provide recommendations for the management of COPD based on the best scientific information available. Its aim has been a non-biased review for the practising clinician to aid in the assessment, diagnosis and treatment of patients with COPD. 

In the 2011 GOLD update, the ‘ABCD’ assessment tool was a major advance from the spirometric grading system of earlier GOLD annual reports. The update widened the ABCD assessment tool to include multimodality assessments and symptom burden and highlighted the importance of preventing future exacerbations.

In 2017, GOLD split out separately the spirometry grading from the ABCD system. Spirometry was was still central in the diagnosis, prognosis, and use of non-pharmacological therapies, such as exercise therapy. However, the ABCD groups, and their associated implications for pharmacotherapy, were now based entirely on the patient’s symptoms and the need to prevent future exacerbations. 

The revised ABCD scheme had several benefits for patient management. It responded to the limitation of FEV₁ in influencing treatment decisions at an individual level. However, more importantly, it clearly emphasised the role of symptoms and exacerbation risk in driving therapeutic decisions. Following clinician feedback, however, the GOLD committee realised the potential for misinterpreting the use of the revised ABCD system; patients were erroneously receiving ICS/ICS-containing regimens in the early stages of COPD (Vestbo et al., 2014). The committee set about refining the ABCD assessment tool further for publication in GOLD 2019 (Figure 1). 

In GOLD 2019, the initial treatment of patients following assessment is still guided by the ABCD system. However, follow-up treatment is no longer associated with the ABCD system. Instead, it is based on an assessment of the patient’s major treatable traits of dyspnoea (symptoms) or exacerbations, together with the drugs the patient is taking for their COPD.

Note that, in GOLD 2020, the basic principles remain the same, with additional minor revisions in the use of non-pharmacological treatments, the use of blood eosinophils as a biomarker for the efficacy of inhaled corticosteroids and alternative diagnoses to exacerbations.

An expert faculty discusses the updated approach and its clinical applications in the COPD Spotlight Webinar on the 2019 GOLD update for COPD management. This includes a short series of three videos that explain how the revised GOLD 2019 works in practice, starting with discussion of the initial treatment algorithm, the change in the management cycle with GOLD 2019 to one that is symptom- and/or exacerbation-led, and then finishing with an interactive Q&A session with clinicians from around the globe.

Click here to go to the COPD Spotlight Webinar on the 2019 GOLD update for COPD management. 

Regional or national guidelines

While global guidelines report on global findings , regional or national guidelines are able to guide policies at a much more local level and adjust their recommendations to the environments of their patients.

Please note that these links will take you to external sites outside the control of epgonline.org.

Global

GOLD

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) works with healthcare professionals and public health officials to raise awareness of Chronic Obstructive Pulmonary Disease (COPD) and to improve prevention and treatment. (English)

GINA

The Global Initiative for Asthma (GINA) aims to reduce asthma prevalence, morbidity, and mortality by providing resources such as evidence-based strategy documents for asthma management and running events such as World Asthma Day. (English)

ATS

The American Thoracic Society (ATS) aims to improve global health by advancing research, patient care, and public health in pulmonary disease, critical illness, and sleep disorders. They do this via publications, guidelines and statements, educational activities, research, and advocacy. (English)

ERS

The European Respiratory Society (ERS) brings together physicians, healthcare professionals, scientists and other experts working in respiratory medicine to promote lung health in order to alleviate suffering from disease and drive standards for respiratory medicine. (English)

IPCRG

The International Primary Care Respiratory Group (IPCRG) is a clinically-led charitable organisation with the prime mission of carrying out and promoting research into the care, treatment and prevention of respiratory diseases and tobacco dependence in the community.

Regional and national

German

The German COPD guidelines, developed by the German Respiratory Society, are largely based on the GOLD recommendations. (German)

Spanish

The Spanish COPD Guidelines (GesEPOC) is an initiative of SEPAR, which, together with the scientific societies involved in COPD patient care, and the Spanish Patient Forum, has developed clinical practice guidelines for the treatment of stable COPD. (Spanish & English)

French

Recommendations for the clinical management of COPD from the Société de Pneumologie de Langue Française. (French)

Italian

COPD guidelines from AIMAR (Interdisciplinary Association for Research in Lung Disease), AIPO (Italian Association of Hospital Pulmonologists), SIMER (Italian Society of Respiratory Medicine), and SIMG (Italian Society of General Medicine). (English)

Finnish

Finnish COPD guidelines developed by the Finnish Medical Society Duodecim, a body set up to educate Finnish doctors, conduct research, and publish guidelines. (English)

ALAT

The Latin-American Thoracic Society (ALAT) focuses on the prevention and management of chest diseases, education, communication and research, advocacy to reduce risk factors, and promotion of public health initiatives to improve Respiratory Health. (English)

NICE

The National Institute for Health and Care Excellence (NICE) is a UK-based body that aims to improve health and social care by providing evidence-based guidance, developing quality standards and performance metrics, and providing a range of information services. (English)

Considerations in Women

This section within COPD and its Management aims to provide information surrounding the management of COPD in women.

COPD is a highly debilitating disease that represents a substantial and growing health burden in women¹. Despite this burden, COPD receives scant attention as a women’s health issue¹. Women with COPD symptoms may delay seeking medical advice; reasons for this delay could include: dismissing symptoms as ‘smoker’s cough’ and fear of social stigma^2,3. In addition, evidence suggests that some physicians are more likely to correctly diagnose COPD in men compared with women^1,4,5,6. There is a need for greater awareness to minimise the risk of COPD in women and to ensure timely and appropriate disease management¹.

Desktop helper

Improving care for women with COPD: guidance for primary care

The Desktop Helper highlights the need for increased awareness of COPD in women. It emphasises the importance of educating women early on the signs and symptoms of COPD and of ensuring that physicians are aware of the optimal strategies for managing COPD in women. It further describes the differences between men and women with COPD.

Treatment options references

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