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BMJ. Nov 25, 2000; 321(7272): 1349.
PMCID: PMC1119077
The ISOLDE trial
Side effects with inhaled steroids should not be forgotten
Brian J Lipworth, professor of allergy and respiratory medicine
Ninewells Hospital, Dundee DD1 9SY ; b.j.lipworth/at/dundee.ac.uk
Editor—Burge et al in the ISOLDE study have shown a small but significant improvement in clinical outcomes with high dose inhaled fluticasone in patients with chronic obstructive pulmonary disease, without influencing the decline in lung function.1 Their recommendation for using high dose inhaled steroids needs to be tempered on the basis of their potential for producing systemic adverse effects, especially in susceptible elderly patients.
In the ISOLDE study there was a significant but small degree of adrenal suppression, as shown by 11% and 14% falls in serum concentrations of cortisol measured at 8-10 am after six and 24 months of fluticasone compared with no change in the placebo group. Spot measurement of cortisol concentrations at 8-10 am is extremely insensitive at detecting adrenal suppression,2 which makes the finding of any significant fall even more relevant as a surrogate marker for potential systemic bioactivity in these patients. This is supported by the fact that there are more patients with bruising after taking fluticasone than placebo: 7% compared with 4% of patients. As bruising is a visible marker of altered collagen turnover in skin, similar collagen adverse effects might conceivably have also occurred in bone tissue. A recent study of asthmatic patients found a significant inverse relation between cumulative inhaled steroid dose and lumbar bone density.3
Consequently, the modest efficacy gains with high dose fluticasone should be balanced against the long term potential for systemic adverse effects. Without long term data on bone mineral density it is difficult to make rational recommendations for the use of high dose fluticasone in elderly patients with chronic obstructive pulmonary disease who may be at risk of developing steroid induced osteoporosis.
This may particularly be the case for fluticasone, which, because of its high lipophilicity, has a large volume of distribution and consequently a large reservoir of drug at steady state residing in systemic fat tissues, which equilibrates with the blood.4 An analogy is to consider a wet sponge with the constant drip representing the low plasma levels of fluticasone and the total body exposure as the amount which comes out when the sponge is squeezed. This is supported by meta-analysis of 21 studies where fluticasone exhibited significantly greater dose related adrenal suppression than other inhaled steroids—for example, 4.3-fold (P<0.001) greater than budesonide.5
Footnotes
Competing interests: Professor Lipworth's wife and his mother have shares in GlaxoWellcome. The department has received financial support from GlaxoWellcome for attending scientific meetings and has received second hand computer equipment. The department has also received financial support from AstraZeneca, Aventis, Schering Plough, and 3M for clinical trials, giving talks, and meetings.
1. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslem TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297–1303. . (13 May.) [PMC free article] [PubMed]
2. Lipworth BJ, Seckl JR. Measures for detecting systemic bioactivity with inhaled and intranasal steroids. Thorax. 1997;52:476–482. [PMC free article] [PubMed]
3. Wong CA, Walsh LJ, Smith CJ, Wisniewski AF, Lewis SA, Hubbard R. Inhaled corticosteroid use and bone mineral density in patients with asthma. Lancet. 2000;355:1399–1403. [PubMed]
4. Thorsson L, Dahlstrom K, Edsbacker S, Kallen A, Paulson J, Wiren JE. Pharmacokinetics of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol. 1997;43:155–161. [PubMed]
5. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. 1999;159:941–955. [PubMed]

Side effects are source of concern
Dougal Jeffries, general practitioner
Bemerton Heath Surgery, Salisbury SP2 9DJ ; dougal.j/at/virgin.net
 
Editor—Since the topic of the paper by Burge et al is important in primary care, and its methods, results, and conclusions are clearly presented,1-1 I thought that it might make an interesting subject for a tutorial on critical reading with my general practice registrar. A more than normally careful scrutiny made me realise how much I must miss in my usual scanning of the BMJ. I would like to raise three points.
(1) The diagnostic criteria chosen differ from those currently recommended by the British Thoracic Society, which do not refer to forced expiratory volume in one second after bronchodilatation, and mild chronic obstructive pulmonary disease is defined as 60-79% predicted, compared with 85% in the article.1-2 What is the rationale behind these criteria?
(2) Table 2, under forced expiratory volume in one second after bronchodilator, refers to predicted forced expiratory volume in one second at three months and three years: should this read “mean forced expiratory volume in one second?”
(3) The finding that an oral steroid trial does not predict response to an inhaled steroid not only runs counter to the current guidelines, which recommend such a trial, but surely demands more discussion than it is accorded.
I share other commentators' concerns at the side effects, such as hoarseness and bruising, and the doubtful cost benefit, given the high cost of inhaled fluticasone and the comparatively minor reduction in exacerbations on treatment.
Footnotes
Competing interests: None declared.
References
1-1. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslem TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297–1303. . (13 May.) [PMC free article] [PubMed]
1-2. COPD Guidelines Group of Standards of Care Committee of BTS. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax. 1997;52(suppl 5):S1–28. [PMC free article] [PubMed]

Pharmaceutical companies should admit high cost of treatment
Graham K Crompton, recently retired consultant physician, Respiratory Unit, Western General Hospital, Edinburgh
14 Midmar Drive, Edinburgh EH10 6BU ; gcromp/at/hotmail.com
 
Editor—I refer to the paper by Burge et al on the use of fluticasone in patients with mild chronic obstructive pulmonary disease.2-1 Since inhaled corticosteroids are of great value in chronic asthma one can understand the clinical logic of assessing this form of treatment in chronic obstructive pulmonary disease and also the commercial incentives behind this form of research. The AstraZeneca attempt to cash in on this enormous market failed to convince astute clinicians that inhaled steroids were of benefit to patients with comparatively mild chronic obstructive pulmonary disease.2-2 Now we have to contemplate whether inhaled fluticasone propionate in a dose of 500 μg twice daily has any convincing cost efficiency benefits, when given for three years, to patients with more advanced chronic obstructive pulmonary disease.2-1
Burge et al conclude that these improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease. The improvements refer, however, to a minimal reduction of inadequately defined exacerbations and an improvement of an assessment of health status. The fact that there was no change in the primary end point of decline in forced expiratory volume in one second between the active and placebo groups has apparently not dampened the enthusiasm of Burge et al with regard to the value of fluticasone in chronic obstructive pulmonary disease.
I do not believe in any cost benefits of treatment with inhaled corticosteroids in patients with chronic obstructive pulmonary disease of any severity. This study should have been performed using a dry powder inhaler rather than a pressurised metered dose inhaler since the surfactants in the pressurised inhaler could have had a deleterious effect in the placebo group, as has been reported to occur in asthmatic subjects.2-3,2-4 The effect of twice daily inhalation of a placebo by pressurised metered dose inhaler for three years in patients with chronic obstructive pulmonary disease is unknown but could be responsible for the slightly greater number of exacerbations in this group. Any adverse effects of the surfactants or lubricants in these inhalers might have been negated by fluticasone in the active group.
Gratitude is due to AstraZenica and GlaxoWellcome for sponsoring these huge expensive trials. I believe, however, that both companies should now admit that the value of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease of any severity has not yet been established. This form of treatment is not inexpensive, and on the present evidence the NHS should not be expected to fund the long term use of inhaled corticosteroids in patients with chronic obstructive pulmonary disease.
Footnotes
Competing interests: Dr Crompton retired from the NHS in June 1999. Before his retiral he accepted fees and funds for attending symposia, lecturing, research, and staff funding from AstraZeneca and GlaxoWellcome. He also holds shares in AstraZeneca.
References
2-1. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslem TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297–1303. . (13 May.) [PMC free article] [PubMed]
2-2. Pauwels RA, Löfdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med. 1999;340:1948–1953. [PubMed]
2-3. Yarbrough J, Lyndon RN, Mansfield E, Ting S. Metered dose inhaled induced bronchospasm in asthmatic patients. Ann Allergy. 1985;55:25–27. [PubMed]
2-4. Selroos O, Löfroos A-B, Pietinalho A, Riska H. Comparison of terbutaline and placebo from a pressurised metered dose inhaler and a dry powder inhaler in a subgroup of patients with asthma. Thorax. 1994;49:1228–1230. [PMC free article] [PubMed]
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