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Advances in asthma preventer medicines

Nicola O'Connell
BA(Hons)
Freelance Healthcare and Medical Writer
London

Traditional asthma treatments opened the blocked airways following an asthma episode (reliever medicines), but the development of preventer medicines in the 1970s, which aim to control the underlying airway inflammation, proclaimed a new age of asthma therapy and these agents continue to transform the management of the disease.
For over a decade now, asthma treatment has focused on inflammatory suppression with corticosteroids, with symptomatic treatment from short-acting bronchodilators. The emergence of new preventers during recent years now provides asthma patients with more choice, resulting in higher expectations for keeping asthma symptoms at bay and achieving good quality of life.
Now, increasingly, the goal of asthma management is to maintain disease control. This is the main objective of the revised guidelines for Asthma Management and Prevention released from The Global Initiative for Asthma (GINA) at the end of 2006.(1) The guidelines emphasise that the overall aim of asthma treatment is to achieve and maintain long-term control of all manifestations of the disease - including symptoms, sleep disturbances, limitations of daily activity, impairment of lung function and use of rescue medications.
Nevertheless, survey and audit data suggest that large numbers of adult asthma patients are uncontrolled. Medication adherence and overall satisfaction with treatment are likely to have a significant impact.

ICS and LABAs
Inhaled steroids are the first choice preventer drug; they are the most effective preventer drug for adults and older children achieving overall treatment goals, according to BTS guidelines. Furthermore, there is an increasing body of evidence demonstrating that they are also safe and effective in infants and younger children with asthma.(2)
The GINA guidelines recommend that treatment should be adjusted in a continuous cycle depending on the patient's level of control, stepping up when control is lost and then brought back down when control is achieved. In people with asthma that is poorly controlled with inhaled corticosteroids, data demonstrate that adding regular long-acting inhaled ß-2 agonists (LABAs) to inhaled corticosteroids improves symptoms and lung function, reduces the need for rescue medication, and reduces the risk of exacerbations.3 Indeed, LABAs are recommended as the first choice of add-on therapy to inhaled steroids.
However, LABAs have been associated with increased asthma-related mortality.(3) The GINA guidelines advise that LABAs must only be used in combination with an appropriate dose of inhaled corticosteroid (ICS), as LABAs alone are no longer presented as an option for add-on treatment at any step of therapy, unless accompanied by ICS. The Medicines and Healthcare products Regulatory Agency has warned that LABAs should only be prescribed when patients do not adequately respond to other asthma medications.(4)
"Survey data show, however, that physicians in Europe consider prescribing LABAs as firstline treatment for adults and children with mild-intermittent asthma," comments Dr Martin Adler, a GP based in Harrow, Middlesex. "While there have been some clinical trials showing that long-acting ß-2 agonists may have some benefit as firstline therapy among patients with chronic bronchitis and COPD, there is nothing to suggest this is the case with asthma.
"Physicians may think that it is not worth trialling inhaled corticosteroid alone when you can get faster control with a combined preparation. Furthermore, patients often have worries and misconceptions about the long-term effects of taking inhaled corticosteroids, which could be another reason for going straight on to LABAs. In accordance with BTS guidelines, medication should not be changed until a patient has been taking a reasonable dose of corticosteroid for least eight to 12 weeks."

Advantages and concerns with corticosteroids
Clinical studies have demonstrated the efficacy of ICS in reducing airway inflammation and hyper-responsiveness, as well as in preventing acute exacerbations, improving lung function and decreasing symptom severity.5 Corticosteroids act by binding to an intra-cellular receptor, leading to increased transcription of anti-inflammatory genes and reduced transcription of proinflammatory genes.
Nevertheless, ICS can cause systemic and local side-effects. Systemic side-effects may include the suppression of the hypothalamic-pituitary-adrenal (HPA) axis, osteoporosis, reduced growth velocity in children, skin thinning, cataracts and glaucoma.5 Local side-effects include oropharyngeal candidiasis, dysphonia and occasionally coughing from upper airway irritation.1
While the systemic side-effects of ICS are few compared with those of oral steroids, they are certainly a problem for some patients. "People worry about weight gain, as well as thinning and bruising of the skin," says Sam Prigmore, nurse consultant in respiratory care at St Georges Hospital, Tooting, London. "But the most common reason why people stop taking ICS is due to local side-effects such as oral thrush and a hoarse voice."
A recent survey by Asthma UK shows that 23% of people with asthma concerned about side-effects do not take their steroid medication as prescribed.6 Eighty-two percent of people prescribed steroids surveyed said they have some concerns about side-effects, and of those not offered the opportunity to discuss and agree how to manage their asthma with a GP or asthma nurse, 31% did not take their steroid medication.

Newer ICS options
The older ICS drugs, including beclometasone dipropionate (Becotide [A&H], Becloforte [A&H], Beclazone series [IVAX], AeroBec Series [3M Healthcare], Filair Series [3M Healthcare], Qvar Series [IVAX]), budesonide (Pulmicort [AstraZeneca]), and fluticasone (Flixotide [A&H]) continue to be commonly prescribed in the UK. Yet newer treatments may have improved therapeutic margins compared with some of those currently available and thus the potential to improve therapeutic outcomes.(7)
Mometasone furoate Dry Powder Inhaler (Asmanex Twisthaler [Schering-Plough]) was launched in the UK in January 2003. The treatment has demonstrated improvement in lung function and decreased rescue medication use compared with placebo among patients with persistent asthma previously dependent on ICS.(8) According to BTS guidelines, the relatively limited number of studies suggests that mometasone is equivalent to twice the dose of beclomethasone dipropionate and chlorofluorocarbon (BDP-CFC).
Ciclesonide (Alvesco [Atlana]) was launched more recently in the UK, in January 2005. Ciclesonide is inhaled as an inactive parent compound and is converted to its active metabolite - desisobutyryl-ciclesonide - by esterases in lung epithelium. As the inactive parent compound is not activated until it reaches the lung, the potential for oropharyngeal side-effects is reduced.(5) Evidence from clinical trials suggests that it has less systemic activity and local oropharyngeal side-effects than conventional inhaled steroids.(2) Ciclesonide has been shown to have a favourable safety profile and to be as effective as budesonide and fluticasone.(9-11)
Says Ms Prigmore: "Alvesco is still a new treatment, but it's now beginning to be prescribed more widely." Its once-daily dosage may help adherence among some patients. BTS guidelines recommend that while patients should be given inhaled steroids initially twice daily, the one exception is ciclesonide, given once daily.

Additional add-on therapies
In addition to LABAs (salmeterol and formoterol), some newer options for add-on therapy are emerging. Omalizumab (Xolair [Novartis]) is a novel drug designed to counteract the effects of immunoglobulin E (IgE). It is given as an injection once every two to four weeks. Omalizumab is currently licensed for use as add-on therapy in severe persistent asthma with an allergic component. A review of clinical trials reveals that omalizumab is generally well tolerated and effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids, and during steroid tapering phases of clinical trials.(12) However, a review published in the Drug and Therapeutics Bulletin last year questions the drug's efficacy and cost-effectiveness.13 NICE expects to publish guidance on omalizumab in 2008.
Newer oral preparations, the leukotriene modifiers, which include montelukast (Singulair [MSD]) and zafirlukast (Accolate [AstraZeneca]), have been introduced as a new class of asthma medications for the chronic treatment of persistent asthma. Clinical studies demonstrate that these agents have a small and variable bronchodilator effect, reduce symptoms including cough, improve lung function, and reduce airway inflammations and exacerbations.1
BTS guidelines recommend that leukotriene modifiers are added if asthma control still remains sub-optimal after increasing the dose of ICS and a trial of LABA.2 Most studies have shown that these agents are less effective than LABAs as add-on therapy and when used alone their effect is generally less than that of low doses of ICS.1,14
Theophylline tablets are now more typically used as preventers - they were originally used as bronchodilators - and while they may improve lung function and symptoms, side-effects occur more commonly.2

Maintaining control
The GINA guidelines point out that ongoing monitoring is essential to maintain control and establish the lowest step and dose of treatment to minimise cost and maximise safety. Typically, patients should be seen one to three months after the initial visit and every three months thereafter. If asthma is not controlled on the current treatment regimen, treatment should be stepped up.
Before intimating a new drug therapy, practitioners should recheck compliance, inhaler technique and eliminate trigger factors, says the BTS. A switch to another ICS drug may help to improve patient satisfaction with treatment. Rosie Newbigging, executive director of Nations, Regions and Services at Asthma UK says: "The decision to switch asthma medication should only be done by the healthcare professional in consultation with the patient, in response to changes to their asthma or as part of an asthma review. It is vital that changes in medication are always discussed with the patient to ensure symptom control and these should be monitored in a personal asthma action plan." 

Conclusion
The latest guidelines on asthma, combined with the launch of new more advanced treatments, means that patients should be able to expect good control. Regular reviews are recommended and in cases where adequate control is not achieved, BTS and GINA guidelines should be followed in accordance to adding additional treatments as required. A switch in choice of ICS drug may also help, particularly if side-effects and adherence are problems.

References
The Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. November 2006. Available from: http://www.ginasthma.com/download.asp?intId=214
2. British Thoracic Society/Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Available from: http://www.brit-thoracic.org.uk/c2/uploads/ch4_pharmacologicalmanagment2...
3. Dennis RJ, Solarte I, Fitzgerald JM. Adding long-acting inhaled ß-2 agonists in people with mild to moderate, persistent asthma that is poorly controlled by inhaled corticosteroids. BMJ Clin Evid Available from: http://www.clinicalevidence.com/ceweb/conditions/rdc/1501/1501_I17.jsp
4. Medicines and Healthcare products Regulatory Agency. Safety information for long acting ß-2 agonists. Available from: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&use

Secondary=true&ssDocName=CON2022601&ssTargetNodeId=221
5. Buhl R. Local oropharyngeal side-effects of inhaled corticosteroids in patients with asthma. Allergy 2006;61:518-26.
6. Asthma UK survey. Side-effects concerns lead to non-compliance. 2007. Available from: http://www.asthma.org.uk/news_media/news/side_effect.html
7. Meltzer EO, Derendorf H. The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide. Ann Allergy Asthma Immunol 2006;97:149-57.
8. D'Urzo A, Prenner B, Vandewalker M, Staudinger H, Sacks H. Effects of once-daily evening dosing with mometasone furoate dry-powder inhaler on symptom control in mild to moderate asthma.
J Allergy Clin Immunol 2003;111 Suppl 2:S218.
9. Colice GL. The newly developed inhaled corticosteroid ciclesonide for the treatment of asthma. Expert Opin Pharmacother 2006;7:2107-17.
10. Boulet L-P, Drollmann A, Magyar P, et al. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. Respir Med 2006;100:785-94.
11. Pedersen S, Garcia Garcia ML, Manjra A, et al. A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol 2006;41:954-61.
12. Walker S, Monteil M, Phelan K, et al. Anti-IgE for chronic asthma in adults and children. Cochrane Database Systematic Rev 2006;Issue 2.
13. Omalizumab for severe asthma? Drug Ther Bull 2006;44:86-8.
14. Bleecker ER, Welch MJ, Weinstein SF, et al. Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma.
J Allergy Clin Immunol 2000;105:1123-9.