An increasing range of therapeutic options can be considered alongside non-pharmacological strategies for people diagnosed with COPD, says Professor Dave Singh
- Make the diagnosis of COPD based on symptoms and history of exposure and spirometry
- Important non-pharmacological aspects of management include smoking cessation and increasing activity levels, e.g. pulmonary rehabilitation
- There is an increasing choice of LAMAs with apparently similar efficacy; cost and inhaler device characteristics should be considered when making prescribing decisions
- LABA/LAMA combination inhalers are an effective new option for patients with significant symptoms despite long-acting bronchodilator monotherapy
- Only use ICS/LABA combinations in patients with frequent exacerbations
- Regular review is essential to monitor disease progression, including the development of co-morbidities
- Consider the co-diagnosis of bronchiectasis in patients with suggestive symptoms.
Chronic obstructive pulmonary disease (COPD) is a common condition and cigarette smoking is the main risk factor in the majority of cases. Approximately 3 million people in the UK have COPD,1 and it is a leading cause of death worldwide.2
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) published a management strategy document in 2011, which comprised a set of recommendations for management of COPD based on a comprehensive review of current scientific evidence. GOLD has subsequently updated this document to incorporate new evidence, with the latest update published in 2014.3 Other guidance relevant to the UK was published by NICE in 2010: Clinical Guideline (CG) 101 Chronic obstructive pulmonary disease is scheduled for review in June 2016.
Prior to publication of the GOLD strategy document in 2011, the severity of COPD was graded using only the severity of airflow limitation measured by the forced expiratory volume in 1 second (FEV1).1,3 The 2011 advice from GOLD recommended a multidimensional assessment of COPD, to encompass the level of symptoms, risk of future exacerbations, and the presence of co-morbidities in addition to the severity of airflow obstruction.3 This article will explain the important aspects of the 2011 strategy document, focusing mainly on diagnosis, assessment, and the management of patients with stable COPD, as these are key areas for COPD management in primary care. The 2014 updates that are most relevant to clinical practice will also be considered, with a particular focus on inhaled pharmacotherapy as this is a rapidly changing field with the recent introduction of a number of new medicines.
The diagnosis of COPD requires three criteria to be met:
- history of exposure to risk factors
- typical symptoms
- the presence of airflow obstruction on post-bronchodilator spirometry.
How to make a diagnosis of COPD is explained in Figure 1. A common mistake in clinical practice is to make a diagnosis of COPD based on only one or two of these criteria. Importantly, older patients with airflow obstruction and symptoms should not be diagnosed with COPD unless they also have a history of exposure to risk factors. Good quality spirometry is essential, otherwise interpretation of the results can become difficult; for example, the forced vital capacity (FVC) needs to be properly completed, otherwise a low FVC causes the FEV1/FVC ratio to be misleadingly high. The results of bronchodilator reversibility should not be considered when making the diagnosis; both asthma and COPD patients can show reversibility, and a positive result does not favour the diagnosis of either condition.
The multidimensional assessment of COPD includes symptom assessment. The modified British Medical Research Council (mMRC) Questionnaire is a short and easy way to quantify the degree of breathlessness.4 Alternatives are the COPD Assessment Test (CAT)5 and the Clinical COPD Questionnaire (CCQ),6 which again are short and easy to complete, but provide more comprehensive assessments of health status. Any of these tools may be used.
An exacerbation is defined as an acute worsening of symptoms beyond the normal day-to-day variation.7 The frequency of exacerbations varies between patients, and a history of previous exacerbations predicts the probability of future events.8 Patients who have frequent exacerbations have a worse prognosis.9 A 'frequent exacerbator' is defined by GOLD as a patient who has experienced two exacerbations requiring oral corticosteroids and/or antibiotics, or one hospitalisation in the past year. Assessment of COPD is completed by considering the presence of co-morbidities, such as cardiovascular disease.3
The combined COPD assessment uses spirometry, symptoms, and exacerbation risk to categorise patients into groups A, B, C, or D, for the purpose of individualising treatment decisions (see Figure 2). Patients with more symptoms (mMRC ≥2 or CAT ≥10) are categorised as group B or D. Patients with greater future risk (of exacerbations, hospitalisation, or death) are those with FEV1 <50% predicted, or those with frequent exacerbations, and are classified as group C or D.3 There is often a different risk categorisation when evaluating exacerbation history and FEV1, as one of these may predict low risk while the other predicts high risk; in these cases, the patient should still be categorised as high risk.
The pharmacological management of COPD focuses on alleviating symptoms, improving health status and exercise tolerance, and preventing exacerbations. The majority of drugs for COPD are delivered by inhalation, in order to maximise therapeutic benefits while minimising side-effects. There is a wide range of inhaler devices available to patients, and it is important to consider ease of use and cost when deciding which drug to prescribe.
Beta-agonists and anti-muscarinics are bronchodilators that act through different mechanisms.10 Short-acting bronchodilators can be prescribed on an 'as required' basis for rapid symptom relief, while long-acting bronchodilators such as formoterol, salmeterol, tiotropium, and indacaterol are administered on a regular basis. These drugs improve lung function, symptoms, and exercise performance, and reduce exacerbation rates.11-14
While bronchodilator therapy is suitable for all patients with COPD, the use of inhaled corticosteroids (ICS) should be restricted to patients with a history of exacerbations, as these drugs improve lung function and health status and reduce exacerbation rates in this subset of patients.11,15Combination ICS/longacting beta agonist (LABA) inhalers are licensed in the UK for the treatment of patients with COPD who have a history of exacerbations. Theophylline provides a modest degree of bronchodilation and symptom benefit, but is associated with a high rate of side-effects. It is not recommended for use in countries where long-acting bronchodilators are available.3 Long-term, regular use of antibiotics is not recommended for the treatment of COPD. Mucolytics may provide some benefit in patients with very viscous sputum.3 Roflumilast is an anti-inflammatory drug that acts through phosphodiesterase-4 inhibition; it reduces exacerbation rates by 15% - 20% and provides modest improvements in pulmonary function. However, mild side-effects including weight loss and nausea may occur.3 Roflumilast is not recommended by NICE, and is rarely used in the UK. Other recommended pharmacological treatments for COPD include influenza and pneumococcal vaccination.3
2014 updates on pharmacotherapy
Tiotropium is a once-daily, long-acting muscarinic antagonist (LAMA) that has been successfully used for many years to treat COPD.13,14 There are now alternative LAMAs available: glyopyrronium (administered once daily using a single dose dry-powder inhaler) and aclidinium (administered twice a day using a multidose dry-powder inhaler); the key characteristics of the currently available LAMAs are shown in Table 1. These new LAMAs have similar effects on lung function and breathlessness to tiotropium.16,17 Decisions regarding which LAMA to prescribe will be based on the ease of inhaler device use, cost, and preference for once or twice a day dosing. Although aclidinium has lower systemic exposure compared with other LAMAs, the overall side-effect rate of these drugs is low and concerns about the safety of tiotropium delivered by the Respimat inhaler were reduced by the TIOSPIR study, which showed no difference in mortality or exacerbations comparing tiotropium delivered via Respimat and dry powder inhaler.18
There are an increasing number of publications concerning the benefits of combination inhalers containing a LABA and LAMA compared with longacting bronchodilator monotherapy.10 The GOLD 2014 update states that LABA/LAMA combination inhalers significantly improve lung function compared with monotherapy, although the benefits to patient-reported outcomes such as breathlessness have been limited.3 Publications regarding the once-a-day combination of indacaterol and glycopyrronium QVA149 were reviewed,3 but there have subsequently been more publications with this drug and the once-daily combination of the LABA vilanterol with the LAMA umeclidinium. The evidence base in this area is rapidly changing, with results showing a common pattern of large improvements in lung function with LABA/LAMA combinations compared with monotherapy, coupled with greater improvements in symptoms measured by questionnaires and significantly lower reliever medication use; overall, this indicates clinically relevant symptomatic benefits for LABA/ LAMA combinations compared with monotherapy.
The GOLD 2014 update considers that there is too little evidence to determine whether LABA/LAMA combination treatments reduce exacerbations more than LAMA alone,3 as there is only one study published in this area.19
Other therapeutic interventions
Smoking cessation interventions remain an important part of COPD management, as success can alter the natural history of the disease. The use of pharmacotherapies for smoking cessation should be as part of a structured programme that includes support such as counselling.
Pulmonary rehabilitation is an extremely effective non-pharmacological intervention, and the benefits include an increase in exercise performance, a reduction in symptoms, and increased confidence. Pulmonary rehabilitation programmes often vary in content, but usually include exercise training, smoking cessation advice, and education. The success of pulmonary rehabilitation often depends on the motivation and functional ability of the patient, as patients with very severe disease or comorbidities often cannot complete the programme. Well-motivated patients with less severe disease often experience the most benefits. The GOLD 2014 update states that the benefits of pulmonary rehabilitation in terms of exercise capacity may not translate into increased patient activity on a daily basis,3 highlighting the complexity of psychological and social factors that impact on activity levels. Long-term oxygen therapy is indicated for patients who meet criteria based on resting levels of blood oxygen. Noninvasive ventilatory support can be considered for more severe patients with hypoxia and hypercapnia. Lung volume reduction by surgery or bronchoscopy may benefit selected patients who have emphysema.3
|Drug||Type of inhaler||Dose (μg)||Duration of action|
|Aclidinium bromide||DPI||322||12 hours|
|Glycopyrronium bromide||DPI||44||24 hours|
Management of stable COPD
The management of stable COPD includes reducing exposure to risk factors such as smoking, encouraging physical activity, providing pulmonary rehabilitation for appropriate patients, and vaccination. Regular follow up is required to monitor lung function, symptoms, exacerbation history, and the possible development of co-morbidities. The use of inhaled medicines should be tailored towards the patient's symptoms and exacerbation history. This personalised approach uses the A, B, C, or D categorisation to guide the choice of treatment (see Figure 2).
Treatment of infrequent exacerbators
Patients categorised as A or B do not suffer with frequent exacerbations and so do not require corticosteroid therapy; these patients require short- and longacting bronchodilators, according to the level of symptoms. The new combination LABA/LAMA inhalers are a treatment option for GOLD B patients, offering potential cost savings compared with using separate LABA and LAMA inhalers, in addition to a simplified treatment regimen.
Patients with COPD who are not frequent exacerbators include GOLD A and B, and also the GOLD C and D patients who have FEV1 <50% but are not frequent exacerbators. For all of these COPD patients who are not frequent exacerbators, a possible treatment algorithm is shown in Figure 3.
Treatment of frequent exacerbators
Patients with COPD may initially present as frequent exacerbators, or become frequent exacerbators during the natural history of the disease. Those who are frequent exacerbators at initial presentation can be treated firstly with a long-acting bronchodilator to prevent future events. There is good evidence to support the use of LAMAs to reduce exacerbation rates.13,14
For patients who become frequent exacerbators despite treatment with a long-acting bronchodilator, ICS/LABA combination therapy is an option. The long-term side-effects of ICS include osteoporosis, diabetes, and cataracts, and there is evidence that some COPD patients treated with ICS develop pneumonia.11 It is important that ICS/ LABA combination treatments are used only in GOLD C and D patients with a history of exacerbations, where the benefits of these drugs outweigh the potential risks. The different pharmacological options for the prevention of exacerbations in frequent exacerbators are shown in Figure 4. There is less evidence currently for the efficacy of LABA/LAMA combination inhalers in this COPD phenotype.10,19 Nevertheless, a practical approach to the treatment of frequent exacerbators could be to use either LAMA/LAMA or ICS/LABA for patients who are frequent exacerbators despite LAMA monotherapy. Those patients who subsequently still require additional therapy could then step up to 'triple therapy', comprising ICS/LABA plus LAMA.
Management of COPD exacerbations
Common co-morbidities in COPD include cardiovascular disease, osteoporosis, depression, and lung cancer. These may arise independently of COPD, or be related to COPD. Regardless of the relationship to COPD, the treatment should be the same as for patients without COPD.
The GOLD 2014 update includes more information on the management of cases where bronchiectasis and COPD co-exist. For patients with a primary diagnosis of COPD, it is becoming apparent that some also have a degree of bronchiectasis. This should be suspected in patients with frequent exacerbations, a productive cough, and persistent bacterial growth on sputum culture. The diagnosis can be confirmed by high resolution CT scanning. Such patients may benefit from more aggressive antibiotic treatment.3
The recent introduction of new inhaled medicines for the treatment of COPD offers more choices for patients and prescribers. In particular, LABA/ LAMA combination inhalers provide a logical and effective new treatment option.10 These new medicines need to be used as part of a treatment pathway that considers clinical benefit, potential side-effects, inhaler device characteristics, and cost. There are many patients with COPD in the UK treated with triple therapy (ICS/LABA plus LAMA), who are not, and have never been, frequent exacerbators; the cost of such treatment is high, and there are potential long-term adverse effects of ICS use.
The updated advice from GOLD recommends an individualised approach to pharmacotherapy, based on the classification system shown in Figure 2. A simplified approach for doctors treating COPD patients could be to identify frequent and infrequent exacerbators, and then to follow the treatment algorithms set out in Figure 3 (for infrequent exacerbators) and Figure 4 (for frequent exacerbators). This individualised approach can be used to ensure personalised treatment tailored towards disease characteristics, while also ensuring that drug costs do not spiral through the inappropriate use of triple therapy.
Written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
- Diagnosis of COPD now requires a reduced post-bronchodilator spirometry combined with typical symptoms AND a history of exposure to risk factors; this may mean that, historically, many patients have been over-diagnosed with COPD:
- GPs could be encouraged to review the diagnosis against these standards, through annual COPD checks
- GOLD recommends that only people who are frequent exacerbators should be given inhaled corticosteroids, yet many patients with FEV1< 50% predicted may be on these drugs without having a history of exacerbations
- Combination ICS/LABA drugs are expensive and so review of patients on these drugs to check that they are exacerbators could help save prescribing costs and ensure that patients are on the correct treatments
- Clinical commissioning groups should:
- review local formularies to identify the indications for LABAs and LAMAs and combination LABA/LAMA inhalers in the various categories of COPD, and display these as treatment pathways based on GOLD guidance
- ensure they commission effective pulmonary rehabilitation services for patients with COPD
- It is likely that a local education programme for GPs and practice nurses to share the formulary choices and updated GOLD guidance will help deliver better patient outcomes.
- NICE. Chronic obstructive pulmonary disease. Clinical Guideline 101. NICE, 2010. Available at: www.nice.org.uk/guidance/CG101
- Mathers C, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3 (11): e442. doi:10. 1371/journal.pmed.0030442
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2014. Available at: www.goldcopd.org/guidelines-global-strategy-for-diagnosismanagement.html
- Bestall J, Paul E, Garrod R et al. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 581–586.
- GlaxoSmithKline. COPD assessment test. Available at: catestonline.org
- van der Molen T. Clinical COPD Questionnaire. 1999. Available at: ccq.nl (accessed 25 November 2014).
- Burge S, Wedzicha J. COPD exacerbations: definitions and classifications. Eur Respir J 2003; 21: (Suppl. 41): 46s–53s.
- Hurst J, Vestbo J, Anzueto A et al for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 363: 1128–1138.
- Soler-Cataluña J, Martínez-Garcia M, Román Sánchez P et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60: 925–931.
- Singh D. New combination bronchodilators for COPD: current evidence and future perspectives. Br J Clin Pharmacol 2014 Nov 6. doi: 10.1111/ bcp.12545. [Epub ahead of print]
- Calverley P, Anderson J, Celli B et al for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356 (8): 775–789.
- Tashkin D, Fabbri L. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149–162.
- Tashkin D, Celli B, Senn S et al for the UPLIFT study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359 (15): 1543–1554.
- Vogelmeier C, Hederer B, Glaab T et al for the POET-COPD investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364 (12): 1093–1103.
- Calverley P, Pauwels R, Vestbo J et al; TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361 (9356): 449–456.
- Jones P, Singh D, Bateman E et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012; 40 (4): 830–836.
- Kerwin E, Hébert J, Gallagher N et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J 2012; 40 (5): 1106–1114.
- Wise R, Anzueto A, Cotton D et al for the TIOSPIR Investigators. Tiotripium Respimat Inhaler and the risk of death in COPD. N Engl J Med 2013; 369 (16): 1491–1501.
- Wedzicha J, Decramer M, Ficker J et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, doubleblind, parallel-group study. Lancet Respir Med 2013; 1 (3): 199–209