An update on the pharmacological management of stable COPD

Key practice points:

• Non-pharmacological interventions continue to underpin COPD management, including smoking cessation, regular exercise, pulmonary rehabilitation and annual influenza vaccination
• All patients with COPD should be prescribed a short-acting bronchodilator for relief of acute breathlessness, i.e. the short-acting muscarinic antagonist (SAMA) ipratropium or a short-acting beta₂-agonist (SABA) either salbutamol or terbutaline, or the combination SABA/SAMA salbutamol + ipratropium
• Long-acting muscarinic antagonists (LAMAs), e.g. tiotropium, glycopyrronium and umeclidinium, are now recommended as the first-line long-acting bronchodilators for patients with persistent symptoms of COPD; long-acting beta₂-agonists (LABAs) are prescribed if LAMAs are contraindicated or not tolerated, whereas previously LABAs were first-line with LAMAs.
• Combination LABA/LAMAs are recommended for patients with persistent or troubling symptoms or whose lung function has declined significantly or who continue to experience exacerbations, despite LAMA or LABA monotherapy
• Triple therapy, i.e. a LABA/LAMA + an inhaled corticosteroid (ICS), may be appropriate for patients who have experienced two or more exacerbations in a year
• A blood eosinophil count may help predict which patients with COPD are most likely to benefit from ICS treatment; levels ≥ 0.3 x 10⁹/L are associated with the greatest likelihood of benefit, levels < 0.1 x 10⁹/L the least benefit. Spirometry is no longer recommended to guide the use of ICSs.
• It is now clearer when withdrawal of ICS treatment may be beneficial, i.e. where there is no evidence of benefit, the patient develops pneumonia or if they are clinically stable without a history of recent exacerbations

N.B. Information on aspects of care not covered in this article such as patient education, COPD action plans, nutritional guidance, exacerbation management, treatment of advanced symptoms and end-of-life care is available from: “The optimal management of patients with COPD – Part 2: Stepwise escalation of treatment” and the Asthma + Respiratory Foundation NZ COPD guidelines (2021)

An outline of COPD essentials in primary care

Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and an airflow limitation caused by noxious exposure to particles or gases.¹ It is estimated to be the fourth leading cause of death in New Zealand, following ischaemic heart disease, stroke and lung cancer.²

The exact prevalence of COPD in New Zealand is unknown. It has been conservatively estimated that one in every 15 people aged over 45 years has COPD, with a substantial number of additional people with undetected early-stage disease.³

COPD is associated with significant health disparities. Hospitalisation rates due to COPD are over five times higher for people living in the most deprived quintile, compared to people living in the least deprived quintile.⁴ Māori have COPD hospitalisation rates that are 3.5 times higher and COPD mortality rates 2.2 times higher, than people of non-Māori, Pacific or Asian ethnicity.⁴ Early investigation and diagnosis of COPD, combined with optimal management is critical in reducing these disparities in the most affected communities.

Diagnosis, assessment and non-pharmacological management

A diagnosis of COPD is typically based on the following factors, particularly in patients aged over 40 years:^{1, 5}

• Breathlessness on exertion, cough and sputum production
• Long-term exposure to tobacco smoke or noxious exposure to respiratory irritants, e.g. pollution, occupational chemicals or unventilated cooking fires (more common in immigrants from less developed countries)
• Post-bronchodilator FEV₁/FVC^* < 0.70 on spirometry

^* FEV₁ = Forced expiratory volume in 1 second, FVC = forced vital capacity

Further information on COPD diagnosis is available from: https://bpac.org.nz/BPJ/2015/February/copd-part1.aspx

Assess COPD severity with spirometry and by the level of symptoms the patient is experiencing at diagnosis and review annually to measure progression. The COPD Assessment Test (CAT) is a short eight-item tool that provides a broad assessment of the patient’s quality of life, e.g. sputum production, sleep quality and confidence in leaving their home, on a scale of zero to 40 (most severe). The Modified Medical Research Council (mMRC) dyspnoea scale is a brief assessment of functional disability that determines the impact of breathlessness on the patient’s daily life.¹ The CAT and mMRC can both be useful when assessing COPD in primary care.¹

The CAT and mMRC are available from: www.catestonline.org/patient-site-test-page-english.html and the CAT is also available in Appendix 2 of the NZ COPD guideline, found here: https://www.nzrespiratoryguidelines.co.nz/copdguidelines.html

Non-pharmacological interventions are first-line in COPD management as they are the most effective way to improve symptom control and quality of life and modify disease progression, regardless of what pharmacological treatments are ultimately required. Non-pharmacological interventions include:^{1, 5}

• Smoking cessation; the most important factor to improve symptoms and slow disease progression
• Regular exercise; at least 20 – 30 minutes per day, ideally more if fitness allows
• Weight loss for people who are obese; adequate nutrition for those who are malnourished
• Pulmonary rehabilitation; offered to all patients, where available as it improves breathlessness substantially more than inhaled medicines (see Appendices 4 and 5 of the NZ COPD guidelines for some non-pharmacological strategies for breathlessness: https://www.nzrespiratoryguidelines.co.nz/copdguidelines.html)
• Creating a written COPD action plan indicating what to do if the patient’s condition deteriorates – an example plan is provided in Appendix 3 of the NZ COPD guideline https://www.nzrespiratoryguidelines.co.nz/copdguidelines.html
• Annual influenza immunisation and appropriate pneumococcal immunisation reduces the risk of serious respiratory infections and COPD exacerbations^*

^* People with COPD are eligible for a funded influenza vaccination but not a funded pneumococcal vaccine. If affordable to the patient, it is recommended they receive both PCV13 and Pneumovax23 (see Immunisation Handbook for further details)

Further information on smoking cessation is available from: https://bpac.org.nz/BPJ/2015/October/smoking.aspx

Further information on pulmonary rehabilitation is available from: https://bpac.org.nz/2017/copd.aspx

A stepwise approach guides the use of inhaled medicines in the management of patients with stable COPD, taking into account:^{1, 5}

• Symptom severity
• Exacerbation frequency
• Patient preference for medicine and inhaler type, e.g. some patients may find manipulating certain inhaler types difficult
• Likelihood of experiencing adverse effects
• Regimen complexity

Check the patient’s treatment adherence and inhaler technique at each consultation, and especially before making changes to their treatment regimen. This can also be done by community pharmacists; consider adding a note to the prescription asking the pharmacist to check the patient’s technique.

Treatment of COPD with inhaled medicines

All patients with COPD require inhaled medicines. Alongside non-pharmaceutical interventions, medicines improve symptoms, exercise tolerance and quality of life and may reduce the frequency and severity of COPD exacerbations.^1,6 There is, however, no conclusive evidence that medicines can prevent the long-term decline in lung function associated with COPD.¹

Bronchodilator treatment regimens need to be individualised as the effect is often difficult to predict.¹ Inhaled medicines are initiated as therapeutic trials and the patient’s response monitored; a different inhaler or class of bronchodilator can be prescribed if the treatment response is not sufficient, after checking adherence and inhaler technique. Table 1 provides updated recommendations on the use of inhaled medicines for patients with COPD including initiating LAMAs at Step 2, in preference to LABAs, and the use of blood eosinophil levels to guide the use of ICSs.

Table 1: The stepwise escalation of pharmacological treatment for COPD, based on disease severity, adapted from the Lung Foundation Australia (2018) to include GOLD and Asthma + Respiratory Foundation NZ guidance (2021)^1,6,7

Step 1: Prescribe short-acting bronchodilators to control occasional symptoms

Continue prescribing short-acting bronchodilators to all patients with COPD for the relief of acute breathlessness.¹ The following medicines all provide short-term improvements in breathlessness for patients with occasional symptoms of COPD:^{1, 5}

• Short-acting muscarinic antagonist (SAMA), ipratropium
• Short-acting beta₂-agonists (SABAs), salbutamol or terbutaline
• Combination SABA/SAMA, salbutamol + ipratropium

Ipratropium produces greater improvements in lung function than SABA monotherapy and is generally better tolerated.⁵

The frequent use of short-acting bronchodilators, e.g. more than four times daily, is not recommended and if this is occurring, a long-acting bronchodilator should be initiated.¹

For easy reference, Table 2 provides the trade names for inhaled medicines funded for COPD treatment.

Table 2: Inhaled medicines funded in New Zealand for the treatment of COPD, by class and trade name

Step 2: Add a long-acting bronchodilator for persistent breathlessness

Long-acting muscarinic antagonists (LAMAs) are now first-line at Step 2 for patients with continuous COPD symptoms or frequent exacerbations, despite regular and correct use of a short-acting bronchodilator, if they meet the endorsement criteria for: ^5,6

• Glycopyrronium
• Tiotropium
• Umeclidinium

This is a change in guidance that has occurred in recent years as previously there was insufficient evidence to recommend one class of long-acting bronchodilator over another. LAMAs improve symptoms and quality of life and are associated with greater reductions in exacerbation rates and possibly fewer adverse effects, compared to LABAs.^1,6

If LAMAs are contraindicated, however, a LABA will help to reduce COPD symptoms and may also improve lung function and patient quality of life.⁵

N.B. Concurrent treatment with an ICS is not needed in patients with COPD (without features of asthma) who are taking a LABA. Combined ICS/LABA treatment is essential in patients with asthma due to the increased mortality risk associated with LABA monotherapy.

Ipratropium should be withdrawn before initiating a LAMA and a SABA prescribed for as-needed symptom relief. Explain to patients that a SAMA and a LAMA should not be taken concurrently. A SABA may be prescribed to patients taking a LABA, e.g. salmeterol, indacaterol or formoterol. Ipratropium may continue to be used for occasional symptom relief by patients taking a LABA.

It is not necessary to trial a short-acting bronchodilator before initiating a long-acting bronchodilator;^{1, 5} SABA-induced tachyphylaxis does not occur in people with COPD, therefore in contrast to asthma, trialling a short-acting inhaler is not predictive of the patient’s tolerance to a long-acting medicine. If a patient has previously been taking a short-acting bronchodilator, the initiation of a long-acting inhaler aims to decrease the need for the short-acting inhaler.

Step 2a: Prescribe a combination long-acting bronchodilator if monotherapy is not effective

For patients with persistent or troubling symptoms, e.g. CAT score ≥ 20, or whose lung function has declined significantly or who continue to experience exacerbations, despite LAMA or LABA monotherapy, one of the following combination LABA/LAMAs is recommended for those meeting Special Authority criteria:^1,5,6

• Indacaterol/glycopyrronium
• Olodaterol/tiotropium
• Vilanterol/umeclidinium

Combination LABA/LAMAs may improve lung function and reduce symptoms and exacerbations more than LAMA or LABA monotherapy.^1,5 LABA/LAMA combinations are generally preferred to ICS/LABA combinations due to the increased risk of pneumonia associated with ICS treatment (see: “ICS use and pneumonia risk in patients with COPD“).^{1, 5}

Step 3: Reserve ICS treatment for patients with exacerbations and eosinophilic COPD

An eosinophilic pattern of COPD may help to predict which patients may receive more benefit from an ICS/LABA, e.g. fluticasone (furoate) + vilanterol, budesonide + formoterol or fluticasone (propionate) + salmeterol compared with a LABA/LAMA.¹ Those most likely to benefit include patients with:¹

• A history of exacerbations, i.e. ≥ 2 a year or one exacerbation requiring hospitalisation
• A blood eosinophil count ≥ 0.3 x 10⁹/L
• Asthma-COPD Overlap Syndrome (ACOS [see: “Asthma COPD overlap is managed with an ICS/LABA”])

Patients with a blood eosinophil count < 0.1 x 10⁹/L are least likely to benefit from an ICS/LABA (see: “Use an eosinophil count and exacerbation history to determine ICS benefit”).¹ Previously, exacerbation history and spirometry to assess reversibility were used to determine which patients were likely to benefit from an ICS.

Weigh the potential benefits of long-term ICS treatment against the risks of adverse effects, including oral candidiasis and hoarseness, skin bruising and pneumonia.^5,6 There is less robust evidence that ICS treatment is also associated with decreased bone density and increased fracture risk, an increased risk of diabetes and reduced glycaemic control in patients with diabetes, cataracts and mycobacterial infection, including tuberculosis, although, the risk is substantially lower than that associated with oral corticosteroids.⁶ Localised adverse effects such as oral candidiasis and hoarseness may be prevented by using a spacer with metered dose inhalers (MDIs) and by oral rinsing following actuation.

Triple therapy may be appropriate for patients with severe COPD

Patients who have experienced two or more exacerbations in a year or one exacerbation requiring hospitalisation or those who are severely symptomatic, while taking a LABA/LAMA or ICS/LABA may benefit from triple therapy, i.e. LABA/LAMA + ICS.^1,6 A beneficial response to an ICS may be expected to occur in patients with a blood eosinophil count > 0.1 x 10⁹/L and greater improvements are more likely as eosinophil numbers increase.^1,6 The potential benefit of triple therapy, however, needs to be balanced against the increased risk of pneumonia associated with long-term ICS use.¹

When to consider withdrawal of ICS treatment

In recent years it has become clearer when withdrawal of ICS should be considered, i.e. if the patient:¹

• Shows no evidence of benefit after eight to 12 weeks and does not have a history of exacerbations
• Develops pneumonia or another ICS-related adverse effect
• Is clinically stable and does not have a history of frequent exacerbations, i.e. less than two moderate exacerbations or one exacerbation requiring hospitalisation per year

Closely monitor symptom severity and exacerbation frequency following ICS withdrawal; review patients four to six weeks after stopping ICS to assess for worsening of symptoms.^1,5 There is an increased risk of exacerbations following ICS withdrawal in patients with a blood eosinophil count > 0.3 x 10⁹/L,¹ and ICS withdrawal may not be appropriate for these patients.

In summary: regular assessment is crucial to optimise treatment

Non-pharmacological interventions (especially smoking cessation and pulmonary rehabilitation) remain the most effective tools in the management of stable COPD. Inhaled medicines, however, provide an important additional level of symptom control; assess the patient’s adherence and inhaler technique at every consultation. The key recent changes concerning the use of inhaled medicines for patients with COPD include:

• LAMAs are recommended as the first-line long-acting bronchodilators, whereas previously LABAs were first-line with LAMAs
• Blood eosinophil levels are recommended to help predict which patients are most likely to benefit from ICS treatment
• Clearer guidance is now available for when withdrawal of ICS treatment may be beneficial

Any changes to the patient’s treatment should be accompanied by meaningful assessment, e.g. what is the effect on the patient’s COPD assessment test (CAT) score? Any improvements in symptoms should be expected within six weeks. Positive effects on exacerbation frequency require longer to become apparent, i.e. six to 12 months.

Further information on the selection and use of inhaler devices in COPD is available from the Goodfellow webinar: www.goodfellowunit.org