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
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Inhaled steroids do appear to somewhat enhance quality of life for
those with emphysema, but is not without risk.
thinning of the lung wall can progess to the point of hemmorraging as
it did with my mother three years ago, resulting in her death.
caution would especially apply if the patient is on anticoagulants or
herbs which have an anticoagulant effect.
Competing interests: No competing interests
Chronic Obstructive Pulmonary Disease is very common in India because
of increased habit of cigarette and ‘ bidi’ smoking. Majority of
patients take oral steroid tablets for years without realizing the
dreadful complications of corticosteroid. Moreover, less than 10% of these
patients get some symptomatic relief.
The inflammatory pattern in COPD differs markedly from that seen in
asthma, with preponderance of macrophages and CD8+ T-lymphocytes in the
airways and lung parenchyma, and an increase in macrophages and
neutrophils in sputum and bronchoalveolar lavage, in contrast to the
increase in eosinophils and activation of mast cells and CD4+ T-cells
that are characteristic of asthma . In both chronic diseases there is an
increased production of cytokines, but the pattern differs with IL-8
predominating in COPD, compared to IL-4 , IL-5 , and IL-13 in asthma. Even
high dose of corticosteroids do not suppress inflammation in COPD.
Neutrophilic inflammation which is characteristic of COPD is
resistant to corticosteroid whereas eosinophilic inflammation
characteristic of asthma is suppressed by inhaled steroids.Inhaled
corticosteroids treatment should not be routinely recommended for the
management of COPD, unless there is coexisting asthma.
Competing interests: No competing interests
Editor – Chronic obstructive pulmonary disease (COPD) represents a
significant health economic burden and exacerbations of the condition
commonly lead to hospitalisation. Recent evidence(1) suggests that
systemic
corticosteroids facilitate quicker attenuation of exacerbations requiring
hospitalisation: the direct therapeutic cost of Prednisolone (30mg daily
for
2 weeks) in these circumstances is £2.00. Dr Burge et al (2) conclude
that the data from the ISOLDE Trial provides an objective rationale for
the widespread use of high dose inhaled corticosteroids in all patients
with moderate to severe COPD: one may speculate that the observed annual
reduction in exacerbation frequency accompanying their use (25%) may
impact on subsequent hospitalisations.
These issue have been partly addressed in a cost description in our health
district in N. E. England (total population ~ 350,000), an area with high
pulmonary morbidity and socio-economic deprivation, in which there is an
estimated local population of 5,000 patients with moderate to severe COPD
(data acquired through a community spirometric screening programme in
general practice).
In the twelve monthly period April 1998 – March 1999, there were 1165
admissions due to exacerbations of COPD with mean duration of hospital
stay 9.5 days. The integrated health care cost per patient exacerbation
episode was estimated at £1445, with an annual accumulative cost of £1.68
million.
The annual cost of inhaled fluticasone propionate (FP) 500ugs twice daily
delivered from a 120 metered dose unit inhaler is £473. If our entire
local population with COPD was administered inhaled FP at a dose of 500ugs
twice
daily, the incurred direct tangible therapeutic cost would approach £2.4
million annually.
Is this a justifiable prospective health or cost
economic intervention given that it remains clinically speculative as to
how many
hospitalisations directly or indirectly would be offset by this
therapeutic strategy, assuming otherwise optimal clinical care?
Competing Interests: None
1. Davies L, Angus R. M, Calverley P. M. A. Oral corticosteroids in
patients admitted to hospital with exacerbations of chronic obstructive
pulmonary disease: A prospective randomised controlled trial. Lancet
1999; 354:
456-460
2. Burge P. S, Calverley P. M A, Jones P. W, Spencer S, Anderson J.
A, Maslen T. K. on behalf of the ISOLDE study investigators. 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 (13th May).
I.K. Taylor
Consultant Physician
Department of Respiratory Medicine,
Chest Clinic,
Sunderland Royal Hospital,
Kayll Road,
Sunderland
SR4 7TP
S. A. Haggerty
Respiratory Nurse Specialist
Department of Respiratory Medicine,
Chest Clinic,
Sunderland Royal Hospital,
Kayll Road,
Sunderland
SR4 7TP
A. D. Lawrence
Research Associate
Department of Respiratory Medicine,
Chest Clinic,
Sunderland Royal Hospital
Kayll Road,
Sunderland
SR4 7TP
N. P. Keaney
Consultant Physician
Department of Respiratory Medicine,
Chest Clinic,
Sunderland Royal Hospital
Kayll Road,
Sunderland
SR4 7TP
Competing interests: No competing interests
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
Critical reading exercise
Since the topic of this paper is important in primary care, and its
methods, results and conclusions clearly presented, I thought that it
might make an interesting subject for a tutorial on critical reading with
my GP 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 (having already read previous e-responses to the
article which cover others).
1. The diagnostic criteria chosen differ from those currently
recommended by the B.T.S.; the latter do not refer to FEV1 after
bronchodilatation, and mild COPD is defined as 60-79% predicted, compared
to 85% in the article. What is the rationale behind these criteria?
2. Table 2, under FEV1 after bronchodilator refers to Predicted FEV1
at 3 months and 3 years: should this read "Mean FEV1" or have I
misunderstood?
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.
Finally, 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 relatively minor reduction in
exacerbations on treatment.
All the same, I thank the authors for prompting me to spend an hour
in analytical mode instead of on automatic pilot!
Dougal Jeffries
Competing interests: No competing interests