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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 doi: https://doi.org/10.1136/bmj.320.7245.1297 (Published 13 May 2000) Cite this as: BMJ 2000;320:1297

Rapid Response:

Dont forget about side effects with inhaled steroids in COPD

Burge and coworkers in the Isolde study have shown a small but
significant improvement in clinical outcomes with high dose inhaled
fluticasone in COPD, without influencing the decline in lung
function.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 who have this
condition.

In the Isolde study there was a significant but small degree of
adrenal suppresion, as a 11% and 14% fall in 8-10 am serum cotrisol after
6 and 24 months of fluticasone compatared to no change in the palcebo
group.Given that spot measurement of 8-10 am cortisol is extremely
insensitive at detecting adrenal suppression[1],this makes the finding of
any significant fall even more relevant as a surrogate marker for
potetnial systemic bioctivity in these patients .This is supported by
there being more patients with bruising with fluticasone than palcebo:4%
versus 7% of patients.As bruising is a visable marker of altered collagen
turnover in skin,it is conceiveable that similar collagen adverse effects
might have also occured in bone tissue .Indeed in a recent study of
asthmatic patients there was a significant inverse relationship between
cumulative inhaled steroid dose and lumbar bone density [2].

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 COPD who may be at risk from developing steroid
induced osteoporosis.

This may particularly be the case for fluticasone which due 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[3]. 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-as for example 4.3 fold
[p<_0.001greater than="than" budesonide4.="budesonide4." p="p"/> References

[1]Lipworth BJ,Seckl JR.Measures for detecting systemic bioactivity with
inhaled and intranasal steroids.Thorax 1997;52:476-482

[2]Wong CA,Walsh LJ,Smith CJP,et al .Inhaled corticosteroid use and bone
mineral density in patients with asthma.Lancet 2000:355:1399-403

[3]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;43:155-61

[4]Lipworth BJ. Systemic adverse effects of inhaled corticosteroid
therapy: A systematic review and meta analysis.Arch Intern Med 1999;159:941
-55

Conflicts of Interest
The spouse of BJL has shares in Glaxo-Wellcome and AstraZeneca .The
department has recived financial support from Glaxo-Wellcome for attending
scientific meetings and has recieved second hand computer equipment.The
department has also received finacial support from AstraZeneca ,Aventis
and 3M for clinical trials ,giving talks and meetings.

Competing interests: No competing interests

16 May 2000
Brian J Lipworth
Professor of allergy and respiratory medicine
Ninewells Hospital ,Dundee