Description of the condition
Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disease characterised by chronic and progressive breathlessness, cough, sputum production, and airflow obstruction, which leads to restricted activity and poor quality of life (GOLD). The World Health Organisation (WHO) has estimated that COPD is the fourth or fifth most common single cause of death worldwide and the treatment and management costs present a significant burden to public health. In the UK the annual cost of COPD to the National Health Service (NHS) is estimated to be £1.3 million per 100,000 people (NICE 2011). Furthermore, because of the slow onset and the under-recognition of the disease, it is heavily under-diagnosed (GOLD). COPD comprises a combination of bronchitis and emphysema and involves chronic inflammation and structural changes in the lung. Cigarette smoking is the most important risk factor, however air pollution and occupational dust and chemicals can also increase the risk of developing the disease. COPD is a progressive disease leading to decreased lung function over time, even with the best available care. There is currently no cure for COPD, though it is both a preventable and treatable disease. As yet, apart from smoking cessation and non-pharmacological treatments such as long term oxygen therapy in hypoxic patients and pulmonary rehabilitation, no intervention has been shown to reduce mortality (GOLD; Puhan 2011). Management of the disease is multi-facetted and includes interventions for smoking cessation (van der Meer 2001), pharmacological treatments (GOLD), education (Effing 2007) and pulmonary rehabilitation (Lacasse 2006; Puhan 2011). Pharmacological therapy is aimed at relieving symptoms, improving exercise tolerance and quality of life, slowing decline and even improving lung function and preventing and treating exacerbations. COPD exacerbations impair patients' quality of life (GOLD) and a large part of the economic burden of COPD is attributed to the cost of managing exacerbations, particularly those resulting in use of acute care services or hospitalisations (Hutchinson 2010). In the UK, one in eight emergency admissions to hospital is for COPD, which makes it the second largest cause of emergency admissions, and one of the most costly conditions treated by the NHS (NICE 2011). Appropriate pharmacological management of the disease is therefore important, particularly to reduce and prevent exacerbations.
Description of the interventions
Pharmacological management for COPD tends to begin with one treatment and additional therapies are introduced as necessary to control symptoms and reduce the frequency and severity of exacerbations (GOLD). The first step is often a short-acting bronchodilator for control of breathlessness when needed: either a short-acting beta2-agonist (SABA) e.g. salbutamol, or the short-acting muscarinic antagonist (SAMA) ipratropium. Both bronchodilators have a duration of action of four to six hours (Beeh 2010) and they improve lung function and breathlessness (Sestini 2009; Appleton 2006). For persistent or worsening breathlessness associated with lung function decline, long-acting bronchodilators may be introduced (GOLD). These comprise long-acting beta2-agonists such as salmeterol or formoterol (LABA, duration of action 12 hours) and indacaterol (duration of action 24 hours); and long-acting anticholinergic agents, such as tiotropium (duration of action 24 hours) and more recently aclidinium bromide and glycopyrronium bromide. Regular treatment with long-acting bronchodilators is preferred over treatment with regular short-acting bronchodilators based on efficacy and side effects (Beeh 2010; GOLD). An alternative if bronchodilators are not available or affordable is theophylline, an oral phosphodiesterase (PDE) inhibitor. However, theophylline is less effective and less well tolerated than inhaled long-acting bronchodilators. For patients with severe or very severe COPD (FEV1 < 50% predicted) and with repeated exacerbations, GOLD recommends the addition of inhaled corticosteroids (ICS) to bronchodilator treatment. ICS are anti-inflammatory drugs that are licensed as combination inhalers with LABAs. The most common combinations of ICS and LABA in combination inhalers are fluticasone and salmeterol, and budesonide and formoterol. The most severe group of patients with advanced COPD may also benefit from treatment with the PDE4 inhibitor roflumilast which may reduce the risk of exacerbations (GOLD), alongside other beta2-agonists or anticholinergic agents and ICS, but these combinations are not considered in this review.
How the intervention might work
Long-acting muscarinic antagonists
Long-acting muscarinic antagonists (LAMA) are an anticholinergic agent, which blocks the action of the neurotransmitter acetylcholine. The LAMA tiotropium has gained widespread acceptance as a once-daily maintenance therapy in stable COPD for its effects on symptoms and exacerbations (Barr 2005; GOLD). Two newer LAMAs, aclidinium bromide and glycopyrronium bromide, have recently been licensed for the maintenance treatment of people with COPD. Anticholinergic side effects that may occur include dry mouth, constipation and tachycardia (Tashkin 2008).
Inhaled long-acting beta2-agonists (LABA) activate beta2-receptors in the smooth muscle of the airway leading to a cascade of reactions resulting in bronchodilation. Commonly used LABAs include salmeterol and formoterol, and the ultra-long acting beta2-agonist (U-LABA) indacaterol. The duration of action for salmeterol and formoterol is approximately 12 hours, and therefore are usually taken twice daily. Indacaterol has a duration of action of 24 hours and can, therefore, be taken once daily. The mechanism for action differs between the LABAs, and different efficacy and safety profiles can be expected between the long-acting and ultra-long acting beta2-agonists. As with long-acting muscarinic antagonists, LABAs and U-LABAs are commonly used to control symptoms and reduce exacerbations in stable COPD (Moen 2010; Rodrigo 2008). Possible side effects of LABAs include cardiac effects such as arrhythmia and palpitations, muscle tremors, headache and dry mouth (Berger 2008).
Inhaled corticosteroids (ICS) are anti-inflammatory drugs. ICS are licensed as combination inhalers with LABA. The most common combinations of ICS and LABA in combination inhalers are fluticasone and salmeterol, and budesonide and formoterol. Combination inhalers have similar effects to LABA alone, reducing exacerbation rates and improving patients' quality of life. However, the difference is small (Rodrigo 2009) and ICS therapy, alone or in combination with beta2-agonists, is associated with an increased risk of pneumonia and osteoporotic fractures (GOLD; Loke 2011; Singh 2010).
Why it is important to do this overview
Several systematic reviews have looked at the risks and benefits of specific inhaled therapies compared to placebo or other inhaled therapies. However for patients or clinicians facing patients, the question is often which of the long-acting therapy options is the most beneficial treatment option for patients no longer obtaining symptom relief from short-acting therapies, but for whom PDE4 inhibitors or other combination therapies are not yet necessary. Two recent network meta-analyses have focused primarily on safety outcomes (Decramer 2013; Dong 2013).