Juggling inhalers in COPD: Finding a way through the confusion

The Australian and New Zealand Guidelines for the Management of Chronic Obstructive Pulmonary Disease (COPD-X) describe 30 different inhalers recommended for treatment.1

Decisions about the choice, sequencing and combination of medication has become a challenge for physicians and GPs, but recent trials including AFFIRM,2 FLAME3 and WISDOM4,5 have provided additional guidance.

What do we know about treatment in the real world?

Little is known about how COPD is currently treated in Australia and whether or not guidelines such as COPD-X are implemented in everyday care.

For example, the most recent report on respiratory medication use from the Australian Institute of Health and Welfare covered the period from 2003 to 2013, pre-dating the introduction of several new medications, and it was unable to distinguish between inhalers used for COPD and those used for asthma.6

A review on guideline implementation, by COPD-X chair Professor Ian Yang and colleagues, noted that knowledge of clinical guidelines was low worldwide, for chronic diseases generally and specifically for COPD.7

For example, a study of 11,858 British patients who had COPD without asthma identified an inappropriate ‘inevitable drift’ to triple therapy with long-acting beta-agonist bronchodilators (LABA), long-acting muscarinic antagonists (LAMA) and inhaled corticosteroids (ICS).8

“Real-world prescription pathways leading to triple therapy…differ from the Global initiative for chronic Obstructive Lung Disease (GOLD)9 and National Institute for Health and Care Excellence10 treatment recommendations,” it said.

In the British study8 triple therapy was commenced in 19%, 28%, 37%, and 46% of patients classified as GOLD A, B, C, and D, respectively. Triple therapy was commenced within one year of diagnosis in a quarter of patients, irrespective of GOLD classification.

The most common pathway was to commence treatment on a LABA plus ICS then add a LAMA.

“Prescription pathways… highlight the common practice of prescribing ICS-containing regimens and overuse of triple therapy, particularly in low-risk patients,” the researchers said.8

“The results also highlight the relatively low prescribing of bronchodilators as first-line therapy. This reflects the persistent uncertainties of physicians in prescrib­ing the most appropriate therapy to patients with COPD, and emphasises that more efforts are required to improve education on and the implementation of COPD guidelines regarding COPD therapies.”8

Similar rates of triple therapy had been found in studies in Japan (21%), France (33%) and Greece (45%), they said.8

The Australian and New Zealand COPD-X guideline includes discussion of the British study in its most recent version (2.46), released in June 2016.

“This study highlights the importance of commencing bronchodilators as initial pharmacological therapy for patients with symptomatic COPD,” COPD-X states.1

What is the evidence base for treatment decisions?

A number of key clinical studies have helped to consolidate the evidence base for clinical decisions on COPD medication.

Most recently the AFFIRM study compared the LAMA/LABA combination of twice-daily aclidinium bromide/eformoterol fumarate via Genuair with the LABA/ICS combination of salmeterol/fluticasone propionate via Accuhaler in 933 patients with stable, moderate-to-severe COPD.2

Aclidinium/eformoterol was superior to salmeterol/fluticasone in the primary endpoint of change in peak FEV1 at week 24. The LAMA/LABA and LABA/ICS combinations resulted in similar, clinically relevant improvements in the Transition Dyspnoea Index focal score, COPD Assessment Test and St George’s Respiratory Questionnaire at week 24.

There were no significant differences between the two groups in the incidence of exacerbations. Pneumonia was reported in 0.6% of patients in the aclidinium/eformoterol group and 1.9% in the salmeterol/fluticasone group.

“These findings support the GOLD recommendations for LAMA/LABA use in patients with symptomatic COPD and demonstrate that aclidinium/eformoterol is an effective treatment for these patients,” the study concluded.

The FLAME study also compared LAMA/LABA and LABA/ICS combinations – once-daily glycopyrronium/indacaterol and twice-daily salmeterol/fluticasone – in 3,362 patients with COPD with a history of at least one exacerbation during the previous year.3

The LAMA/LABA was found to be superior to LABA/ICS, reducing the annual rate of all COPD exacerbations by 11% (3.59 vs 4.03, P=0.003). The effect was independent of the baseline blood eosinophil count. The incidence of pneumonia was 3.2% in the indacaterol/glycopyrronium group and 4.8% in the salmeterol/fluticasone group (P=0.02).

The WISDOM study found that in patients with severe COPD initially receiving triple therapy with the LAMA tiotropium, the LABA salmeterol and the ICS fluticasone propionate, the risk of moderate or severe exacerbations was similar among those who discontinued the ICS and those who continued it.4

There was, however, a greater decrease in lung function during the final stepwise reduction of a three-step regimen of glucocorticoid withdrawal.

Interactions between eosinophil levels and the impact of ICS therapy were explored in a post-hoc analysis of the WISDOM study.5

The post-hoc analysis revealed that higher blood eosinophil counts at baseline were associated with a greater risk of exacerbation after complete ICS withdrawal in patients with severe to very severe COPD (FEV1 <50%) and a history of exacerbations.

“Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds,” the analysis concluded. Only 19% of the WISDOM patients exceeded this threshold for high eosinophil levels.5

Clinical guidance

Professor Christine McDonald, Director of the Department of Respiratory and Sleep Medicine at Austin Hospital in Melbourne, is a member of the COPD-X Guidelines Committee. She told the limbic that, despite reliable estimates of the prevalence of COPD in Australia, there is a lack of formal studies on its current management.

“My impression is that confusion is common,” she says. “We see patients who have been trialled on many medications, and some are using treatments such as an ICS/LABA inhaler and a LAMA/LABA inhaler that should not be used together.

“Patients are more likely to have been treated with too much medication rather than too little.”

COPD-X provides clear advice and additional supporting material for specialists and GPs, as well as patients and their carers, available online at

It recommends a stepwise approach to the treatment of stable COPD, irrespective of disease severity, until adequate control has been achieved.

The guidelines emphasise the need to check device usage technique and adherence at each visit. They state that up to 90% of patients do not use devices correctly.1

The first step is the use of a short-acting beta-agonist or short-acting muscarinic antagonist bronchodilator, followed by the introduction of a LAMA or LABA when needed, the guidelines advise.

LAMAs and LABAs may help prevent exacerbations as well as providing symptomatic relief.1

They also state that ICS/LABA combination therapy should be used when FEV1 <50% predicted and the patient has experienced two or more exacerbations in the previous 12 months.1

“A high number of eosinophils is a potential marker of benefit from ICS, but I think we need more evidence of its utility,” Professor McDonald says.

“It’s very easy to get an eosinophil count, but eosinophils respond very rapidly to systemic steroid therapy so it can be difficult to interpret the results in patients who have been treated for exacerbations.”

Asthma-COPD overlap syndrome may be driving ICS use

‘Asthma-COPD overlap syndrome’ has attracted increasing interest in the past few years. “A suspected asthma component might be one factor driving the use of ICS,” Professor McDonald says.

“Classically, asthma has a variable course, and starts at a younger age, is often associated with a history of atopy and no or light smoking.

“COPD is usually progressive, has a later onset of symptoms and is associated with a moderately heavy smoking history. COPD-X includes a checklist to help in differentiating between the two conditions,” Professor McDonald says.

In some patients, however, it can be difficult to distinguish between asthma and COPD as the primary cause of a patient’s chronic airflow limitation. In addition, a significant number of patients with asthma are, or have, been smokers, increasing the risk that they may also have COPD.

Professor McDonald says that spirometry is still under-used as a diagnostic tool in COPD, especially in primary care but also in specialist practice.

“An MBS rebate review is under way, and this might increase the incentives for spirometry, which will help to accurately identify COPD patients and define the extent of reversible airflow limitation,” she says.

Pulmonary rehabilitation plays a key role

Professor McDonald strongly supports the central role of non-pharmacological interventions in COPD, including pulmonary rehabilitation.

“We have had evidence for many years that it is effective, leading to improved exercise capacity and quality of life, as well as fewer exacerbations,” she says. “But the rate of uptake is still very low.”

A study published very recently by Professor McDonald and colleagues compared 8 weeks of pulmonary rehabilitation by either the standard outpatient centre-based model, or a home-based model including one home visit and seven once-weekly telephone calls from a physiotherapist.11

The home-based program, delivered with minimal resources, produced short-term improvements in 6-minute walk distance that were equivalent to centre-based pulmonary rehabilitation.

“Other essential elements of care include support of smoking cessation, influenza and pneumococcal vaccinations, encouragement of physical activity, and attention to comorbidities,” Professor McDonald says.

“We are making progress in COPD management. Patients using newer medications are achieving improvements of several hundred mL in their lung function, based on accurate diagnosis, appropriate medication use and a comprehensive approach to care.

“The challenge in the future is to prevent progression of the disease and reduce its mortality.”


  1. Lung Foundation Australia. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease, Version 2.46, June 2016.
  2. Vogelmeier C et al. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J 2016; 48: 1030-1039.
  3. Wedzicha JA et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med 2016; 374: 2222-34.
  4. Magnussen H et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371: 1285-94.
  5. Watz H et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 2016; 4: 390-8.
  6. AIHW: Correll PK, Poulos LM, Ampon R, Reddel HK & Marks GB 2015. Respiratory medication use in Australia 2003–2013: treatment of asthma and COPD. Cat. no. ACM 31. Canberra: AIHW.
  7. Overington JD et al. Implementing clinical guidelines for chronic obstructive pulmonary disease: barriers and solutions. J Thorac Dis 2014; 6: 1586-96.
  8. Brusselle G et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis 2015; 10: 2207-17.
  9. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from: Accessed 9 November 2016.
  10. National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: Diagnosis and management. Available from Accessed 9 November 2016.
  11. Holland AE et al. Home-based rehabilitation for COPD using minimal resources: a randomised, controlled equivalence trial. Thorax 2016 Sep 26. pii: thoraxjnl-2016-208514. doi: 10.1136/thoraxjnl-2016-208514. [Epub ahead of print]

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