Asthma is a challenging, chronic inflammatory condition which is characterised by reversible symptoms such as wheezing, chest tightness and shortness of breath1.
Patients on short-acting ?2 agonists (SABA) and inhaled corticosteroids (ICS) without adequate asthma control, such as one or more nights a week of awakening, should have their therapy optimised2. The British Thoracic Society guidelines currently state that the next step to the treatment should be the addition of a long-acting ?2 agonist (LABA). However, the new NICE guidelines recommend that the patient should be offered a leukotriene receptor antagonist (LTRA). A patient case has been presented whereby a 32-year-old asthmatic male, on optimal treatment with Clenil 200 mcg twice daily.
He has been suffering from nocturnal wheeze, which is associated with airway inflammation defined by a 15% decrease in the forced expiratory volume in one second (FEV1) between bedtime and awakening1,3, for the past 4 weeks. This report will compare LABA versus LTRA for use in his stepwise management. Montelukast is an example of an LTRA. It is a cysteinyl receptor antagonist, which blocks the leukotriene D4 receptors located in the lungs 1. These receptors are highly selective in inducing eosinophil and mast cell-induced bronchoconstriction and inflammation associated with asthma.
Cysteinyl leukotrienes are pro-inflammatory mediators; inhibiting its production reduces inflammation in the airways. LTRA’s are particularly effective in allergen, exercise, and aspirin induced asthma4. In the Cochrane review by Ducharme, the benefits of adding LTRA as an add-on therapy to ICS was studied and LTRA were shown to achieve modest improvement in asthma control4. In the COMPACT study, a comparison of a moderate dose of ICS combined with montelukast and high ICS dose produced similar beneficial effects5. Some of these effects included reduction of nocturnal wheeze and exacerbations. While both treatments have a similar safety profile, there is an increased risk of airway infectious disease associated with high dose ICS. Moreover, with the addition of montelukast, it was later possible to reduce or discontinue ICS without loss of asthma control6; this results in fewer steroid-induced side effects such as oral thrush.
Studies have shown montelukast to be better when used concomitantly with ICS rather than monotherapy in mild-to-moderate asthma7. Although some indicated LTRAs to have a slower onset of symptomatic relief; the long-term safety profile was proven to be better8. Yet another advantage of LTRAs is that it’s a once daily orally administered drug which has been demonstrated to improve patient compliance.
Since LTRA and ICS are available separately, titration of dose is much easier and without the implication of huge costs. LABAs are potent bronchodilators providing a quick, long-lasting spasmolytic effect. They work by agonising the ?2 adrenergic receptors on the smooth muscle causing bronchodilation of the airways9.
Although there is some evidence of reducing eosinophils and mast cells especially when added to ICS, LABAs do not seem to possess clinically relevant anti-inflammatory properties7. Over time the negative feedback mechanism of the ? adrenergic system is desensitized to the stimulation of the receptors by LABA and this is believed to be responsible for the worsening of asthma control10. There is a synergistic effect of ICS with LABA; LABAs reduce airway hyper-responsiveness by means of functional antagonism while ICS increase the expression of ?2 adrenergic receptors4. A multi-centre study has shown LABA clinically improves various parameters similar to high dose ICS alone, with average exacerbation reductions of 40% and 37% respectively. However, in the study, the most reduction of exacerbations (62%) was with a combination of LABA and high dose ICS. A systematic study compared the effectiveness of the addition of LABA or LTRA to ICS; six trials involving 5571 adult participants indicated that the risk of exacerbations was significantly lower with LABA compared to LTRA4.
Patients who received LABA showed better improvements in FEV1 comparative to LTRA. A number of studies also showed that the LABA/ICS combination resulted in an increase of percentage of days free from symptoms and rescue medication compared to LTRA/ICS. A meta-analysis stated that there is an increase in asthma related deaths in patients who are being treated with LABA solely4. The Cochrane review comparing the use of LABA and LTRA found that when analysing serious adverse events, there was a wide confidence interval range, pointing to a likelihood of increased events for LABA. However, studies have shown that there is no significant difference in headache, cardiovascular events and death between the two groups4. The most common side effects of montelukast are headaches and abdominal pain,11 although these are still quite uncommon.
A study conducted by Koorsgard on 114 patients showed that the most reported side effects of LABA were muscle cramps and muscle twisting 12. The cost implication should also be taken into consideration. Based on a review undertaken by NICE, with the assumption that the clinician time needed for treatment is the same, there is a significant difference in the annual cost of treatment between LTRAs and LABAs (£48 and £319 respectively)13. A review concluded that there was no significant difference in hospitalization between the two drugs. With that considered, LTRA is more cost effective in the long term. While the various resources used are good, they all have their own limitations. The NICE impact resource made several assumptions for the annual cost of drugs, and does not elaborate fully on how cost is analysed13. The multi-centre study had a fairly small sample size (852 patients)14.
This is significant as a large sample size tends to have a wider demographic so is more representative of the population limiting the influence of outliers. Another limitation with the study was that markers of inflammation have not been included in this study, for this reason there is limited data to support substantial pathophysiological data. Based on the evaluation of the evidence, LTRAs were deemed with the best option due to them being effective for the nocturnal symptoms, the long-term safety profile, cost effectiveness and their role in reducing inflammation of the airways. There is also reduced risk of developing tolerance comparative to LABA and less serious adverse effects. Furthermore, therapeutic level is more consistent with LTRAs due to dose uniformity.