Description of the condition
There are periods where asthma, a chronic respiratory disease, may be relatively well controlled, and then abruptly followed by a marked deterioration (referred to as an exacerbation). Currently, the number of people with asthma is estimated at 300 million, and forecasts suggest that by 2025 the total will be closer to 400 million (WHO 2007). Between 2001 and 2009 there was an increase from 20 million to 25 million in the US, where there are slightly lower prevalence rates among adults (8%) than children (10%) (CDC 2012; CDCP 2011). There are also considerable differences in asthma prevalence among different ethnic groups. Between 2008 and 2010 the US rates were: Multiple-race (14.1%), Alaskan Native (9.4%), American Indian (also 9.4%), black (11.2%), white (7.7%) and Asian (5.2%) populations (CDCP 2011). The prevalence of wheezing symptoms in children varies geographically with the UK having the highest recorded prevalence of current wheezing at 32.3% and Ethiopia the lowest at 1.7% (Patel 2008).
Asthma is associated with impaired quality of life (Clayton 2005); in particular, it is also noted that there are financial implications associated with the condition (Wu 2007). Each year, asthma exacerbations impact on approximately 10 million people with asthma in the US (Krishnan 2006). Elsewhere, there are similarly high incidence rates; in the UK there were over 65,000 hospital admissions for asthma in the period 2005 to 2006 (NHS 2011). There are well recognised factors that can be addressed to prevent hospital admissions in children with acute asthma (Ordonez 1998). In recent years a number of evidence-based clinical guidelines have emerged, at both national (e.g. BTS/SIGN 2012; NIH 2007) and international (e.g. GINA 2011) levels, to provide guidance for the management of asthma. Asthma is a consequence of airways inflammation, however, with appropriate clinical management it is possible to maintain health-related quality of life for considerable periods (WHO 2011). Mortality specifically associated with asthma and asthma morbidity is a major health concern (Braman 2006).
Description of the intervention
Asthma is a chronic inflammatory disorder of the airways that is characterised by reversible airways obstruction. A combination of inhaled corticosteroid (ICS) and long-acting ß2 agonist (LABA) is recommended for patients at step three of the British Thoracic Society guidelines; that is, patients not controlled on inhaled corticosteroids alone. There is evidence that addition of a LABA in patients who have uncontrolled symptoms on ICS alone can lead to improved lung function, improved symptoms, reduced use of rescue medications and a reduction in asthma exacerbations (BTS/SIGN 2012). Although generally less effective, the combination of ICS and leukotriene antagonist (LTRA) is a valid alternative to ICS and LABA (Montuschi 2008; Montuschi 2010)
Inhaled corticosteroids are fundamental in the treatment of asthma and fluticasone furoate belongs to this class of drugs. Inhaled corticosteroids work by reducing inflammation and airway hyper-responsiveness (Barnes 1998), thus improving the symptoms of asthma and the patient's lung function (Montuschi 2011). The majority of ICS are administered twice daily and studies have shown that using most of the presently available ICS once daily is less effective and leads to an increase in the requirement for rescue medication (BTS/SIGN 2012; Weiner 1995).
Vilanterol (VI) is a new drug that belongs to the LABA class. It is an ultra-LABA with rapid onset action in experimental models and has a 24-hour duration of bronchodilating effect in patients with asthma (Fuso 2013). The addition of LABA therapy to ICS treatment in asthma has been shown to improve lung function and reduce asthma symptoms and exacerbation rates (Remington 2005). Presently, the available LABAs require twice-daily administration apart from indacterol, approved for chronic obstructive pulmonary disease (COPD),which requires once-daily administration.
At the present time, there are several combination inhalers available for the treatment of asthma in adults, that is containing both ICS and LABA. However, these all involve twice-daily dosing, which is less convenient for patients and leads to a reduction in compliance with long-term therapy. Therefore, a once-daily combination inhaler would hopefully lead to increased compliance with treatment long term in people with asthma.
There are few data on once-daily combination treatments other than vilanterol and fluticasone furorate for asthma. A 12-week randomised controlled double blind study of 531 children aged six to 15 years, showed taking a single inhaler containing budesonide and formoterol once daily maintained pulmonary function but taking the same inhaler twice daily resulted in improved pulmonary function, fewer discontinuations for worsening asthma, and less daytime rescue medication (Eid 2010). Once-daily budesonide/formoterol has shown improved asthma control variable compared to once-daily budesonide alone (at a four times higher dose) in four to 11 years olds (Bisgaard 2006).
How the intervention might work
Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment and are initiated when patients require the use of short-acting ‘reliever’ medications on a regular basis. As well as the benefits mentioned previously, patients who are compliant with ICS therapy demonstrate a reduction in asthma exacerbations and mortality related to asthma (Powell 2003). It is well recognised that poor compliance is a major issue in patients with poorly controlled symptoms (BTS/SIGN 2012). One of the issues that may contribute to this is the twice-daily dosing regimen of most ICS.
Fluticasone furoate is a relatively new long-acting inhaled corticosteroid. It remains active for at least 24 hours after administration. Early studies have shown an improvement in lung function tests and a favourable safety and tolerability profile (Bleecker 2011; Woodcock 2011).
In recent years, there has been increasing evidence for the addition LABAs to ICS in the treatment of asthma and the benefit appears to be more than bronchodilatation alone. The action of corticosteroids is mediated by cytoplasmic glucocorticoid receptors (GRs) and after binding with the corticosteroids, the GR translocates to the nucleus where it is able to regulate gene expression (Montuschi 2011). LABAs have also been shown to induce GR nuclear translocation, although not as effectively as glucocorticoids. By studying the sputum epithelial cells and macrophages of people with asthma, it has been shown that the LABA, salmeterol, in combination with fluticasone propionate, was more effective at enhancing GR nuclear translocation than low-dose fluticasone propionate alone (Usmani 2005).
Interleukin-8 (IL-8) is a chemokine that has been implicated in the abnormal airway inflammation seen in asthma and it has been demonstrated that patients with clinically stable asthma have higher levels of IL-8 in broncho-alveolar lavage samples compared with normal healthy control particIpants (Nocker 1996). In a study looking at IL-8 production from neutrophils stimulated by cigarette smoke, it was shown that salmeterol and fluticasone propionate additively suppressed IL-8 release from neutrophils when compared with either agent alone. Interestingly, this effect is not seen in all human cell types and appears to be cell-specific. The mechanism of action is not yet clear but is has been suggested that increased translocation of the GR receptor to the nucleus may be involved (Mortaz 2008).
In patients who are uncontrolled on regular ICS, current BTS guidelines recommend the addition of a LABA, such as salmeterol or formoterol (BTS/SIGN 2012). Both these medications have a twice-daily dosing regimen that affects compliance and therefore, asthma control. LABAs are of benefit due to their bronchodilation effect and vilanterol (VI) is a new selective ß2 agonist within this class (Cazzola 2011). It has been shown that vilanterol is well tolerated with no significant adverse effects (Kempsford 2013) and also leads to an increase in symptom-free periods and a reduction in the use of rescue medication (Lotvall 2012).
In summary, limited studies suggest that there are effective once-daily ICS and LABAs that would allow a once-daily dosing regimen. This would hopefully lead to increased adherence and improved asthma control in adults and in children
Why it is important to do this review
There are published randomised trials on vilanterol and fluticasone furorate. This review will aim to establish whether vilanterol and fluticasone furorate may have a positive role in the management of chronic asthma in children and adults.