Dear Editor,

It is generally appreciated that the practice of stepping-down inhaled corticosteroid (ICS) therapy in patients with stable asthma is poorly implemented, albeit in the background of limited evidence.¹ Indeed, the appreciation for stepping-down ICS therapy once asthma control is attained is well established within the Global Initiative for Asthma (GINA) guidelines² and has recently been adopted by the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) consortium.¹

In the latter guidelines, it is recommended that a 25 – 50% of reduction in ICS dose be implemented at 3-monthly intervals.¹ A large study in primary care has shown that patients with stable asthma on moderately high doses of ICS can be safely stepped-down without compromising asthma control.³ However, there are currently no data evaluating the practice of stepping-down ICS therapy in patients with stable asthma in secondary care. Despite transforming the management of asthma, ICS therapy exposes an individual to both local and systemic adverse effects.⁴ Indeed, when taken at high doses, the ICS dose-response curve for systemic adverse effects becomes steep, with little further therapeutic gain.^5,6 Furthermore, the addition of second-line controller therapy may be more advantageous than merely increasing the ICS dose alone.⁷

We carried out a retrospective study to establish whether asthmatic patients attending a respiratory clinic in secondary care were being advised to reduce their ICS dose following a period of stability.

Methods

We assessed patients with asthma being followed-up in the respiratory clinic and retrospectively analysed data for the preceding 12-month period. Strict exclusion criteria were applied. Patients who were actively receiving or had received either oral or parenteral corticosteroids, or immunosuppressive therapy during the 12-month period were not considered eligible for inclusion. Patients also had to be exacerbation-free during this period. Classification of asthma severity was based on GINA guidelines.²

Results

Sixty consecutive patients with asthma were assessed in clinic. 2 patients were receiving parenteral corticosteroids, 4 patients were receiving immunosuppressant therapy, 14 patients were receiving oral corticosteroids, and 28 patients had an asthma exacerbation during the preceding 12 months. Therefore, using strict exclusion criteria, 12 patients were included in the data analysis.

Patient demographic data are shown in Table 1. 3 men and 9 women with mean ± standard error of mean age of 56 ± 6 years and forced expiratory volume in 1 second (FEV₁) of 1.97 ± 0.26 l (73 ± 6 % predicted) completed the study. The mean BDP equivalent ICS daily dose was 1267 ± 140 µg and patients had either moderate (n = 6) or severe (n = 6) asthma. 2 out of 12 patients had step-down in ICS therapy where one patient (number 10) had a 33% reduction in ICS dose from an initial daily dose of BDP 1500µg, having had stable asthma for 11 months, while the other patient (number 11) had a 50% reduction in ICS dose from an initial daily dose of fluticasone propionate (FP) 1000µg, having had stable asthma for 8 months. The remaining 10 out of 12 patients continued on the same dose of ICS despite having had stable asthma during the preceding 12 months. There were no significant differences in any outcomes comparing patients with and without step-down in ICS therapy.

Table 1 Patient demographic details

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Patient

Sex

Age (years)

FEV1 (l)

FEV1 (% predicted)

ICS

Dose (µg)

Second-line

Severity

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1	F	56	1.50	56	FP	500	SM, ML	S
2	F	40	1.83	73	FP	1000	SM	M
3	F	83	1.21	58	BDP	800	SM	S
4	F	66	0.86	61	FP	500	SM, ML	S
5	M	76	2.00	73	FP	1000	SM	M
6	F	70	0.81	41	BDP	800	SM	S
7	M	29	3.44	78	FP	500	SM	M
8	F	35	3.04	110	FP	500	SM	M
9	F	42	2.51	93	FP	1000	SM	M
10	M	83	1.54	66	BDP	1000	SM	M
11	F	41	3.15	104	FP	500	SM, ZL	S
12	F	55	1.69	66	BDP	1600	SM, ML	S

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FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; FP, fluticasone propionate; BDP, beclomethasone dipropionate; SM, salmeterol; ML, montelukast; ZL, zafirlukast; S, severe; M, moderate.

Discussion

This is the first study to demonstrate that stepping-down ICS therapy in patients with stable asthma is not being routinely adopted in secondary care. Most of the patients were maintained on their usual dose of ICS irrespective of the fact that their asthma had been clinically stable during the preceding 12 months. It is noteworthy that no deterioration in asthma control occurred in the two patients who had step-down in ICS therapy.

We appreciate that our cohort of patients were small in numbers. This was simply a reflection of the difficulty in recruiting patients for such a study in secondary care. Asthma is a chronic condition that is mainly managed in primary care. Indeed, patients who are referred for specialist input, consist primarily of difficult-to-control asthmatics or those who pose diagnostic uncertainties. Therefore, patients with asthma are seldom followed-up in secondary care, especially when diagnosis has been established and treatment commenced. Furthermore, many patients being actively followed-up in secondary care consist of severe asthmatics requiring oral or parenteral corticosteroids, with some requiring immunosuppressant therapy. Such patients were excluded from our study due to the strict criteria that was employed. The requirement for patients not to have an exacerbation or a course of corticosteroids during the preceding 12 months further reduced our number of suitable patients. Therefore, we acknowledge that the population of asthmatics in secondary care may not reflect the true asthmatic population as a whole when compared to those seen in primary care. Nevertheless, these asthmatics do fulfill the criteria for step-down in ICS therapy and there was indeed no reason to treat them any differently in keeping with current guidelines.

A possible reason for the lack of the adoption of stepping-down ICS therapy in secondary care could be attributable to the relatively selective asthmatic population served by secondary care physicians, where most patients have severe, brittle or difficult-to-control asthma. When such patients are using appropriate pharmacotherapy and clinically stable, there is understandably a disinclination to titrate therapy downwards, in case one offsets the control of asthma, which has been difficult to attain in the first instance. Another reason for the less-than-ideal implementation of stepping-down ICS therapy may be attributable to the fairly recent adoption and recommendation of such an approach in asthma management by the BTS and SIGN consortium, owing in part to the substantial lack of available data on this issue.

The rationale behind recommending stepping-down ICS therapy once asthma control is achieved is indisputable. ICS has the propensity to be absorbed from the lungs and gastrointestinal tract into the systemic circulation, leading to adverse effects in a variety of body systems.⁴ Additionally, studies have shown that most of the therapeutic benefit of ICS can be achieved at fairly low doses; 100 – 250µg daily for FP⁵ and 400µg daily for budesonide.⁶ Moreover, the validity of high dose ICS therapy has been put into question in light of recent data showing that stepping-up therapy by doubling the dose of ICS may be ineffective in influencing asthma exacerbations.^8,9 With the increasing popularity of combination ICS and long-acting ß₂-agonist inhalers (67% of our patient cohort), stepping-down is more complicated as it is more difficult to reduce the ICS dose without first splitting the combination inhaler into its separate moieties.

In conclusion, secondary care physicians need to have a heightened awareness in terms of stepping-down ICS therapy in patients with stable asthma. Failing to do so may expose patients to unnecessary and prolonged treatment with high doses of ICS with potentially serious long-term adverse sequelae. Stepping-down ICS therapy not only reflects good practice but is also in accordance with current asthma guidelines.

References

1. BTS/SIGN. The British Thoracic Society and Scottish Intercollegiate Guidelines Network 2004 update to the British guideline on the management of asthma. Available at: http://www.brit-thoracic.org.uk/docs/asthmafull.pdf.
2. GINA. The National Heart, Lung, and Blood Institute and World Health Organisation 2004 update to the Global Initiative for Asthma guideline on the global strategy for asthma management and prevention. Available at: http://www.brit-thoracic.org.uk/docs/asthmafull.pdf.
3. Hawkins G, McMahon AD, Twaddle S, et al. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003;326:1115-20.
4. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf 2000;23:11-33.
5. Holt S, Suder A, Weatherall M, et al. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253-6.
6. Masoli M, Holt S, Weatherall M, et al. Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur Respir J 2004;23:552-8.
7. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320:1368-73.
8. Harrison TW, Oborne J, Newton S, et al. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271-5.
9. FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-6.

Dear Editor

We thank Dr Chanarin for his interest in the new Asthma Guideline. We will answer the points made in the order in which he raises them.

1. The quoted studies on breast-feeding appear to be equivocal in terms of the protective effect on asthma, but both show protection against wheezing illness in the first years of life. The recommendation in the guideline specifies such wheezing illnesses rather than asthma and is therefore justified. We do agree that this is a difficult area, principally because of the problem of distinguishing asthma from the other causes of childhood wheeze. We believe other pertinent data will be available for the next revision of the guideline, and we will consider whether the current recommendation should be changed or its grading altered.

2. Dr Chanarin is wrong to accuse us of ignoring the conclusions of the Cochrane reviews on house dust mite (HDM) avoidance. The second, updated Cochrane report concludes that definitive evidence is still lacking, that routine use of HDM control measures cannot be recommended, and suggests possible benefit from “physical� methods as opposed to “chemical�. Our paragraphs on the topic reproduce these views. Faced with this conclusion, but knowing that patients and parents of asthmatic children may well wish to take reasonable measures to reduce HDM exposure, we simply listed methods which might be used by those who feel that they wish to follow this course despite the uncertain benefits. We do not recommend that HDM control is advocated routinely.

3. There has been little information available regarding the criteria for moving between treatment steps (although we note with interest the recent publication on monitoring sputum eosinophilia). The conventional advice includes, among other things, the advice that treatment should minimize bronchodilator requirements, and using a bronchodilator more than once a day is often taken as indicating the need to step up. However, this is not supported by any hard data. In the guideline, we do not suggest 10-12 puffs a day as the correct threshold, and Dr Chanarin will recognise that no such recommendation is made. This was simply quoted in the text in relation to one paper which had addressed the issue of assessing asthma control. In retrospect, we can see how this might be taken in a different context and we will address it in the next revision.

4. Regarding intravenous Aminophylline, Dr Chanarin seems to take the opposite stance to his position on HDM avoidance. Here he wants us to ignore the available evidence. The papers on Aminophylline are not all old (several of them are from the 1990s) and the Cochrane review judged them to be of moderate quality rather than poor. We therefore have to take note of these studies and it is difficult to recommend Aminophylline in the face of the consistent absence of benefit which they show, particularly when there are better alternatives. We too recognise the power of personal experience on this issue, but feel that intravenous Aminophylline has been justifiably down-graded.

In relation to introducing the new pieces of advice to his hospital, we can only say to Dr Chanarin that this is simply a guideline, and we fully understand that each doctor must take responsibility for his own treatment strategies. However, we can assure him that these recommendations were all given careful thought and, whilst some may prove to be wrong, we would hope that they are not rejected without equally careful consideration.

We thank Dr Chanarin again for the attention he has obviously given to the document and for taking the time to feed back to us.

Dr BG Higgins
Co-Chairman
British Thoracic Society/SIGN Asthma Guideline Committee

Dr G Douglas
Co-Chairman
British Thoracic Society/SIGN Asthma Guideline Committee

Dear Editor

The New Guidelines use evidence based methodology extensively. This methodology has been developed by the Scottish Intercollegiate Guidelines Network and is not only well respected but has been widely applied to develop other guidelines. The guidelines use levels of evidence, I quote
“Level A is: At least one meta analysis, systematic review, or RCT rated as 1++ and directly applicable to the target population or A body of evidence consisting principally of studies rated as 1+ and directly applicable to the target population and demonstrating overall consistency of results.�

How have these principles been applied?

The section on Primary prophylaxis makes only one grade A recommendation and this is on breast feeding. In the evidence the authors site two main pieces of evidence which contradict each other. The first is a systematic review and a meta-analysis involving 8183 subjects followed for 4 years which apparently revealed a significant protective effect of breast feeding against the development of asthma. The second study contradicts this. The second study is in 1246 patients and found that there was a reduction in early life wheeze but an increase in asthma at six years. If the question is does breast feeding protect against the subsequent development of asthma then the answer on the given evidence is clearly undecided and surely no evidence based advice can be given, certainly not level A guidance. What advice should I give to a worried mother to be if she asks me what she can do to prevent her child developing asthma?

The section on secondary prophylaxis is also confusing. House dust mite control measures are reviewed and no less than two Cochrane reviews are quoted. Both reviews concluded that current physical and chemical methods are ineffective. By the SIGN methodology a clear recommendation could be made at grade A level that house dust mite control measures can not be recommended. The guidelines do not do this. The guidelines instead use a tick box to suggest that the user can ignore the evidence and use all the techniques for house dust mite avoidance which have just been reviewed and shown to be ineffective.

There are other confusing statements. There is a comment in the section on dosing of inhaled short acting beta 2 agonists which refers to
“>10-12 puffs per day as a marker of poorly controlled asthma.�

Surely this is an understatement. The previous BTS guidelines, the American Thoracic Society Guidelines and Consensus international guidelines have used doses of greater than 1 puff a day as a sign of poor asthma control. The inference being that 1 or more puffs a day should lead to a stepping up of treatment. Are the new guidelines suggesting that we step up only when patients are using >10-12 puffs of beta 2 agonist a day?

Finally intravenous aminophylline is removed from the routine management of acute severe asthma and replaced by magnesium. Aminophylline will never do well in any evidence based guidelines as the studies are old, usually underpowered and poorly designed. The guidelines methodology permits a
“tick box�
to represent
“recommended best practice based on the clinical experience of the guideline development group�.

Why could intravenous aminophylline not have received such a commendation? It is hard to find a GP or consultant who can not remember using aminophylline with good effect. Clearly this is anecdote but is a good example of
“recommended best practice based on the clinical experience of�
doctors who look after patients with acute severe asthma. I feel very unhappy about this change and will hesitate before recommending that our hospital adopt the new management charts for acute severe asthma as set out in Annex 2 of the guidelines.

Yours Faithfully

Dr Nicholas Chanarin