Description of the condition
Chronic obstructive pulmonary disease (COPD) is "a common, preventable and treatable disease, characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases" (GOLD 2013). Tobacco smoke is the major risk factor in the pathogenesis of COPD; chemicals, occupational exposures, indoor and outdoor air pollution are also recognised risk factors (GOLD 2013; Hogg 2009; MacNee 2006; TSANZ 2012; WHO 2012).
COPD is the third leading cause of death after heart diseases and malignancy in the United States (CDC 2011) and accounts for approximately 30,000 deaths each year in the UK (NICE 2010). It was the fourth leading cause of mortality in 2004 with three million deaths worldwide (WHO 2008). Ninety per cent of deaths from COPD occurred in low and middle-income countries in 2008 (WHO 2010). The World Health Organization (WHO) has estimated that COPD will become the third leading cause of death worldwide in 2030 due to a projected increase in smoking and environmental pollution (WHO 2012a). Exacerbations and co-morbidities contribute to the overall severity of COPD in patients (GOLD 2013). Currently available prevalence data do not reflect the actual total burden of COPD because of under reporting and diagnosis being made only when clinically apparent (GOLD 2013).
COPD also has a significant economic impact, mainly due to exacerbations. The total annual cost of COPD to the National Health Service (NHS) in the UK is estimated to be over GBP 800 million for direct healthcare costs (NICE 2011). It accounts for 56% (EUR 38.6 billion) of the total cost of respiratory diseases in the European Union, while the estimated cost in the United States is USD 29.5 billion and USD 20.4 billion, for direct and indirect costs respectively (GOLD 2013).
Acute exacerbations are the main cause of morbidity and mortality in COPD patients and are defined as "an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough, and/or sputum, that is beyond normal day-to-day variations, is acute in onset and may warrant a change in medication in a patient with underlying COPD" (GOLD 2013).
Currently there is no cure for COPD. Apart from smoking cessation and long-term oxygen therapy in severely hypoxic patients, other therapeutic options do not improve survival (GOLD 2013). Thus, the major goal of medication is to relieve symptoms, reduce the frequency and severity of exacerbations, and improve quality of life (ATS/ERS 2011; Chong 2012; GOLD 2013; Sutherland 2004; TSANZ 2012).
Management of stable COPD is multidisciplinary, with options such as smoking cessation (van der Meer 2012), education (Effing 2009), vaccination for influenza (Poole 2010) and pneumococcal infections (Walters 2010), breathing exercises (Holland 2012), pulmonary rehabilitation (Lacasse 2009), pharmacotherapy with inhaled bronchodilators, inhaled corticosteroids for severe COPD or frequent exacerbations (GOLD 2013; TSANZ 2012; Yang 2012), phosphodiesterase-4 inhibitors (Chong 2011), long-term domiciliary oxygen therapy (Cranston 2008) and lung volume reduction surgery (Tiong 2009). Regular long-term use of oral corticosteroids is not recommended for stable COPD and is associated with an increased risk of systemic side effects (GOLD 2013; Walters 2009). Oral theophylline has a modest bronchodilator effect (Ram 2009) but is less effective than inhaled long-acting bronchodilators (GOLD 2013). Mucolytic agents show a slight reduction in exacerbations but have no effect on the overall quality of life (Poole 2012). Neither of these are routinely recommended for stable COPD (GOLD 2013). Long-acting bronchodilators, either long-acting beta2-agonist (LABA) (Nannini 2012; Welsh 2011) or long-acting muscarinic antagonist (LAMA) (Karner 2012), are the first-line maintenance therapy for moderate to severe, stable COPD (GOLD 2013; NICE 2010).
Description of the intervention
Aclidinium bromide is a new long-acting antimuscarinic agent that blocks the action of the neurotransmitter acetylcholine. It was approved by the US Food and Drug Administration (FDA) on 23 July 2012 for use in moderate to severe, stable COPD patients (FDA 2012). It is marketed as Tudorza Pressair by Forest Laboratories and Almirall in the US. It is a dry powder formulation (Sims 2011) and the FDA approved dosage is 400 µg inhaled twice daily. In Europe and the UK it has been launched as Eklira Genuair by Almirall.
It is delivered by a state-of-the-art multidose dry powder inhaler (MDPI), termed Genuair or Pressair, which is preloaded with a one-month supply of medication. The MDPI is specially designed with a visible dose level indicator with anti-double dosing mechanism, multiple feedback mechanisms to indicate successful inhalation such as audible click and a slightly sweet taste, as well as an end-of-dose lock-out system to prevent further use after the final dose (Maltais 2012; Sims 2011).
How the intervention might work
Airway obstruction mediated by vagal cholinergic tone is the major reversible contributor to COPD (Jones 2011). Currently there are five known subtypes of muscarinic cholinergic receptors (M1 to M5), of which three (M1, M2 and M3) are present in the bronchial airway smooth muscle (Karakiulakis 2012; Maltais 2012).
Acetylcholine acts on M1 receptors to facilitate further neurotransmission from parasympathetic ganglia, which then binds to M3 receptors located on the airway smooth muscle cells to induce bronchoconstriction. M2 receptors mediate feedback inhibition of acetylcholine release at the cholinergic nerve endings (Karakiulakis 2012; Sims 2011; Vogelmeier 2011).
Aclidinium bromide is a LAMA which inhibits the action of acetylcholine at the muscarinic receptors with approximately six-fold kinetic selectivity for M3 receptors compared to the M2 subtype, causing more effective bronchodilator action with fewer M2 mediated cardiac side effects (Maltais 2012; Sims 2011). The onset of action of aclidinium bromide (30 minutes) is similar to ipratropium (30 minutes) but faster than tiotropium (80 minutes). The duration of action of aclidinium (t1/2 = 29 hours) is shorter than tiotropium (t1/2 = 64 hours) but longer than ipratropium (t1/2 = 8 hours) (Maltais 2012).
These muscarinic receptors are also present in other parts of the body, such as M1 receptors in the central nervous system (CNS), M2 in the heart, M3 in the gastrointestinal tract (GIT), iris and sphincter and M4 in the neostriatum, whereas the functional role of M5 is not clear (Gavaldà 2010). Thus, the non-selective blockade of muscarinic receptors can have the potential for systemic side effects.
Aclidinium has been shown in preclinical and clinical studies to rapidly hydrolyse into two inactive metabolites in the plasma, with a very short plasma half life of 2.4 minutes, while that of ipratropium is 96 minutes and tiotropium is more than six hours (Maltais 2012). This low and transient level in the plasma leads to less drug-drug interaction and contributes to a more favourable safety profile.
Why it is important to do this review
Although a long-lasting bronchodilator effect and favourable safety profile of aclidinium bromide has been shown in a number of clinical trials (Jones 2011; Jones 2012), the summarised safety and efficacy profile of this agent compared to placebo, or currently established treatment options such as LABAs or LAMAs, is lacking. We aim to fill this gap by performing a systematic review of the findings of all available randomised controlled trials (RCTs), to help clinicians provide evidence-based long-term management of stable COPD.