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The editorial content below has been developed solely between Guidelines in Practice and the expert author.

sapey

Guest Editor—Dr Elizabeth Sapey

Honorary Respiratory Consultant, Queen Elizabeth Hospital, Birmingham
Senior Lecturer in Respiratory Medicine, University of Birmingham

‘We have never had so many choices to help patients with COPD, and sometimes, choosing the right type of medication can be confusing. This articles aims to provide simple steps to help you to decide what kind of medication to prescribe, depending on your patient’s main concerns or presenting symptoms.’

Introduction

Treatment aims for chronic obstructive pulmonary disease (COPD) are to reduce:1

  • symptoms—relieve symptoms, improve exercise tolerance, and improve health status
  • risk—prevent and treat exacerbations, prevent disease progression, and reduce mortality.

In the UK, the diagnosis and management of COPD is guided by NICE, however, the most recent NICE Clinical Guideline (CG) on COPD, Chronic obstructive pulmonary disease in over 16s: diagnosis and management (CG101) was published in 2010,2 before some of the newer combinations of inhalers became licensed in the UK. An updated version is expected to be published in late 2018.

Breathlessness

Breathlessness is the most common and often the most debilitating symptom experienced by patients with COPD.3,4 Airflow obstruction prevents effective emptying of the lungs, causing air trapping. This sensation can be worse with exercise, leading to reduced physical activity, deconditioning, and reduced quality of life.5,6

Consider the case studies below; the main problem experienced by both Pamela and William is breathlessness—they do not have frequent chest infections or exacerbations of COPD.

Pamela’s COPD is of moderate severity, and William’s is severe, based on their forced expiratory volume in 1 second (FEV1).1,2

Case study: Pamela

Age:  53 years old

Occupation: works in a restaurant

Smoking status: former smoker, 21 pack-year history

Post-bronchodilator spirometry:

  • FEV1/FVC ratio: 61%
  • FEV1: 66% predicted—moderate severity

Symptoms:

  • increasing breathlessness on exertion over the last 3 years with reducing exercise capacity
  • no significant history of chest infections
  • CAT score—11

Co-morbidities/medications:  none.

FEV1 =forced expiratory volume in 1 second; FVC=forced vital capacity; CAT=COPD assessment test

Case study: William

Age:  65 years old

Occupation:  works in an office

Smoking status:  former smoker, 35 pack-year history

Post-bronchodilator spirometry:

  • FEV1/FVC ratio: 47%
  • FEV1: 41% predicted—severe

Symptoms:

  • initially, shortness of breath with every activity
  • steadily worsening breathlessness over 2 years
  • contemplating retirement as finding it difficult to commute
  • CAT score—22
  • only 1 exacerbation/chest infection in the previous year

Co-morbidities/medications:

  • hypertension, hypercholesterolaemia, osteoarthritis
  • ACE inhibitor, diuretic, statin.

FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; CAT=COPD assessment test; ACE=angiotensin converting enzyme

Bronchodilation

Symptoms of breathlessness, caused by airflow obstruction or air trapping, and health-related quality of life can be improved by bronchodilation.7 The most symptomatic improvement is seen in those who achieve maximal bronchodilation, in other words, the better the improvement in FEV1, the better the symptom control.8

Short-acting vs long-acting bronchodilators

In my experience, if symptoms are present every day a short-acting bronchodilator is unlikely to provide sufficient control, and so in both Pamela and William’s cases I would suggest starting therapy with a long-acting bronchodilator (see Box 1), with a short-acting bronchodilator as needed.

Single agent vs combination therapy

To date, there are no studies on when to start a monotherapy versus a combined LABA/LAMA inhaler in COPD.9–11

Box 1: Long-acting bronchodilators

LAMAs and LABAs

There are a wealth of data showing the benefits of long-acting beta2 -agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) in COPD, and their use is recommended both by NICE and the Global Initiative for Chronic Obstructive Lung Disease (GOLD).1,2 Head-to-head studies comparing a single LAMA with a single LABA suggest that LAMAs may be more effective at reducing symptoms of breathlessness, but both improve FEV1 and health-related quality of life.1,12,13

Using a LABA and a LAMA together: combination therapy

There is a clear rationale for using LABAs and LAMAs together as both work in different but complimentary ways; LAMAs block M3 receptors in the lungs, preventing the contraction of airway smooth muscle, while LABAs increase levels of cyclic adenosine monophosphate (cAMP) causing smooth muscle relaxation.14

Symptom control

Working together but by different mechanisms, LABA/LAMA combination inhalers lead to greater improvements in lung function, symptom control, and exercise capacity than either a LABA or a LAMA given singly.15–17

Generally well tolerated

LAMAs and LABAs are generally well tolerated by patients, with no increase in side effects when used in combination compared with when used separately.1,16

GOLD strategy

The most recent GOLD strategy (GOLD 2017) advises that combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared with increasing the dose of a single bronchodilator.1

Pamela

I have suggested (Figure 1) a single agent bronchodilator for Pamela (probably a LAMA) because her lung disease is of moderate severity, her COPD Assessment Tool (CAT) score is 11, and a single agent may be sufficient to control her symptoms. There is no evidence that starting a combined LAMA/LABA inhaler protects lung health in the long term, and unnecessary polypharmacy should be avoided.1,11

Potential indicators for stepping Pamela’s therapy up to a dual LABA/LAMA combination include insufficient symptomatic response, a sustained and increased requirement for rescue medication, the occurrence of exacerbations, and reductions in lung function.11

The choice of starting therapy with a LAMA or a LABA depends on patient choice and the potential side effects, while the choice of medication may depend on the device (e.g. once or twice daily delivery) and specific considerations such as the presence of renal disease.1

pamela algo v2

William

For William, (Figure 2) I have suggested starting a combination LABA/LAMA inhaler straight away, as his lung disease and symptom burden is more severe, but starting therapy with a single agent and stepping up if needed would also be appropriate.1

william algo v2

Review

Different drugs take different times to reach their maximal effect and this should be discussed with patients so that they know what to expect. For example, tiotropium requires 14 to 21 days to reach its maximal effect, while aclidinium achieves this in 2 days, but, there may be no difference in overall response to the drugs after 3 weeks.18

I have suggested reviewing the patient again after 1 month, to take this into account.

What to do if symptoms are still poorly controlled

The first thing to do if symptoms are still poorly controlled is to check the basics—see Box 1, and the diagnosis, however, a proportion of patients will remain poorly controlled. If this is the case, consider:

  • inhaled corticosteroids—a recent study found improvements in breathlessness with ICS/LAMA/LABA in one inhaler (triple combination therapy) compared with a LAMA alone,19 however given the potential side effects of ICS and their over-use in COPD,20 it may be appropriate to refer to secondary care
  • theophyllines—used in COPD with some evidence of benefit,21 but their efficacy in patients already on LABA/LAMA therapy is unknown; secondary care may help with this decision
  • lung volume reduction surgery and endobronchial valves for patients with severe emphysema1—a referral to secondary care can assess the potential for these treatments
  • consider co-morbidites—this topic will be discussed later in the email series.

Learning points

  1. The most common presenting symptom for patients with COPD is breathlessness
  2. Breathlessness is caused by airflow obstruction and air-trapping in the lungs
  3. Bronchodilation using a LAMA, LABA, or both will improve symptoms of breathlessness, FEV1, and health related quality of life in most patients
  4. Combination LAMA/LABA inhalers are associated with greater improvements in breathlessness than a single LAMA and LABA
  5. The role of ICS in treating patients with breathlessness already taking a LAMA/LABA is less clear.

References

  1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2017. Available at: goldcopd.org
  2. NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NICE Clinical Guideline 101. NICE, 2010. Available at: www.nice.org.uk/guidance/cg101
  3. Jones P, Brusselle G, Dal Negro R, et al. Health-related quality of life in patients by COPD severity within primary care in Europe. Respir Med 2011; 105 (1): 57–66.
  4. Kessler R, Partridge M, Miravitlles M, et al. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J 2011; 37: 264–272.
  5. Corhay J, Dang D, Van Cauwenberge H, Louis R. Pulmonary rehabilitation and COPD: providing patients a good environment for optimizing therapy. Int J Chron Obstruct Pulmon Dis 2014; 9: 27–39.
  6. Lavorini F, Magnan A, Dubus J, et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med 2008; 102 (4): 593–604.
  7. O’Donnell D, Casaburi R, Frith P, et al. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD. Eur Respir J 2017; 49: 1601348.
  8. Jones P, Donohue J, Nedelman J, et al. Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respir Res 2011; 12: 161.
  9. Rodrigo G, Anzueto A, Singh D, et al. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2017; 12: 907–922.
  10. Cazzola M, Page C. Long-acting bronchodilators in COPD: where are we now and where are we going? Breathe 2014; 10 (2): 110–120. 
  11. Thomas M, Halpin D, Miravitlles M. When is dual bronchodilation indicated in COPD? Int J Chron Obstruct Pulmon Dis 2017; 12: 2291–2305.
  12. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364 (12): 1093–1103.
  13. Decramer M, Chapman K, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med 2013; 1: 524–533.
  14. Tashkin D, Fabbri L. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149.
  15. Bateman E, Chapman K, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respiratory Research 2015; 16: 92. 
  16. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-componenets in COPD (GOLD 2–4). Eur Respir J 2015; 45; 969–979.
  17. Calzetta L, Rogliani P, Ora J, et al. LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment. Eur Respir Rev 26: 160043.
  18. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012; 141 (3): 745–752.
  19. Vestbo J, Papi A, Corradi, M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389: 1919–1929.
  20. White P, Thornton H, Pinnock H, et al. Overtreatment of COPD with inhaled corticosteroids—implications for safety and costs: cross-sectional observational study. PLoS One 2013; 8 (10): e75221.
  21. Kirsten D, Wegner R, Jörres R, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104 (4): 1101–1107.