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National Medicines Information Centre VOLUME 19 NUMBER 4 2013 ST. JAMES’S HOSPITAL • DUBLIN 8 TEL 01-4730589 or 1850-727-727 • FAX 01-4730596 • www.nmic.ie CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death worldwide The assessment of COPD should include the degree of airflow limitation, the severity of symptoms and the risk of future exacerbations Smoking cessation is the intervention which has the greatest capacity to influence the natural progression of COPD Pharmacological treatment should be individualised to the patient and regularly reviewed for effectiveness and technique INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a preventable and treatable condition, which is characterised by chronic slowly progressive airway obstruction.1-3 COPD is now the preferred term for patients with airflow obstruction who were previously diagnosed with chronic bronchitis or emphysema.4 It is a major cause of morbidity and the 4th leading cause of death worldwide; it is expected to be the 3rd leading cause of death by 2020.1,5 It is considered that there is widespread under-recognition and under-diagnosis of COPD.1,6 Studies in Europe estimate the prevalence of COPD to be approximately 10%, however it varies considerably between European countries.6 Ireland has the highest rate of admissions for exacerbations of COPD in the Organisation for Economic Co-operation and Development (OECD) countries.7 COPD is more common in older people; European studies in people aged >70 years showed a prevalence of COPD of 20% in men and 15% in women.6 COPD is associated with a significant economic burden in terms of the direct medical costs associated with it and the care provided by family members to patients with COPD.1,5,6 The Global Initiative for Chronic Obstructive Lung Disease (GOLD), which was established to increase the awareness of the burden of COPD and to improve prevention and management, published updated guidelines for the management of COPD in 2013.1 Guidelines have also been published by other groups including the National Institute for Health and Care Excellence (NICE).4 This bulletin will provide an update on the management of COPD. PATHOPHYSIOLOGY Inhaled cigarette smoke and other noxious particles cause an inflammatory response which induces parenchymal tissue destruction and narrowing of the peripheral airways leading to progressive airflow obstruction.1,4 Significant airflow obstruction may be present before the patient is aware of it.4 In affected individuals lung function deteriorates progressively over several years, with increasing symptoms such as cough, sputum production and dyspnoea.8 Exacerbations of COPD, defined as increased cough, dyspnoea or sputum production, are triggered by factors including infection (bacterial and/or viral) and environmental pollutants. Frequent exacerbations are associated with a more rapid decline in lung function.8 Pulmonary hypertension may develop late in the course of COPD due to hypoxic constriction of small pulmonary arteries; this may progress to right ventricular hypertrophy and cor pulmonale. Many patients with COPD have co-morbidities that have a major impact on quality of life and survival, such as ischaemic heart disease, heart failure, osteoporosis and depression.1,8 The prevalence of COPD is directly related to the prevalence of cigarette smoking and the result of cumulative exposure over decades, however, not all people with the same smoking history will develop COPD.1 Other risk factors for COPD include older age, occupational exposure to noxious particles, passive exposure to cigarette smoke, early childhood lung infections and alpha-1 antitrypsin deficiency. DIAGNOSIS and ASSESSMENT Diagnosis: A clinical diagnosis of COPD should be considered in any patient > 35 years with risk factors for COPD, and symptoms that include dyspnoea, chronic cough or sputum production.1,4 The diagnosis of COPD is based on a combination of history and physical examination with confirmation of the diagnosis using spirometry.1,4 Spirometry measures the volume of air forcibly exhaled from the point of maximal inspiration (FVC - forced vital capacity) and the volume of air exhaled during the 1st second of this manoeuvre (FEV1 - forced expiratory volume in one second); the ratio of these two measurements (FEV1/FVC) is calculated. The presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation of COPD.1,4 In addition to spirometry, patients require a chest x-ray to exclude other conditions such as lung cancer and tuberculosis.4 Additional investigations may include serial peak flow measurements (to exclude asthma, which is frequently indistinguishable from COPD), ECG and echocardiography (to assess cardiac status if there are clinical features of cor pulmonale) and alpha-1 antitrypsin deficiency (if early onset, minimal smoking history or positive family history).4 Assessment of a patient with COPD is based on the severity of airflow limitation, the severity of symptoms and the patient’s risk of future exacerbations.1,4,9 The patient’s risk of exacerbations is assessed by spirometry to determine the GOLD classification of airflow limitation (table 1) and by assessing the number of exacerbations in the previous 12 months. The risk of exacerbation increases in patients with a history of frequent exacerbations (≥2 per year) and worsening airflow limitation.1 There are several validated questionnaires which are used to assess patients’ symptoms in COPD, including the COPD Assessment Test (CAT) (range 0-40) available on http://catestonline.org and the modified Medical Research Council (mMRC) questionnaire (range 0-4).1,10 GOLD classifies patients with COPD into different groups (A-D) depending on their level of future exacerbation risk and symptoms as shown in table 2. This classification guides the management of COPD (see later section). Table 1: Classification of severity of airflow Table 2: Assessment of patients with COPD1 limitation in COPD according to GOLD1 Patient Exacerbations Spirometric GOLD 1 GOLD 2 GOLD 3 GOLD 4 In patients with FEV1/FVC < 0.70 Mild FEV1 ≥80% predicted Moderate 50% ≤ FEV1 < 80% predicted Severe 30% ≤ FEV1 < 50% predicted Very severe FEV1 < 30% predicted GOLD - Global Initiative for Chronic Obstructive Lung Disease, FEV1/FVC - forced expiratory volume in one second/ forced vital capacity Category A B C D Characteristics Low Risk, Less Symptoms Low Risk, More Symptoms High Risk, Less Symptoms High Risk, More Symptoms Classification GOLD 1-2 GOLD 1-2 GOLD 3-4 GOLD 3-4 GOLD - Global Initiative for Chronic Obstructive Lung Disease ≤1 ≤1 ≥2 ≥2 per year MANAGEMENT The main goals in the management of COPD are to improve the patient’s health by: (1) reducing symptoms, (2) reducing the rate of lung function decline, (3) preventing exacerbations and (4) reducing mortality.1,8 A multidisciplinary approach involving non-pharmacological and pharmacological treatment is recommended for the optimal management of a patient with COPD.4 The National COPD programme is working towards establishing an improved national model of care with combined hospital and community based initiatives such as COPD outreach and pulmonary rehabilitation programmes.2 Patients with COPD frequently have other co-morbidities (such as cardiovascular disease, osteoporosis, depression and lung cancer) associated with either smoking or ageing, which should also be managed.1 Non-pharmacological treatment Smoking cessation is the intervention which has the greatest capacity to influence the natural history of COPD and is the key intervention for people who continue to smoke.1,4,8,11 The delivery of smoking cessation messages and interventions to stop smoking can result in 25% long-term quit rates; they should be offered to all smokers visiting a health care professional, even if the visit is unrelated to COPD.1 Pharmacotherapeutic agents should be offered to aid smoking cessation – see below. Patient education is an essential aspect of COPD management. Patients should have a self management plan with advice on how to prevent exacerbations and actions in the event of one occurring.1,4 Physical activity is recommended for all patients with COPD.1 The Irish Thoracic Society has a useful website for patients and healthcare professionals, “Living with COPD” (http://www.livingwithcopd.ie/),12 which can also be accessed from the COPD Support Ireland website (www.COPD.ie).13 Pulmonary rehabilitation programmes have been shown to have a number of benefits in patients with COPD, including reduced dyspnoea, improved exercise capacity, improved health related quality of life (HRQoL), reduced number and duration of hospitalisations and improved survival.1,4,9,14,15 A number of pulmonary rehabilitation programmes have been set up nationally.2,16 Long-term administration of oxygen therapy (LTOT) (> 15 hours per day) in patients with chronic respiratory failure has been shown to increase survival in patients with severe resting hypoxaemia.1,8 LTOT is indicated for patients who have a PaO2 ≤7.3 kPa or a PaO2 of 7.3-8.0 kPa with evidence of pulmonary hypertension, peripheral oedema with congestive cardiac failure or polycythaemia, when assessed on two separate occasions.1,4,8 Patients commenced on LTOT should be reviewed at least yearly to monitor compliance, education and prescription needs. Non-invasive positive pressure ventilation (NIV) is increasingly being used in patients with stable very severe COPD, who may have required assisted ventilation during an exacerbation.1 It may be useful in a subset of patients in combination with LTOT. It has been associated with improved survival but not improved HRQoL.1 Pharmacological Management None of the existing pharmacological agents has been shown to modify the long-term decline in lung function associated with COPD, however appropriate therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations and improve health status and exercise tolerance.1 Tables 3 and 4 outline the most commonly used medicines in the management of COPD. Inhaled therapy whenever possible is the preferred route in stable COPD.1 Table 3: Currently authorised inhaled medications for COPD Inhaler device types and dosage (microgram) Short-acting beta2 agonists (SABA)17-19 Salbutamol **, ***, **** MDI (100, 200) DPI (100, 200) Terbutaline DPI (500) 2.73-2.96 4.15-8.24 5.83 4-6 Tachycardia, tremor, headache 4-6 Long-acting beta2 agonists (LABA)20-23 Formoterol DPI (4.5 – 12) Tachycardia, tremor, headache, palpitations, muscle spasms, hypokalaemia 18.67-23.44 12 Salmeterol DPI (50) 26.63 12 Indacaterol DPI (150-300) 30.72-33.32 24 Short-acting muscarinic antagonists (SAMA)24 Ipratropium bromide *** MDI (20) Caution in patients with cardiovascular disease. Risk of QT prolongation. Palpitations, headache, tremor Caution in patients with cardiovascular disease. Risk of drug interaction with potent CYP3A4 inhibitors. Headache, tremor, palpitations, muscle cramps Caution in patients with cardiovascular disease. Upper respiratory tract infection, nasopharyngitis, sinusitis, headache, dizziness, cough, throat irritation, rhinorrhoea, muscle spasm, chest pain, peripheral oedema 2.47 6-8 Long-acting muscarinic antagonist (LAMA)25-28 Tiotropium bromide DPI (18) SMI (5) Glycopyrronium bromide▼ DPI (44) Caution in patients with glaucoma or urinary retention. Headache, dizziness, throat irritation, cough, dry mouth, nausea, gastrointestinal motility disorder 38.57 38.57 34.50 24 Drug Monthly costs in Euros # Duration of action Undesirable Effects/Special precautions include* (hours) Aclidinium bromide▼ DPI (322) Combination of LABA and LAMA29 Indacaterol/ DPI (85/43) Glycopyrronium bromide▼ Inhaled corticosteroids (ICS)30-32 Budesonide DPI (100,200,400) Not marketed in Ireland 12 Caution in patients with glaucoma, urinary retention or cardiovascular disease. Dry mouth Caution in patients with glaucoma, urinary retention or cardiovascular disease. Nasopharyngitis, insomnia, headache, dry mouth, gastroenteritis, urinary tract infection Sinusitis, nasopharyngitis, headache, cough, diarrhoea Not marketed in Ireland 24 See individual drugs 13.91-16.83 Fluticasone 8.19-34.20 5.65-31.85 Caution in patients with tuberculosis. Oropharyngeal candidiasis, cough, hoarseness, throat irritation Risk of drug interaction with ritonavir. Oropharyngeal candidiasis, pneumonia, hoarseness 46.40-45.49 See individual drugs MDI (50-500) DPI (50-500) Combination of LABA and ICS33,34 Budesonide/formoterol DPI (200/6, 400/12) 24 Salmeterol/fluticasone DPI (50/100, 50/250, 50/500) 29.09-51.12 See individual drugs # monthly costs according to MIMS Ireland October 2013, * - the Summary of Product Characteristics should be consulted for full prescribing information, ** - oral formulation also available, *** - nebule formulation also available, **** - intravenous formulation also available, MDI – metered dose inhaler; DPI – dry powder inhaler; BD - twice daily, SMI – soft mist inhaler, ▼ - drug subject to additional monitoring Table 4: Currently authorised oral formulations for COPD Drug Methylxanthines35-38 Aminophylline** Theophylline Monthly costs in Euros # Special Precautions /Undesirable Effects Include* Caution in patients with cardiac disease. Drug interactions common. Headache, nausea, vomiting, gastric irritation, anorexia Therapeutic drug monitoring recommended 2.70 2.13-7.73 Phosphodiesterase-4 inhibitors39 Roflumilast▼ Not available Associated with risk of psychiatric disorders; rare cases of suicidal ideation reported. Weight loss, anorexia, insomnia, headache, diarrhoea, nausea, abdominal pain Systemic corticosteroids40 Methylprednisolone Prednisolone Variable Hypothalamic-pituitary adrenal suppression, infection, congestive heart failure, peptic ulcer # monthly costs according to MIMS Ireland October 2013,, * - the Summary of Product Characteristics should be consulted for full prescribing information, ** - intravenous formulations also available, ▼ - drug subject to additional monitoring Bronchodilators Airway smooth muscle relaxation, leading to bronchodilatation is achieved mainly by beta2 agonists and muscarinic antagonists.41 Short-acting bronchodilators are used for rescue or as needed treatment and long-acting bronchodilators are used for maintenance treatment.1,8,42 The choice of bronchodilator therapy (see table 3 and 4) depends on the individual patient’s response in terms of symptom relief and tolerability.43 Beta2 agonists: Short-acting beta2 agonists (SABAs) improve bronchodilator function in patients with moderate to severe COPD (see table 3).8 The long-acting beta2 agonists (LABAs) have been shown to significantly improve FEV1, patients’ symptoms and exacerbation rate but they have no effect on mortality and rate of decline in lung function.1,44 There have been cardiovascular safety concerns regarding the use of beta2 agonists, however studies have not found an association between their use and increased mortality in COPD.1,8,45 Muscarinic antagonists: Ipratropium bromide is the only short-acting muscarinic antagonist (SAMA) currently available; its effects are similar to the SABAs.46 There are several long-acting muscarinic antagonists (LAMAs) available (see table 3); they show similar efficacy in terms of improved symptoms, reduced exacerbations and hospitalisation for COPD.1,8,43,47-50 A Cochrane review which compared tiotropium to LABAs concluded that its effects were superior in terms of preventing exacerbations and hospitalisations,51 however the results of an observational study of older adults with COPD suggested that patients prescribed LABAs had a lower mortality than those prescribed LAMAs.52 Tiotropium has also been shown to have more benefits than ipratropium bromide for people with moderate to severe COPD.53 There have been concerns regarding increased mortality in patients receiving tiotropium, in particular with use of the soft mist inhaler device.1,48,50,54-56 A recent study, which excluded patients with recent myocardial infarction or unstable arrhythmia found no difference in mortality between the soft mist and dry powder device.57,58 Post-authorisation safety studies on cardiovascular outcomes have been requested for glycopyrronium bromide▼ and aclidinium bromide▼ (currently not marketed in Ireland).59 Methylxanthines are thought to act as non-selective phosphodiesterase inhibitors (see table 4).1 A methylxanthine should only be used after a trial of short-acting and long-acting bronchodilators and in those unable to use inhaled therapy.1,4 If required, slow release preparations are recommended. Theophylline, the most commonly used preparation, has a narrow therapeutic index and drug monitoring is required. It is metabolised by cytochrome P450 and there is a significant risk of interaction with commonly used medicines including digoxin, warfarin, macrolides and quinolones.1,8 Combination bronchodilator therapy increases the degree of bronchodilation with equivalent or fewer side-effects.1,60-62 The combination of tiotropium and LABA resulted in a better HRQoL and lung function compared to using tiotropium alone, but no difference in hospital admissions or mortality was noted.41,61 Combinations of indacaterol/tiotropium, and indacaterol/ glycopyrronium▼ have also been shown to be associated with significant improvement in symptoms.41,60,63 Other pharmacological agents Inhaled corticosteroids: There are conflicting views on the benefits of inhaled corticosteroids (ICS) in COPD.1,8,64,65 Their use is associated with a reduction in exacerbations and rate of decline of HRQoL, however they are associated with an increased risk of pneumonia.8,65,66 Long-term monotherapy with ICS is not recommended.1 Guidelines recommend combinations of LABA and ICS patients at high risk of exacerbations (not all preparations are licensed for COPD);1 which have been shown to improve lung function and HRQoL and reduce exacerbations.1,8,67-70 The combination of ICS, LABA and tiotropium has also been shown to improve lung function and HRQoL.1,41,71 Phosphodiesterase- 4 (PDE-4) inhibitors’ principal action is to reduce inflammation.1 Roflumilast▼, (not currently marketed in Ireland), is a once daily oral preparation (see table 4). It improves FEV1 in patients treated with salmeterol or tiotropium and has been shown to reduce moderate and severe exacerbations in patients with severe COPD treated with corticosteroids.1 PDE-4 inhibitors should always be used in combination with at least one long-acting bronchodilator.1 Roflumilast▼ is metabolised by cytochrome P450 3A4 to an active metabolite, which itself is metabolised by CYP 3A4,5,39 therefore there is a potential risk of drug-drug interactions. Roflumilast▼ should not be used in patients treated with theophylline.1 Systemic corticosteroids are used to treat exacerbations of COPD, but there is no evidence to support their long-term use in stable COPD,1,73 and they are not normally recommended.4 Some patients with advanced COPD may require maintenance corticosteroids; in these cases the dose of oral corticosteroids should be kept as low as possible.4 Adjunctive therapeutic agents Vaccination: Patients with COPD should receive influenza and pneumococcal vaccines, which reduce serious illness and death in patients with COPD.1 The use of continuous prophylactic antibiotics has shown inconsistent results,74,75 and is not currently recommended for COPD.1 Controversy exists regarding the use of mucolytic agents such as carbocisteine and N-acetylcysteine, however they may provide symptomatic relief in some patients.1,4 Pharmacotherapy for smoking cessation: Unless contraindicated, patients who are planning to stop smoking should be offered nicotine replacement therapy, varenicline▼59 or bupropion as appropriate with a suitable support programme.1,4,8 Inhaler devices The choice of inhaler device for an individual patient is an essential aspect to consider in COPD management.1,41 Each device has different operating and maintenance instructions, and successful use of a given drug/device combination requires that patients are continually instructed in its use.76 Poor inhaler technique is often a major cause of suboptimal COPD management.4,76 In most cases bronchodilators are best administered using a hand-held inhaler device.4 The devices currently available are pressurised metered dose inhalers (pMDI), dry powder inhalers (DPIs) and a propellant soft mist inhaler (SMI) (see table 3). Some patients may have coordination difficulties using the pMDIs; this can be improved by use of a spacer or with breath activated devices. Patients may also find it difficult to use some DPIs, which may require loading by the patient, or there may be low inspiratory flow rate with a severe exacerbation.41 Poor inhaler technique has been reported in 8-59% of patients using pMDIs and 4-94% of patients using DPIs (depending on the type of device) resulting in little or no pulmonary drug deposition.76 Currently the only SMI in clinical use contains tiotropium.76 There are no substantial differences between the effects of drugs delivered via a pMDI and a nebuliser to elderly patients.76 Guidelines recommend nebulisers for patients with stable COPD only when other therapies do not provide symptomatic benefit; they have significant disadvantages particularly as they are less portable and inhibit patient activity.1 PRACTICAL ASPECTS OF MANAGEMENT Stable COPD: The GOLD guidelines recommend a stepwise approach for the management of stable COPD, based according to an assessment of the individual’s disease severity, symptoms and exacerbations as outlined in table 5. Table 5: Pharmacological therapies for stable COPD1 Patient Group 1st Choice Alternative Choice Other Possible Treatments* A: Gold 1-2 Low risk of exacerbations, less symptoms SAMA prn or SABA prn LAMA or LABA or SABA + SAMA Theophylline B: Gold 1-2 Low risk of exacerbation, more symptoms LAMA or LABA LAMA + LABA SABA and/or SAMA Theophylline C: GOLD 3-4 High risk of exacerbation, less symptoms ICS + LABA or LAMA LAMA + LABA or LAMA + PDE-4 inhibitor or LABA + PDE-4 inhibitor SABA and/or SAMA Theophylline D: GOLD 3-4 High risk of exacerbations, more symptoms ICS + LABA and/or LAMA ICS + LABA + LAMA or ICS + LABA + PDE-4 inhibitor or LAMA + LABA or LAMA + PDE-4 inhibitor Carbocisteine SABA and/or SAMA Theophylline * can be used alone or in combination with the recommended first and alternative choice options, SAMA – short-acting muscarinic antagonist, SABA – short-acting β2- agonist, LAMA – long-acting muscarinic antagonist, LABA – long-acting β2- agonist, ICS – inhaled corticosteroid, PDE – phosphodiesterase Management of exacerbations: Exacerbations of COPD can be precipitated by several factors including respiratory tract infections (viral or bacterial). The diagnosis is made following assessment of the patient presenting with an acute change in symptoms. It is estimated that up to 80% of patients can be managed on an outpatient basis with pharmacological therapies such as bronchodilators, corticosteroids and antibiotics.1 Indications for hospital assessment or admission include marked increase in intensity of symptoms (such as sudden onset resting dyspnoea), severe underlying COPD, onset of new physical signs (such as cyanosis, peripheral oedema), failure to respond to initial medical management, frequent exacerbations, older age and insufficient home support.1 SABAs, with or without SAMAs are usually the preferred bronchodilators for treatment of an exacerbation.1 Evidence from in-patient settings has shown that use of systemic corticosteroids in COPD exacerbations shortens recovery time, improves FEV1 and arterial hypoxaemia, reduces the risk of early relapse and treatment failure and lessens duration of hospital stay.1 There is insufficient evidence on the optimal duration of treatment although most guidelines recommend 30-40mg prednisolone for 7-14 days.1,4,77,78 A gradual withdrawal of corticosteroids may be required if they are used at doses ≥40mg/day or for >3 weeks.79 A recent RCT supports the use of 5 days’ treatment with oral corticosteroids for exacerbation of COPD.80,81 The choice of antibiotic therapy to use in COPD should be based on the local bacterial resistance pattern.1 Irish guidelines recommend first line primary care treatment with amoxicillin or doxycycline or clarithromycin; combinations of antibiotics are not required for COPD.82 In addition to pharmacological therapy, hospital management includes respiratory support with oxygen therapy and ventilatory support.1 The use of NIV has increased significantly in patients hospitalised with COPD and has been associated with improved mortality.1,4,83 COPD Outreach Services which allow selected patients with COPD to be discharged early and cared for at home have been shown to be safe and effective and have been instituted in many acute care hospitals around the country.2 Palliative care: At the end of life, patients with advanced COPD have a higher disease burden than those with lung cancer.84 Palliative care is an important aspect to consider in the management of a patient with advanced COPD, however patients with COPD are less likely to receive such services than patients with lung cancer. The hospice foundation has details of recent research on this topic (http://hospicefoundation.ie/what-we-do/palliative-care-for-all/advanced-respiratory-disease/). SUMMARY COPD is a preventable and treatable condition which is associated with high rates of morbidity and mortality; it is widely under-diagnosed. Pharmacotherapy coupled with the active management of smoking, patient education and lifestyle (including planned exercise) helps to reduce the number of exacerbations and hospitalisations.1 Pharmacological treatment should be individualised to the patient and regularly reviewed for effectiveness and technique. The National COPD programme is working towards establishing an improved national model of care with combined hospital and community based initiatives such as COPD outreach and pulmonary rehabilitation programmes. FOR PERSONAL USE ONLY. NOT TO BE REPRODUCED WITHOUT PERMISSION OF THE EDITOR List of references available on request. Date of preparation: October 2013 Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue. Prescribers are recommended to refer to the individual Summary of Product Characteristics (SmPC) for specific information on a drug. References for Chronic Obstructive Pulmonary Disease Vol 19 No 4 2013 1. Global Initiative for Chronic Obstructive Lung Disease 2013, downloaded from www.goldcopd.org on the 9th August 2013 2. Health Service executive, National COPD programme, downloaded from www.hse.ie on the 9th August 2013 3. Crinion S et al, COPD exacerbations – a comparison of Irish data with European data from the ERS COPD audit, IMJ Oct 2013;106(9);268-272 4. NICE clinical guideline 101: Chronic obstructive pulmonary disease – management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update), Issued June 2010, downloaded from www.nice.org.uk/ on the 9th August 2013 5. Reid JR, Pham NT, Review – Emerging Therapeutics Options for the Management of COPD, Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2013;7:7-15 6. European Lung White Book, Chapter 13 accessed from http://www.erswhitebook.org/ on the 1st November 2013 7. OECD (2011), Health at a Glance 2011: OECD Indicators, OECD Publishing. http://dx.doi.org/10.1787/health_glance-2011-en downloaded from http://www.oecd.org/els/health-systems/49105858.pdf on the 31st October 2013 8. Ejiofor S, Turner A, Expert Review: Pharmacotherapies for COPD, Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2013;7:1734 9. Forde D, Forum clinical Challenge, Managing stable COPD in general practice, February 2013 10. COPD assessment test available from http://catestonline.org, accessed 5th October 2013 11. Tonnesen P, Smoking cessation and COPD, Eur Respir Rev 2013;22(127):37-43 12. http://www.livingwithcopd.ie/ accessed Oct 2013 13. COPD Support Ireland website accessed 20th October 2013 www.COPD.ie 14. Puhan MA, Gimeno-santos E, Scharplatz M, Troosters T, Walters EH, Steurer J, Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD005305. DOI: 10.1002/14651858.CD005305.pub3 15. BTS statement, Pulmonary rehabilitation, Thoraz 2001;56:827-834 16. McDonnell TJ et al, Efficacy of pulmonary rehabilitation in an Irish population, Irish Medical Journal 2001;94(2):46-8 17. SmPC for Ventolin Evohaler® downloaded form www.medicines.ie on the 9th August 2013 18. SmPC for Ventolin Diskus® downloaded form www.medicines.ie on the 9th August 2013 19. SmPC for Bricanyl Turbohaler® downloaded form www.medicines.ie on the 9th August 2013 20. SmPC for Oxis Turbohaler 6 & 12® downloaded form www.medicines.ie on the 9th August 2013 21. SmPC for Foradil® downloaded form www.medicines.ie on the 9th August 2013 22. SmPC for Serevent Diskus® downloaded form www.medicines.ie on the 9th August 2013 23. SmPC for Serevent Evohaler® downloaded form www.imb.ie on the 1st October 2013 24. SmPC for Atrovent UDV® downloaded form www.medicines.ie on the 9th August 2013 25. SmPC for Spiriva® downloaded form www.medicines.ie on the 9th August 2013 26. SmPC for Spiriva Respimat® downloaded form www.medicines.ie on the 9th August 2013 27. SmPC for Seebri Breezhaler® downloaded form www.medicines.ie on the 9th August 2013 28. SmPC for Eklira Genuair® downloaded form www.medicines.ie on the 25th September 2013 29. SmPC for Ultibro Breezhaler® downloaded from www.medicines.ie on the 31st Oct 2013 30. SmPC for Pulmicort Turbohaler® downloaded form www.medicines.ie on the 9th August 2013 31. SmPC for Flixotide Evohaler® downloaded form www.medicines.ie on the 9th August 2013 32. SmPC for Flixotide Diskus® downloaded form www.medicines.ie on the 9th August 2013 33. SmPC for Symbicort Turbohaler® downloaded from www.medicines.ie on the 9th August 2013 34. SmPC for Seretide Diskus® downloaded from www.medicines.ie on the 9th August 2013 35. SmPC for Phylocontin Continus® downloaded form www.imb.ie on the 9th August 2013 36. SmPC for Nuelin SA® downloaded form www.imb.ie on the 9th August 2013 37. SmPC for Uniphyllin Continus® downloaded form www.imb.ie on the 9th August 2013 38. SmPC for Zepholin Prolonged Release® downloaded form www.imb.ie on the 9th August 2013 39. SmPC for Daxas® downloaded from www.medicines.ie on the 3rd September 2013 40. SmPC for Deltacortril® downloaded from www.imb.ie on the 20th October 2013 41. Tashkin DP, Ferguson GT, Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease, Respiratory Research 2013;14(49) available on http://respiratory-research.com/content/14/1/49 42. Bollu V et al, Risk of all-cause hospitalisation in COPD patients initiating longacting or short-acting beta agonist therapy, Journal of Medical Economics 2013;16(8):1082-1088 43. Prakash A et al, Novel anti-cholinergics in COPD, Drug Discovery Today August 2013, available on www.drugdiscoverytoday.com 44. Appleton S, Poole P, Smith BJ, Veale A, Lasserson TJ, Chan MMK, Cates CL, Long-acting beta2-agonists for poorly reversible chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001104. DOI: 10.1002/14651858.CD001104.pub2. 45. Rodrigo GJ et al, Safety of Long-Acting Beta Agonists in Stable COPD: A Systematic Review, Chest 2008;133(5):1079-87 46. Appleton S, Jones T, Poole P, Pilotto L, Adams R, Lasserson TJ, Smith B, Muhammed J, Ipratropium bromide versus short-acting beta2-agonists for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001387. DOI: 10.1002/14651858.CD001387.pub2 47. Kerwin E et al, Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study, Eur Respir J 2012;40(5):1106-14 48. Yohannes A, Ten years of tiotropium: clinical impact and patients perspectives, International Journal of COPD 2013;8:117-125 49. Barr RG, Bourbeau J, Camargo Jr CA. Tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002876. DOI: 10.1002/14651858.CD002876.pub2. 50. Karner C, Chong J, Poole P. 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