Asthma, COPD, Coughs
review of medicines against asthma, copd and coughs
Final report
Review of medicines
against asthma,
COPD and coughs
www.lfn.se
the pharmaceutical benefits board
review of medicines against asthma, copd and coughs
Final report – review of medicines against asthma, COPD and coughs
1st edition.
First printed May 2007
This report can be ordered from:
LFN, Box 55, 171 11 SOLNA
Telephone: +46 8 56 84 20 50, Fax: +46 8 56 84 20 99
[email protected], www.lfn.se
review of medicines against asthma, copd and coughs
Authors:
Kajsa Hugosson, Msc Pharm
Andreas Engström, Msc in Economics and business
External experts:
Carl-Axel Hederos, Senior Physician
Children and Youth Clinic,
Health Clinic Gripen in Karlstad
Mona Palmqvist, Senior Physician,
Allergy department, Sahlgrenska
University Hospital in Gothenburg
Björn Tilling, District Physician,
Health Clinic in Åtvidaberg
Project group:
Kajsa Hugosson, project manager
Karl Arnberg
Andreas Engström
Gunilla Eriksson
Love Linner
Leif Lundquist
Decision-makers:
Former director-general Axel Edling
Professor Per Carlsson
Professor Olof Edhag
Docent Lars-Åke Levin
Senior Physician Rurik Löfmark
Specialist in general medicine Ingmarie Skoglund
Professor Rune Dahlqvist
Docent Ellen Vinge
Senior Physician Gunilla Melltorp
Former Member of Parliament Ingrid Andersson
Vice Association Chairperson David Magnusson
GENERAL INFORMATION ON THE THERAPEUTIC GROUP
ATC codes: R03 and R05
the pharmaceutical benefits board
Why is the LFN conducting a review?
On adopting new reimbursement rules in October of 2002, it was not prac­
tically possible to review all medicines according to the new rules. Therefore,
the Pharmaceutical Benefits Board is now conducting a review of approxima­
tely 2,000 medicines to see if they should continue to be given reimburse­
ment status in the future. Each of the medicines will be tried according to the
new rules and will either retain or lose reimbursement status.
More health per tax krona
The purpose of the new reimbursement rules is to allow the Swedish popula­
tion to extract as much health value as possible for every tax krona allocated
to medicines. We exclude those medicines that do not show sufficient effecti­
veness in relation to what they cost. However, this does not mean that we aim
only to have inexpensive medicines in the medical reimbursement system. If
a medicine has positive effects on a person’s health and quality of life, and on
a socio-economic level as a whole, then it may also be worth paying for.
Three principles for making decisions
In reimbursement decisions for a medicine, we shall, among other things,
evaluate whether or not it is cost-effective. This means that we weigh the
effectiveness of the medicine against its cost. We also incorporate other
principles into our evaluation: the needs and solidarity principle, which means that those who have the greatest medical needs shall receive more of our
healthcare resources than other patient groups; and the human value princi­
ple, which means that we must respect the equal value of all individuals.
49 groups to be reviewed
In this review we are testing medicines in one therapeutic area after another.
The review encompasses a total of 49 groups of medicines and the order in
which they are tested is determined by how large the sales figures were for
each respective group in 2003. The medicines that sold the most will be
reviewed first. However, the first two groups – medicines against migraine
and medicines against diseases caused by stomach acid – were pilot groups
selected on the basis of other criteria. The review of these two groups was
presented in 2005 and 2006.
review of medicines against asthma, copd and coughs
Extensive research and groundwork
Before any decision is made, we perform a comprehensive investigation and
analysis of data on medical effect and cost-effectiveness which we request
from pharmaceutical companies in regard to their medicines. We also review
the scientific, medical, and health economic literature available for the group
of medicines to be reviewed. In addition, we sometimes need to construct
our own health economic models. We publish each completed review in a
final report. The report documents the existing body of scientific knowledge
for the group in question. Where possible, the agency also reports on an
evaluation of each medicine’s cost-effectiveness. We also prepare a synopsis
of the report to be printed separately.
Assessment by independent external experts
The assembled knowledge in regard to medical effect and health economic
documentation which we present in the final report has been assessed by
independent external medical experts. The report has also been circulated for
comments to the SBU (The Swedish Council on Technology Assessment in
Health Care), Medical Products Agency and the National Board of Health
and Welfare. The companies and patient organisation groups concerned, as
well as the county councils’ pharmaceutical reimbursement group, have also
had the opportunity to give input.
the pharmaceutical benefits board
The review of medicines against asthma,
COPD and coughs
In this review Läkemedelsförmånsnämnden (LFN) has evaluated medicines
used to treat asthma, chronic obstructive pulmonary disease (COPD) and
coughs. The review also covers medicines used to treat cystic fibrosis. In total
the review comprises approximately forty medicines which prior to the review
were reimbursed in the Swedish reimbursement system.
This review is part and parcel of our review of the entire list of medicines
in Sweden which have been accorded reimbursement status. In this we rule
on the continued reimbursement, or otherwise, of medicines included in
the reimbursement system. Each and every medicine is evaluated and will
either lose or retain its reimbursement status. The purpose of the exercise is
to extract as much health as possible for every tax krona which is expended
on healthcare. This is the third therapeutic group to be presented. Previously
we presented the review of medicines against migraines as well as medicines
against diseases caused by stomach acid.
Medicines against asthma, COPD, cystic fibrosis and coughs
The treatment of asthma, COPD, cystic fibrosis and coughs involves using
medicine to open the airways, decrease swelling and inhibit the production
of mucus. The same medicine is often used to treat different diseases, in
particular for medicines against asthma and COPD. The same medicine can
also be in different pharmaceutical forms. It can for example be available as
a tablet, in liquid form, for use in a nebuliser (a device designed for inhaling
medicines) and as powder for inhalation. For inhalable medicines there are a
number of different aids for inhaling the medicine. A number of the medici­
nes are also available as a double action medicine. Medicines against coughs
are an older type of medicine, often lacking in scientific documentation
which backs up the medical effect of the medicines in question.
Nine medicines to leave the reimbursement system
In total 34 medicines have retained their reimbursement status. Nine medi­
cines have lost their status as a reimbursed medicine while limited reimbur­
sement has been granted for one medicine. Of these ten medicines, six are
cough medicines and four are medicines against asthma. For asthma medici­
nes there are a number of alternatives still in the reimbursement system with
as good as, or better, medical effect.
review of medicines against asthma, copd and coughs
Coughing and mucus production as a result of a common cold cause such
short-term and relatively minor discomfort that it is not reasonable to reim­
burse medicines for the treatment of these symptoms. And furthermore, the
effect of these medicines is rather weak and poorly documented.
The Swedish reimbursement system is product-centred, meaning that reim­
bursement is contingent on the product. There are two possible routes to
reimbursement; General and limited reimbursement. General reimbursement
means that a medicine is reimbursed for the whole range of its therapeutic
uses. Limited reimbursement means that a medicine is only reimbursed for a
specific therapeutic area or patient group.
Table 1: Medicines granted general, limited or no
reimbursement from the 1st of October 2007.
General reimbursement granted:
• Acetylcystein
• Aerobec
• AerobecAutohaler
• Airomir
• AiromirAutohaler
• Atrovent
• Bambec
• BeclometEasyhaler
• Becotide
• Bricanyl
• BricanylDepot
• BricanylTurbuhaler
• BudensonidArrow
• BuventolEasyhaler
• Combivent
• FlutideDiskus
• FlutideEvohaler
• Foradil
• GionaEasyhaler
• Ipramol
• IpratropiumbromidArrow
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Mucomyst
OxisTurbuhaler
Pulmicort
PulmicortTurbuhaler
Pulmozyme
SalbutamolArrow
SeretideDiskus
SeretideEvohaler
SereventDiskus
Singulair
Spiriva
SymbicortTurbuhaler
TeofyllaminIpex
Teovent(oralandrectalsolution)
Ventoline
VentolineDiskus
VentolineEvohaler
VentolineDepot
Viskoferm
Xolair
Limited reimbursement:
• Bisolvon
Bisolvonhasbeengrantedreimbursementonlyforpatientswithcysticfibrosisorprimaryciliarydysfunction.
No reimbursement granted:
• EfedrinhydrokloridAPL(oralsolution)
• EfedrinhydrokloridiQuillaSimplexAPL
• Lepheton-DesentolAPL
• Lomudal(powderforinhalation)
•
•
•
Mollipect
Teovent(tablet)
Theo-Dur
Appealed decisions:
• AsmanexTwisthaler
•
EfedrinhydrokloridAPL(capsule)
ThecompanieshaveappealedtheLFN’sdecisiontoremovethesemedicinesfromthereimbursementlist.
Thesemedicineswillbecauseofthisretaintheirreimbursementuntilthecourtshaveruledotherwise.
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the pharmaceutical benefits board
Decisions free up to 40 million Skr per year
The decisions in this review are estimated to save approximately 40 mil­
lion Skr per year. This money can be used for other more urgent treatments
within the healthcare system.
The decisions take effect on the 1st of October, 2007, unless appealed. Follo­
wing this date the medicines which have been excluded from the reimburse­
ment system will no longer be reimbursed. This means that patients have ap­
proximately four months to contact their doctor and change their treatment.
For those decisions that have been appealed, the medicine will continue to
be reimbursed until the courts rule otherwise. A list of appealed decisions is
available at the LFN website.
Sales value of 1.8 billion Skr
The medicines in this review have a combined sales value of 1.8 billion Skr.
The patients themselves pay approximately a quarter of the costs. Sales are
dominated by inhaled medicine in powder form which stands for 60 percent
of the sales.
This is used mainly for treating asthma, but also for COPD. Over the past
five years there have been some changes across the composition of the sales.
Sales for double action medicines have exhibited strong growth. Simultaneo­
usly, it is possible to discern some decline in the sales of anti-inflammatory
drugs for inhalation and long-acting bronchodilators, both of which are the
key components of double action drugs. It is however clear that the increase
cannot only be explained by a matching decrease in the sales of these two
groups. One probable contributing factor is the usage of double action drugs
for COPD.
There are a number of medicines against coughs. Many are OTC and only a
few are included in the reimbursement system. Sales within the reimburse­
ment system consist mainly of two medicines: Mollipect and Acetylcysteine.
review of medicines against asthma, copd and coughs
Table 2: Composition of sales for medicines in the asthma, COPD and
coughs review.
Pharmaceutical group
Sales value 2006 (M Skr)
Bronchodilatorsforinhalation
966
Anti-inflammatorysubstancesforinhalationand
anticholinergics
536
Bronchodilatorsinotherdosageforms
14
Others
88
Expectorant
120
Coughreductionsubstances
12
Coughreductionsubstancesincombinedforms
58
Total
1 794
Socio-economic costs run to many billions
Treatment of a disease does not only comprise the cost for the medicine.
Diseases can also cause other costs for society. For asthma and COPD these
costs run into the billions. These diseases cause costs within both out and
in-patient care in the form of extra visits to the doctor, emergency visits and
hospital stays. Other costs such as absence from work can be placed on top
of this.
Coughing and other problems probably cause costs both directly in the healt­
hcare system and through decreased productivity at work. The total socio­
economic costs of coughing are however not known.
Three principles for decision-making
When judging whether a medicine should be included in the reimbursement
system we take into account three principles from the Act on Pharmaceutical
Benefits etc. The three principles cover:
•
•
•
cost-effectiveness
needs and solidarity
human value
We are to evaluate whether a medicine is cost-effective, meaning we weigh
the value of the medicine against the cost. We shall also utilise the other two
principles in our evaluations. The needs and solidarity principle means that
those with the greatest medical need should have more healthcare resources
than other patient groups. The human value principle means that healthcare
should respect the equal value of all people.
the pharmaceutical benefits board
Treatment of asthma and COPD is cost-effective
Asthma and COPD are diseases which can have a huge impact on patient
quality of life. They also carry a risk of premature death, although the risk
has decreased considerably since the introduction of anti-inflammatory medi­
cines (steroids) and bronchodilators. If the medicines are used in accordance
with the current recommendations then there is evidence in the scientific
literature that the steps used in the treatment ladder for asthma are cost­
effective.
The health economic evidence in support of medicines used for treating
COPD is somewhat weaker. We judge the long-acting bronchodilators and
anticholinergics to be cost-effective compared to no treatment, and the same
is true for inhaled steroids. All medicines in this area are, however, not cost­
effective.
Cystic fibrosis is a serious disease
Excess mucus in the airways can be a product of various diseases, everything
from the common cold to the constant overproduction of mucus in cystic
fibrosis. Cystic fibrosis is a difficult and chronic disease leading to huge losses
in quality of life and a greatly increased risk of a premature death. That is
why it is crucial that expectorant medicine be reimbursed for these patients.
Coughing is not a serious disease
Coughing and mucus production as a result of a common cold cause such
short-term and relatively minor discomfort that it is not reasonable to reim­
burse medicines for the treatment of these symptoms. And furthermore, the
effect of these medicines is rather weak and poorly documented. Therefore,
patients who wish to use these medicines should stand for the costs them­
selves.
Decisions for the various medicines in this review
This review covers 43 medicines in total. Here is a summary of the main
points in the decisions made.
Short and long-acting bronchodilators for inhalation
retain reimbursement
All bronchodilators have retained their reimbursement status. These medici­
nes are used mainly for treating asthma and COPD, but they are also used in
standard treatment for cystic fibrosis.
We believe it is important with a broad range of medicines in this group.
Short-acting bronchodilators are used in an emergency situation to reverse
review of medicines against asthma, copd and coughs
narrowing of the airways, and it is therefore important that the patient can
choose between different active ingredients and various inhalers.
We have not located any clinical studies which show any difference in effect
between the medicines. We can however say that there are differences in
price. We find the difference in price to be acceptable considering this is an
emergency treatment.
The short-acting bronchodilators which remain in the reimbursement system
are: Airomir (salbutamol), Airomir Autohaler (salbutamol), Bambec (bam­
buterol), Bricanyl (terbutaline), Buventol Easyhaler (salbutamol), Ventoline
(salbutamol), Ventoline Diskus (salbutamol) and Ventoline Evohaler (salbu­
tamol).
Long-acting bronchodilators will also remain in the reimbursement system
and are mainly used for maintenance treatment.
A large number of health economic studies point towards the cost-effective­
ness of these substances in maintenance treatment of asthma in combination
with inhaled steroids. There are differences in price between the substances.
For these medicines we find the price difference to be acceptable as it gives
the patients access to a number of active ingredients and inhalation devices.
The long-acting bronchodilators which remain in the pharmaceutical reim­
bursement system are: Foradil (formoterol), Oxis Turbuhaler (formoterol)
and Serevent Diskus (salmeterol).
Anti-inflammatory substances for inhalation
– Not reasonable to reimburse Asmanex
Inhaled steroids have a well-documented effect and an accepted place in
therapy. Treatment with inhaled steroids as a group can also be considered
cost-effective. However, this does not mean that all inhaled steroids are cost­
effective.
We find anti-inflammatory substances, at directly comparable doses, to
produce similar effects in regard to asthma. At these doses there is a big dif­
ference in price between the products. The price difference varies depending
on which doses you compare. The most expensive substances are between 30
and 70 percent more expensive then the cheapest. For Asmanex Twisthaler
(mometasone) we find the cost in relation to the effect does not merit inclu­
sion in the pharmaceutical reimbursement system.
Therefore there is no reason for Asmanex to retain its reimbursement status.
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the pharmaceutical benefits board
The pharmaceutical company marketing Asmanex has not shown that the
increased cost the treatment incurs adds any value compared to other inha­
led steroids. Asmanex is 60 to 70 percent more expensive than the cheapest
alternative. We do not believe the price difference to be justified and it to be
worth paying so much for yet another product in a range of products which
is already large.
The company has appealed the decision and as a result Asmanex will retain
its reimbursement until the courts have ruled otherwise.
The other six anti-inflammatory steroids retain their reimbursement status.
Also, the inhaled steroids in spray form and solution for nebulisers may
remain in the reimbursement system. It is urgent to have these substances
remain in the reimbursement system as these forms of medicine are mainly
used to treat children and the seriously ill.
The anti-inflammatory medicines which retain their reimbursement status
are: Aerobec (beclometasone), Aerobec Autohaler (beclometasone), Beclo­
met Easyhaler (beclometasone), Becotide (beclometasone), Flutide Diskus
(fluticasone), Flutide Evohaler (fluticasone), Giona Easyhaler (budesonide),
Pulmicort and Pulmicort Turbuhaler (budesonide).
Anticholinergics remain in the system
The medicines in this group are used almost exclusively to treat COPD, but
Atrovent (ipratropium) can also be used to treat asthma. We find that both
Spiriva (tiotropium) and all dosage forms which contain the active ingredient
ipratropium shall remain in the reimbursement system.
Ipratropium has a documented effect on lung function and breathing diffi­
culties for patients with COPD. It can also have an effect on asthma symp­
toms. Spiriva is somewhat more expensive than
ipratropium, but there are indications that Spiriva is cost-effective for the tre­
atment of COPD. The anticholinergics which remain in the reimbursement
system are: Atrovent (ipratropium), Ipratropiumbromid Arrow (ipratropium)
and Spiriva (tiotropium).
Double action drugs retain reimbursement
All double action drugs may remain in the reimbursement system. Seretide
and Symbicort are combinations of a long-acting bronchodilator and an
anti-inflammatory substance (steroid). There are price differences between
the substances but we consider these to be reasonable. We also consider it to
review of medicines against asthma, copd and coughs
be important with access to both of the double action drugs and devices. It
has been proven that it is cost-effective to add a long-acting bronchodilator
to inhaled steroids when the medical effect has been negligible, primarily
when treating asthma but also for COPD.
The cost for the pharmaceuticals becomes lower using a double action drug
than if each of the medicines is bought on their own. It is however important
to first arrive at the lowest effective dose for each of the medicines before
migrating to the double action drugs. This is in order to avoid a too high
maintenance dose of the inhaled steroid.
We consider the combination of an anticholinergic (ipratropium) and a
short-acting bronchodilator (salbutamol) to be of value for patients who are
in constant need of both of the active ingredients. The double action drugs
Combivent
and Impramol are between 10 and 30 percent cheaper than each of the medi­
cines bought on their own.
The double action drugs which retain their reimbursment status are: Combi­
vent (salbutamol and ipratropium), Ipramol (salbutamol and ipratropium),
Seretide Diskus(fluticasone and salmeterol), Seretide Evohaler (fluticasone
and salmeterol) and Symbicort Turbuhaler (budesonide and formoterol).
Singulair remains in the reimbursement system
Singulair (montelukast) in granule form and as a chewable tablet is of value
for children with infection-triggered asthma. The medicine is easy to take
and it is considered relatively free from side-effects. We consider it to be
especially valuable to have other dosage forms for children who can have dif­
ficulties with using inhalation devices in the correct way.
Singulair tablets have advantages which, despite the higher price, result in the
substance being granted continued reimbursement. Singulair has an anti-in­
flammatory effect which differs from the anti-inflammatory effect of inhaled
steroids. It also has a different side-effect profile compared to long-acting
bronchodilators.
We underline that it is important to try treatment with inhaled steroids and
long-acting bronchodilators before using Singulair due to the high cost. It is
also extremely important that the effect is evaluated and that treatment be
terminated if it is not giving results, in order for it to be cost-effective.
the pharmaceutical benefits board
Theophylline for emergency treatment still in reimbursement system
Theophyllines are used for acute and maintenance treatment for asthma.
This group of medicines may to a certain extent also be used for treating
COPD. But is not recommended as a general treatment option due to side­
effects and the risk of interactions when used together with other medicines,
as well as the risk of toxicity.
Theophyllines, in the form of injection fluid and oral solutions and supposi­
tories, are used primarily for emergency treatments. They are because of this
most widely used within in-patient care. Experts whom we have consulted
underline that there are patients who get the above forms of theophyllines on
prescription. This is mainly for patients with frequent asthma attacks who
fail to relieve the attack through using short-acting bronchodilators. In these
cases the patient can get help in stopping an attack by adding theophylline.
Children make up part of the patient group and pediatricians therefore see a
need for having the medicine within the reimbursement system.
The theophyllines which remain in the reimbursement system are: Teofylla­
min Ipex (theophylline), injection fluid and Teovent (choline theophyllinate)
in oral solutions and suppositories.
Theophyllines for maintenance treatment lose their reimbursement
We do not consider it proven that maintenance treatment with theophyllines is cost-effective. Furthermore, there are more modern medicines which are better documented both in terms of effect and safety.
The medical effect from theophyllines is difficult to judge. There is no lite­
rature showing that theophyllines are cost-effective in comparison with more modern medicines.
The theophyllines which lose their reimbursement status are: Teovent (choline theophyllinate) in tablet form and Theo-Dur (theophylline) prolonged-release tablets.
Lomudal leaves the reimbursement system
In our estimation the increased cost when using Lomudal is not compensated
for by any medical or financial advantages. Lomudal should therefore not be
covered by the reimbursement system. The medicine has no clear effect on
asthma according to the latest studies. It may have an effect on exercise-in­
duced asthma, but here there are cheaper treatment alternatives available.
review of medicines against asthma, copd and coughs
Lomudal is available in different formulations. This review only affects
Lomudal powder for inhalation. Our decision does not affect the other for­
mulations, eye-drops, nasal spray and oral solution. These formulations will
retain their reimbursement status.
Xolair retains reimbursement status
Xolair is a medicine which should only be used by people with very serious
asthma. We decided in March 2006 that Xolair should be included in the
pharmaceutical benefits scheme. We draw the same conclusion this time as
we did then, and continued inclusion is dependent on some follow-up con­
ditions. The company shall follow up the usage of Xolair in clinical practice.
These follow ups shall be reported to the LFN at the latest 31st of December,
2010.
Acetylcysteine retains its reimbursement
In our estimation soluble tablets with acetylcysteine shall remain in the
reimbursement system. We believe it to be justified to reimburse long-term
treatment with acetylcysteine for COPD patients with chronic bronchitis, as
well as for patients with cystic fibrosis.
Acetylcysteine is used as a standard treatment for patients with cystic fibrosis
and patients with primary ciliary dysfunction. This is a very serious disease.
Furthermore, these are patients with a great medical need where other treat­
ment alternatives are lacking or severely limited.
Acetylcysteine is also available as a solution for nebulisers. This medicine is
used as a standard treatment for patients with cystic fibrosis. Acetylcysteine as
a solution for nebulisers shall also retain its reimbursement status.
However, we consider coughing and mucus production as a result of a com­
mon cold to cause such short-term and relatively minor discomfort that it is
not reasonable to reimburse medicines for the treatment of these symptoms.
Neither is there any documentation which supports this usage of acetylcysteine.
The question is whether such a usage should be an exception for reimbur­
sement. However, in our estimation, it would be difficult to enforce such a
limitation in practice.
The medicines containing acetylcysteine which retain their reimbursement
status are: Acetylcysteine (acetylcysteine), Muscomyst (acetylcysteine) and
Viskoferm (acetylcysteine).
the pharmaceutical benefits board
A number of medicines against coughing lose their reimbursement
Coughing and mucus production as a result of a cold cause such short-term
and relatively minor discomfort that it is not reasonable to reimburse medici­
nes for the treatment of these symptoms. And furthermore, the effect of these
medicines is rather weak and poorly documented. Therefore, patients who
wish to use these medicines should stand for the costs themelves.
Mollipect contains an expectorant (bromhexine) and a bronchodilator (ephe­
drine) component. The studies done show that the expectorant component
(bromhexine) can have some small effect on the stickiness of the mucus, but
however has no effect on coughing, shortness of breath or lung function.
Ephedrine has a bronchodilator effect but has no effect on coughing unless it
is due to a narrowing of the airways. There are other bronchodilators which
are cheaper, better documented and have a better side-effect profile, if there is
a need for a bronchodilator effect.
The effect of Lepheton-Desentol is badly documented. There is no scientific
evidence showing an effect when used for treating coughing due to croup.
Neither is Lepheton-Desentol recommended for treatment of croup in the
Swedish pharmaceuticals book (Läkemedelsboken) There, instead, cortisone
in inhaled or tablet form is recommended. There is also scientific evidence
for this recommendation. The medicines Lepheton and Desentol have not
either been reimbursed in Sweden as free-standing medicines.
The medicines which, according to the LFN, should lose their reimbur­
sement status are: Mollipect (bromhexin/ephedrine), Lepheton-Desentol
(ephedrine/etylmorphine/diphenhydramine), Efedrinhydroklorid APL, oral
solution and capsules (ephedrine hydrochloride) and Efedrinhydroklorid in
Quilla Simplex APL (ephedrine hydrochloride).
The decision to exclude Efedrinhydroklorid APL capsules from the reim­
bursement system has been appealed. As a result the medicine will retain its
reimbursement until the courts have ruled otherwise.
Pulmozyme retains reimbursement
Pulmozyme is used for treating cystic fibrosis. There is no comparable medi­
cine on the market. Cystic fibrosis is a serious, chronic disease which leads to
great losses in quality of life and a greatly increased risk of an early death. It
is therefore crucial that mucus-reducing medicines be reimbursed for these
patients.
review of medicines against asthma, copd and coughs
Limited reimbursement for Bisolvon
Patients with cystic fibrosis and primary ciliary dysfunction should get this
medicine reimbursed. Most of these patients use Bisolvon for inhalation, but
they should also get reimbursement for Bisolvon tablets as this treats diseases
which lead to great losses in quality of life.
Coughing and mucus production as a result of a cold cause such short-term
and relatively minor discomfort that it is not reasonable to reimburse medici­
nes for the treatment of these symptoms. And furthermore, the effect of these
medicines is rather weak and poorly documented. Therefore, patients who
wish to use these medicines should stand for the costs themelves.
Reimbursement for Bisolvon in tablet form will therefore be limited to those
who have cystic fibrosis or primary ciliary dysfunction.
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the pharmaceutical benefits board
Contents
SUMMARY
1. INTRODUCTION
8
24
2. DISEASES
25
2.1 Asthma
25
2.2 Chronic obstructive pulmonary disease, COPD
29
2.3 Coughing
31
2.4 Cystic fibrosis
31 2.5 Quality of life for patients with asthma, COPD and coughs
33
3. MEDICINES
35
3.1 Medicines against asthma and COPD
35 3.1.1 Bronchodilators for inhalation
35 3.1.2 Bronchodilators in tablet form and other dosage forms
36 3.1.3 Anti-inflammatory substances for inhalation
37 3.1.4 Double action medicines for inhalation
37 3.1.5 Anticholinergics
38 3.1.6 Leukotrien receptor antagonists
38 3.1.7 Theophyllines
39 3.1.8 Anti-allergenics
40
3.1.9 Other medicines against asthma
40
3.2 Medicines against coughing and cystic fibrosis
41 3.2.1 Acetylcysteine
41 3.2.2 Bisolvon
41 3.2.3 Mollipect
41 3.2.4 Pulmozyme
42 3.2.5 Cough medicine from Apoteket’s Produktion & Laboratorier (APL)
42
4. METHOD
43
4.1 Evaluation of medical effect
43 4.1.1 Medical literature in the review 43
4.1.2 Measures of effect 44
4.2 Evaluation of health economic data 44
4.3 Evaluation of quality of life 44
4.4 Evaluation of facts 45
review of medicines against asthma, copd and coughs
5. HEALTH ECONOMICS 46
5.1 Market and sales value 46
5.1.1 Bronchodilators for inhalation 48
5.1.2 Inhaled steroids and anticholinergics 48
5.1.3 Substances against coughing
49
5.2 Socio-economic costs
49 5.2.1 Direct costs for asthma and COPD
50 5.2.2 Indirect costs for asthma and COPD
50
5.3 Cost-effectiveness in the various stages of the treatment ladder for asthma
5.3.1 Stage 1 – short-acting bronchodilators
52 52 5.3.2 Stage 2 – administration of low to medium dose of inhaled steroids 53 5.3.3 Stage 3 – administration of long-acting bronchodilators or leukotrien receptor antagonist
53 5.3.4 Stage 4 and 5 – high dose of inhaled steroids and steroids in tablet form
54 5.4 Cost-effectiveness when used to treat COPD
55 5.4.1 Steroids
55 5.4.2 Long-acting bronchodilators
55 5.4.3 Double action medicines
56 5.4.4 Anticholinergics
56
6. DECISIONS
57
7. REASONS BEHIND DECISIONS
59
7.1 Medicines against asthma and COPD
60 7.1.1 Bronchodilators for inhalation stay in reimbursement system
61 7.1.2 Bronchodilators in other dosage forms stay in reimbursement system 64 7.1.3 Anti-inflammatory medicine for inhalation
– Asmanex loses reimbursement
64 7.1.4 Double action medicines for inhalation stay in reimbursement system 69 7.1.5 Anticholinergics stay in reimbursement system
70 7.1.6 Singulair to stay in reimbursement system 71
7.1.7 Theophyllines for emergency treatment stays in the reimbursement 73
system, maintenance treatment not reimbursed 7.1.8 Antiallergenics – Lomudal inhalation powder is removed from the reimbursement system 74
7.1.9 Other medicines against asthma - Xolair retains reimbursement 75
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7.2 Medicines against coughing and cystic fibrosis 7.2.1. Acetylcysteine, Mucomyst and Viskoferm
– effervescent tablets remain in reimbursement system 76
77
7.2.2 Acetylcysteine – solution for nebuliser stays in reimbursement system 78 7.2.3 Bisolvon – reimbursement limited to patients with cystic fibrosis or primary ciliary dyskinesia
78 7.2.4 Mollipect loses reimbursement
79 7.2.5 Pulmozyme against cystic fibrosis retains reimbursement status
80 7.2.6 Lepheton-Desentol loses reimbursement
81 7.2.7 Ephedrine hydrochloride loses reimbursement
81
8. REFERENCES
82
APPENDICES: Appendix 1 – definition of degrees of severity of asthma
89
Appendix 2 – definition of degrees of severity of COPD
90
Appendix 3 – price comparison for inhaled steroids in powder form
91
Appendix 4 – price comparison long-acting and short-acting bronchodilators 92
Appendix 5 – price comparison of double action medicines (inhaled steroid + long-acting bronchodilators)
Appendix 6 – Health economic literature on asthma and COPD
93
94 review of medicines against asthma, copd and coughs
4
the pharmaceutical benefits board
1. INTRODUCTION
The Swedish pharmaceutical benefits board (Läkemedelsförmånsnämnden,
herein referred to as the LFN) is carrying out a review of approximately 2000
medicines to rule on continued reimbursement for these medicines. In the
review we evaluate medicines based on their therapeutic use. In this group we
are evaluating medicines used against asthma, chronic obstructive pulmonary
disease (COPD), coughing and cystic fibrosis.
When Sweden introduced new regulations for reimbursement on the 1st of
October 2002 it was not practically possible to overnight try all medicines
which were already reimbursed in Sweden against the new regulations.
In total the review of these medicines comprises 49 groups and the order is
decided by the size of the sales value for each group in 2003. We are taking
the groups with highest sales first.
review of medicines against asthma, copd and coughs
2. DISEASES
Asthma and COPD are diseases which decrease the flow of air and as a result
affect the capability of the body to maintain sufficient oxygenization of the
blood.
For cystic fibrosis lung function is negatively affected due to abnormal pro­
duction of phlegm in air passages. Coughing is not a disease, it is a reflex to
expel unwelcome particles from air passages.
Asthma, cystic fibrosis and coughing are prevalent for both adults and child­
ren, while COPD mainly afflicts older persons.
2.1 Asthma
Asthma is a persistent inflammatory disorder in air passages. The inflamma­
tion increases the sensitivity of the air passages and causes them to swell.
The swelling makes it more difficult for the air to flow in and especially
out of the lungs. Patients experience a wheezing and whistling sound from
the chest area, they can feel out of breath, feel pressure over the chest and
coughing. Symptoms are often more apparent at night or early in the
morning. [1]
Common symptoms are also episodes involving shortness of breath such as
when experiencing cold, exercise or pneumonia. Some people are afflicted by
repeated and severe asthma attacks which can be fatal. Admission to hospi­
tal and fatal cases due to asthma have become less common. Between 1987
and 1997 the decrease has been two-thirds. 456 people died from asthma in
1989. The number in 2004 for this was 151 cases. [2]
Asthma is a chronic disease which can be a considerable burden for individu­
als in school, at work and in their free time. [3]
Frequency of the disease
Asthma is often triggered in childhood. The number of school children with
asthma has doubled over the past twenty years and is currently at about 8­
10%. Asthma which starts in childhood has a relatively good prognosis and
when children have reached adulthood approximately half of them are free
from symptoms.
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
The number of asthmatics amongst adults has also doubled. Approximately
8% of the adult population has the disease today. It is unusual for adult asth­
matics to become free from symptoms. This occurs for about 1% per year. [1]
Need for care
Despite the increase in asthma both the number of days in care and fatality
has decreased, for both adults and children. This development is a result of
increased control of symptoms and improved quality of life largely due to
clear national guidelines for asthma treatment, as well as new and properly
administered asthma medicines. [1]
Degree of severity and treatment goals
There are two different ways to classify how severe asthma is. It can be judged
based on the situation before the patient begins maintenance treatment (see
appendix 1). Another way is to evaluate the symptoms and how well the
lungs function when treatment is ongoing. The goal with pharmaceutical tre­
atment is to get control over the disease, that is that the patient is free from
symptoms and side-effects and in general is not afflicted by the disease in
their everyday life. The goals with the treatment are described in fact box 1.
• The patient shall be free from symptoms
• The patient shall not be troubled by side-effects from the
asthma medicine
• Periods when the asthma gets worse shall be prevented
• The patient shall be able to maintain a normal level of activity
• Normal function of the lungs shall be retained
• Permanent narrowing of the airways shall be prevented
Fact box 1: Goals on perfect asthma treatment.
Maintenance treatment of asthma for youths and adults
Pharmaceutical treatment must be adapted to how severe the disease is. For
temporary afflictions inhalation of short-acting bronchodilators is recom­
mended as needed (stage 1 in the Medical Products Agency’s treatment lad­
der which is shown in figure 1).
If the symptoms reappear more than twice per week, then daily inhalation of
anti-inflammatory medicines (steroids) should be taken at the lowest pos­
sible dose. If the patient’s symptoms become worse temporarily then the dose
of anti-inflammatory medicine can be increased by two to four times for a
period of some weeks (stage 2).
review of medicines against asthma, copd and coughs
If maintenance treatment with a low to medium dose of anti-inflammatory
medicine does not give enough effect then a long-acting bronchodilator
can be added, either separately or as a double action medicine. If long-ac­
ting bronchodilators are not suitable then one can try adding a leukotrien
receptor antagonist (stage 3). The next stage in the treatment is to increase
the dose of anti-inflammatory medicines and continue with complementary
treatments (stage 4). If the effect is unsatisfactory despite this treatment then
it may be necessary to give anti-inflammatory medicines in tablet form (stage
5)[4]. We will not review steroids in tablet form this time.
In 2006 a new medicine for treating severe allergic asthma was introduced
(Xolair). This is not yet implemented into the treatment ladder but it will
most likely end up in stage 4 or stage 5 of the treatment ladder.
5
4
3
2
1
Complemented by cortisone
in tablet form.
Inhaled cortisone at a high dose
+ further maintenance treatment.
Inhaled cortisone at a medium dose
+further maintenance treatment,
In the first case long-acting bronchodilators.
Possibly leukotrien receptor antagonist.
Inhaled cortisone at a low-medium dose
+ short-acting bronchodilators as needed.
Short-acting bronchodilators as needed.
As an exception cromoglycate as a preventive measure.
Figure 1. Medical Product Agency’s treatment ladder for maintenance treatment
of asthma for youths and adults
Maintenance treatment of asthma for children
Pharmaceutical treatment for children must be adapted to how severe the
asthma is. Furthermore, it is crucial to take into account the age of the child,
risk of side-effects from the treatment, possible allergies and social situation.
Children over two years old get approximately the same treatment as adults,
while children under the age of two get different doses and devices for inhala­
tion. See figure 1 and 2.
the pharmaceutical benefits board
Infants 0-2 years old
Temporary symptoms
and infections
Short-acting bronchodilators*
for inhalation as needed
Recurring episodes
and infections
Periodical treatment with inhaled
cortisone at a low dose for a max­
imum of 7-10 days. Short-acting
bronchodilators when symptoms show.
Episodes between infections
Infections > 1 time per month
Severe attacks (simultaneous eczema
increases arguments for treatment)
Ongoing treatment with inhaled
cortisone at a low dose and short­
acting bronchodilators
when symptoms show
For more severe asthma
cortisone can possibly be
administered using a nebuliser
Children over 2 years old
Only sporadic and mild symptoms
Short-acting bronchodilators*
For inhalation as needed
Recurring need for bronchodilators
Exercise-induced asthma
Ongoing treatment with inhaled
cortisone at a low dose
Symptoms despite inhaled
cortisone
Addition of bronchodilators*
or leukotrien antagonist
For more severe asthma: combina­
tion of inhaled cortisone, long acting
bronchodilators* and Leukotrien
antagonist. The dose of cortisone is
increased to a medium-high level.
* beta 2 stimulants
Figure 2. Medical Products Agency recommendations for maintenance treatment
of children with asthma.
review of medicines against asthma, copd and coughs
2.2 Chronic obstructive pulmonary disease, COPD
Chronic obstructive pulmonary disease (COPD) is a long-term and slowly
debilitating disease which is characterised by a constant lack of air flow in the
air ways. The disease also causes changes in lung tissue (such as in emphy­
sema) leading to a worsened exchange between oxygen and carbon dioxide.
The COPD patient can be completely free of symptoms at the early stages.
Persistent coughing is however an early sign. In mild cases a patient expe­
riences shortness of breath for “normal” exercise or exertion. Very severe
COPD also has other medical consequences, such as under-nutrition, weak
muscles and osteoporosis as well as a decrease in quality of life and social fun­
ction. Finally the decline in breathing function also affects the heart, kidneys
and blood circulation. The constant shortness of breath in severe COPD
creates anxiety and greatly decreases quality of life. Acute episodes often lead
to visits to the emergency room and hospitalisation.
Since the end of the 1980s mortality for COPD has increased fast. 1 816
people died from the disease in 1989. The comparable number in 2004 was
2 634. The greatest increase here has been amongst women where the num­
ber of fatalities has increased from 673 to 1 301. [2]
COPD differs from asthma. The narrowing of the airways is due to other
causes than simply inflammation, even if this can occur to varying degrees.
In COPD the lung function does not return to normal after bronchdilator
treatment, or after any treatment with anti-inflammatory medicines. The
symptoms of COPD are more ever-present compared to asthma where they
can vary over the day or longer periods of time. [1] [3]
Frequency of the disease
In 2001 there were between 400 000 and 700 000 patients in Sweden who
had been diagnosed as suffering from COPD, depending on which criteria
were used to describe the disease. COPD is unusual before the age of 40 and
smoking is the most common cause of the disease. Fatality in the disease is
considerable. Survival is largely contingent on age, lung function and if the
patient has other diseases such as lung-heart disease. [5]
Degree of severity and treatment
COPD is also divided up based on how severe the disease is (see appendix 2)
[6] [7]. Swedish and international guidelines differ somewhat.
There are crucial differences between pharmaceutical treatment for COPD
and asthma. For COPD the effect of the medicine is somewhat less than for
0
the pharmaceutical benefits board
asthma. Neither is there any strong evidence showing that pharmaceutical
treatment decreases fatality. Smoking cessation is the only measure which can
slow down the disease.
The Medical Products Agency indicates the effect of the treatment should
be evaluated on a continual basis and that each medicine should be evalua­
ted separately [5]. According to more recent international guidelines a fixed
combination treatment is more effective than treatment with each medicine
separately. The Swedish Lung Medicine Association (Svensk Lungmedicinsk
Förening) recommends not starting with a fixed combination, but first eva­
luating each medicine by itself. [7] [6]
A summary of the Medical Products Agency’s recommendations for pharma­
ceutical treatment for COPD is available in fact box 2.
Short-acting
bronchodila­
tors (beta-2
stimulants)
Long-acting
bronchodila­
tors (beta-2
stimulants)
Ipratropium
(anticholiner­
gics)
Theophylline
Acetylcysteine
Inhaled
steroids
Mild COPD
with no
symptoms
Notreatment
Notreatment
Notreatment
Notreatment
Notreatment
Notreatment
Mild COPD
with symp­
toms
Notreatment
Canbe
considered
Canbe
considered
Notrecom­
mended
Forsimultan­
eouschronic
bronchitis
andfrequent
periodswith
increased
coughingand
phlegm-produ­
cingcough
Notrecom­
mended
Moderate­
severe COPD
Notrecom­
mendedas
regular
treatment
Canbe
considered
Canbe
considered
Notrecom­
mended
Forsimultan­
eouschronic
bronchitis
andfrequent
periodswith
increased
coughingand
phlegm-produ­
cingcough
Canbe
considered
especiallyfor
frequently
recurring
worseningof
thedisease
Severe COPD
Notrecom­
mendedas
regular
treatment
Canbe
considered
Canbe
considered
Notrecom­
mended
Forsimultan­
eouschronic
bronchitis
andfrequent
periodswith
increased
coughingand
phlegm-produ­
cingcough
Canbe
considered
especiallyfor
frequently
recurring
worseningof
thedisease
Fact box 2: Medical Products Agency’s recommendations for pharmaceutical
treatment of COPD.
review of medicines against asthma, copd and coughs
After this treatment recommendation was written three more medicines
entered the market for treatment of COPD; tiotropium which is similar to
ipratropium (see fact box) and two double action medicines with inhaled
steroids and long-acting bronchodilators.
After these recommendations were published a study was published questio­
ning the value of acetylcysteine [8].
Chronic bronchitis
Chronic bronchitis is defined as coughing with phlegm for at least 3 months
per year for at least two years in a row. Patients with chronic bronchitis have
a higher risk of getting recurring infections in the airways. [1]
Earlier chronic bronchitis was used as a separate diagnosis. Today it is more
used as a term for a symptom of COPD and this is the way we will treat it in
this review. [9].
2.3 Coughing
Coughing is not a disease, although it may be a symptom of a disease.
Coughing is a protective reflex triggered when the mucus membranes in the
airways are irritated. By coughing the body can rid itself of irritating subjects,
such as dust and phlegm.
There are many different reasons for coughing. A common cold is the
most common, but other diseases also can cause coughing (eg, asthma and
COPD). Cigarrette smoke and other air pollution can also irritate the air­
ways and cause coughing. [10]
There are a number of different medicines with either expectorant or mucus­
reducing effect. Most of these are OTCs and only a few of them are part of
the reimbursement system.
2.4 Cystic fibrosis
Cystic fibrosis (CF) is a hereditary disease which means the body’s mucus
glands do not work as they should. Symptoms and degree of severity vary
from individual to individual but it is most common to see symptoms already during the first year of life. The disease is characterised by abnormally
thick phlegm which affects a number of organs. This thick phlegm creates
problems mainly in the lungs and digestive tract and also in the pancreas, gall
bladder and liver.
the pharmaceutical benefits board
Frequency of the disease
In 2006 there were approximately 575 people with the disease, of which half
were adult. Around 15-20 children are born with the disease each year.
The disease greatly increases the risk of an early death. In the USA in 2005
the expected average life span was 33 years[11]. At present the expected av­
erage life span is 50 years old in Sweden[12]. Through early diagnostics and
active treatment the prognosis can however be positively influenced.
Between five and seven CF patients go through an organ transplant each
year. Lungs are the most common organ, and also liver transplants take place
however to a lesser degree. According to figures from the CF centre in Lund,
survival of 10 years is 65% following such a procedure.
Diagnostics and ongoing treatment, including regular inhalation treatments,
physiotherapy and when needed antibiotics, is administered at special CF
centres. [10, 13]
Symptoms, degree of severity and treatment
The clearest symptom of cystic fibrosis is a stubborn irritating cough and
thick phlegm which is produced. The phlegm houses bacteria and CF
patients are often as a result afflicted by infections. Treatment of the lungs
are often aimed at preventing and treating these infections. This is done via
breathing training, physical training, mucus-reducing inhalation treatments
and antibiotics.
The type of bacteria which is common for infections of CF patients often
demand treatment with intravenous antibiotics. Patients with mild CF can
get by on one treatment per month, while those with severe symptoms may
need a drip feed of antibiotics every week.
The thick phlegm prevents a normal breakdown of fat in the digestive tract.
This leads to CF patients easily being under-nourished and suffering from a
lack of vitamins. CF patients take extra pancreas enzymes and vitamins for
every meal to improve their nutrition.
It is common that CF patients get a milder form of diabetes, that the liver
is affected and that they get bilestones. As the thick phlegm blocks sperm
ducts and the cervix it can be difficult for patients suffering from CF to have
children.
review of medicines against asthma, copd and coughs
Primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD) is a separate diagnosis to CF. For PCD
cases the cilia do not function properly and lead the mucus away from the
airways. Patients who have PCD therefore have similar lung problems as
CF patients.
2.5 Quality of life for asthma, COPD and coughs
Astma and COPD have a huge impact on quality of life for individuals. This
can vary greatly however for patients depending on how severe the asthma or
COPD is.
One problem which we have met during the review of the literature is that
utility (quality-adjusted life year) is seldom used as a measure of effect.
Neither are general quality of life instruments such as SF 36 put to any
extensive use. In the cases where quality of life is measured it is instead the
disease specific measures which are used. This is excellent for discovering the
effects on symptoms of various treatments but is less useful when comparing
quality of life compared to other diseases.
Quality of life for asthma patients has however been measured in a Swedish
study using the general quality of life instrument SF 36. The asthma patients
had lower quality of life in all of the various categories compared to those
who did not have asthma. The differences were greatest for vitality, general
health and physical capacity. [14]
In an international study of chronic diseases in eight countries, chronic lung
disease gave an as equal decline in quality of life as for rheumatism and diabe­
tes (the study did not differentiate between asthma and COPD). Quality of
life was also worse for all categories in this study and the difference compared
to healthy people was greatest for vitality, general health and physical capa­
city. [15]
COPD gave a large decrease in quality of life as measured using SF 36 in a
large clinical study [16]. Also here the effects were greatest on the physical
components such as physical capacity, vitality and general health.
In a study, upper respiratory infections (included in this are patients with ear,
sinus infection, bronchial, and other respiratory infections) gave a decline in
quality of life comparable in size to chronic lung disease, osteoarthritis and
depression [17]. The authors do point out however that an important diffe­
rence here between these diseases is that a respiratory infection quickly passes.
4
the pharmaceutical benefits board
Even if quality of life is greatly decreased during the disease the total loss in
quality of life is small in comparison with chronically ill patients. In the diseases included in the study coughing is only a part of the symptoms. It is not
possible to say how much of the loss in quality of life depends on coughing
and how much on other symptoms such as fever, pain and so on.
review of medicines against asthma, copd and coughs
3. MEDICINES
The medicines which we examine can be divided up into the
following groups:
•
•
•
•
medicines to treat asthma
medicines to treat chronic obstructive lung disease (COPD)
medicines to treat coughing
medicines to treat cystic fibrosis
3.1 Medicines against asthma and COPD
The same medicine is often used for a number of diseases, this is especially
the case for medicines against asthma and COPD. The same medicine can
be available in various forms such as in tablet form, as a potable solution, a
solution to be used in a nebuliser) and powder for inhalation. When it comes
to medicines which should be inhaled then there are also various medical
devices to aid this. An example of this is the five different powder inhalers for
steroids.
3.1.1 Bronchodilator medicines for inhalation
• Available as long-acting and short-acting bronchodilators.
• Sales in 2006: approximately 270 million Skr
(of which short-acting 140 million and long-acting 130 million).
We have examined the following medicines:
Short-acting bronchodilators
Product
Active substance
Dosage form
Airomir
salbutamol
inhalationspray
Bricanyl
terbutaline
inhalationpowder,inhalationspray,solutionfornebuliser
Buventol
salbutamol
inhalationpowder
SalbutamolArrow
salbutamol
solutionfornebuliser
Ventoline
salbutamol
inhalationpowder,inhalationspray,solutionfornebuliser
Long-acting bronchodilators
Product
Active substance
Dosage form
Foradil
formoterol
inhalationpowder
OxisTurbuhaler
formoterol
inhalationpowder
SereventDiskus
salmeterol
inhalationpowder
the pharmaceutical benefits board
Short-acting bronchodilators
Short-acting bronchodilators are used to ease mild symptoms of asthma and
COPD. In the group there are two active substances and in total four medici­
nes are included in the pharmaceutical benefits system. A large part of the
prescriptions are prescribed to children according to the sales statistics.
Long-acting bronchodilators
Long-acting bronchodilators are used for treating asthma as a complement to
maintenance treatment with anti-inflammatory medicines (inhaled steroids),
if these do not give the desired effect [4]. In the group there are two active
substances and in total three medicines are included in the pharmaceutical
benefits system.
The medicines can also be used to ease symptoms of COPD [18] [19].
The medicine Oxis can also be used to ease acute asthma symptoms and to
prevent asthma which arises as a result of physical exercise [19].
3.1.2 Bronchodilators in tablet form and other dosage forms.
•
Injections and oral solution used to treat acute symptoms of asthma.
• Tablets and extended release tablets used for maintenance treatment.
•
Sales in 2006: approximately 14 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Bambec
bambuterol
oralsolution,tablet
Bricanyl
terbutaline
oralsolution,injectionfluid,tablet
BricanylDepot
terbutaline
extendedreleasetablet
Ventoline
salbutamol
oralsolution,tablet
VentolineDepot
salbutamol
extendedreleasetablet
Oral solutions and injection fluids are used for easing acute asthma symp­
toms. Oral solutions are mainly used by children, but not as a first-line treat­
ment rather only when inhalation is not suitable or has not given satisfactory
results. According to doctors at Stockholm’s CF centre these medicines are
also part of basic treatment for children with cystic fibrosis.
Tablets and extended release tablets can be used for maintenance treatment if
the patient cannot use inhaled medicines. They are seldom used for treating
asthma, but for COPD there is some usage as patients with severe symptoms
tend to get access to all available treatments. Evaluating the effect is however
difficult. [9]
review of medicines against asthma, copd and coughs
3.1.3 Anti-inflammatory medicines for inhalation
• Used for maintenance treatment mainly for asthma but also for COPD
• Sales 2006: approximately 314 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Aerobec
beclometasone
inhalationspray
Asmanex
mometasone
inhalationpowder
Beclomet
beclometasone
inhalationpowder
inhalationpowder,inhalationspray
Becotide
beclometasone
BudesonidArrow
budesonide
solutionfornebuliser
Flutide
fluticasone
inhalationpowder,inhalationspray
GionaEasyhaler
budesonide
inhalationpowder
Pulmicort
budesonide
inhalationpowder,inhalationspray,
solution(suspension)fornebuliser
In the group there are four active substances and in total eight medicines are
included in the pharmaceutical benefits system. All medicines are used for
maintenance treatment of asthma. Flutide is also used to treat COPD [20].
Inhaled steroids are administered early in the treatment ladder (see figure 1
and 2). For children the medicines are used early for mild asthma to, where
possible, counteract a decline in the function of the lungs in the long term.
3.1.4 Double-action drugs for inhalation
• Used (mainly) for maintenance treatment of asthma when only the inhaled steroid does not give an effect.
• Sales 2006: approximately 686 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Combivent
ipratropium/salbutamol
solutionfornebuliser
solutionfornebuliser
Ipramol
ipratropium/salbutamol
Seretide
fluticasone/salmeterol
inhalationpowder
Symbicort
budesonide/formoterol
inhalationpowder
Sales within this group have increased greatly over the past five years. The
increase depends most probably on increased usage by COPD patients. [21]
Treatment of asthma and COPD should not be started with double-action
medicines (long-acting bronchodilators and steroids) without first having
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
tried other medicines in the treatment ladder without success [4]. Children
and teenagers use double-action medicines to a certain degree, especially if
they are having difficulties taking a number of medicines properly [9].
Seretide has a fixed dose while Symbicort can also be used with variable
doses and as an acute and maintenance treatment. Variable doses means that
patients can adjust the dose of medicine they take based on how severe their
symptoms are and also that they use Symbicort to ease mild asthma symp­
toms.
Combivent/Ipramol is a combination of short-acting bronchodilators and
anticholinergics which is used for acute treatment for asthma and COPD. It
can also be used for maintenance treatment for COPD.
3.1.5 Anticholinergics
• Bronchodilator medicine for acute and maintenance treatment of (mainly) COPD
• Sales 2006: approximately 220 million Skr
We have examined the following medicines:
Product
Active substance
Dosage form
Atrovent
ipratropium
inhalationpowder,inhalationspray,
solutionfornebuliser
IpratropiumbromidArrow
ipratropium
solutionfornebuliser
Spiriva
tiotropium
inhalationpowder
The medicines in this group are used in general exclusively for COPD,
however Atrovent can also be used for treating asthma. The main usage of
Atrovent to treat asthma is if other bronchodilator medicines have given
troublesome side-effects. [4].
3.1.6 Leukotrien – receptor antagonists
• Alternative to long-acting bronchodilators as a complement to maintenance treatment.
• Sales 2006: approximately 77 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Singulair
montelukast
oralgranules,chewabletablets,tablets
review of medicines against asthma, copd and coughs
In Sweden there is only one medicine in this group. The medicine is available
as oral granules, chewable tablets and tablet form. Singulair has an anti-in­
flammatory effect but with a different mechanism than inhaled steroids. It
can be used as an alternative to or complement to long-acting bronchodila­
tors at stage 3 of the treatment ladder. It can also be used to prevent asthma
which arises as a result of physical exercise. [4] [22]
According to the SBU maintenance treatment decreases the number of acute
attacks. Furthermore, the need for complementary medicines decreases com­
bined with an increase in quality of life for patients with mild or moderate
asthma. For treatment of adults however Singulair has less effect than inhaled
anti-inflammatory medicines in a medium dose [3].
3.1.7 Theofyllines
• One of the oldest bronchodilator medicines.
• Used for both acute and maintenance treatment.
• Problems with side-effects and other simultaneously taken medicines.
• Sales 2006: approximately 9 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Teovent
cholinetheophyllinate
oralsolution,rectalsolution,tablet
Theo-Dur
theophylline
extendedreleasetablets
TeofyllaminIpex
theophylline
injectionsolution
The medicines in this group are older products. They work by relaxing the
muscles of the air passages and causing them to widen. Disadvantages to the
medicines are that they have serious side-effects and there is a risk of toxicity.
Small changes in the dose can give considerable problems in the form of side­
effects and toxicity.
There are more modern, better documented and less dangerous alternatives
for maintenance treatment. Because of this it is unusual to use these medici­
nes for new patients. It is used to a limited extent for acute treatments, but as
a first-line other medicines are tried to open up the air passages. The group
does have some use for COPD but is not generally recommended due to
side-effects and the risk of interactions/complications. [5].
Theophylline can be used for acute treatment or as maintenance treatment.
When inhaled steroids, short-acting bronchodilators (beta stimulants) and
other more modern alternatives became available, the use of theophylline as a
treatment for asthma decreased. Tablet doses are mainly used for maintenance
40
the pharmaceutical benefits board
treatment. In 2005 sales for this type of dose was 7 million Skr within the
benefits system. Approximately 90 percent is used by patients over 60 years
old. [21]. Over the past few years sales have decreased steadily.
3.1.8 Antiallergenics
• Used as a maintenance treatment to prevent asthma attacks
• Sales 2006: approximately 2 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Lomudal
sodiumcromoglycate
powderforinhalation
This medicine is used to suppress inflammation in the air passages. It is not
however a steroid but works in a different way. Lomudal can be used as a
complement to inhaled steroids with the purpose of decreasing the dose of
these. Lomudal can also be used to prevent asthma symptoms which arise
from physical exercise. [23]
The market has been steadily decreasing over the past years. Possible users are
patients who want to use a lower dose of inhaled steroids out of fear of side­
effects, and patients who mainly have allergy-triggered asthma.
3.1.9 Other medicines against asthma
• Used for severe allergic asthma.
• Introduced 2006.
We have examined the following medicines:
Product
Active substance
Dosage form
Xolair
omalizumab
injectionsolution
Xolair should only be used by people with severe allergic asthma. Before
commencing treatment with Xolair the person must have had a number
of periods of worsened symptoms, despite daily doses of inhaled steroids
in combination with long-acting bronchodilators. The medicine works by
blocking a substance produced constantly by the body and which is important to allergic reactions. Xolair stops the allergic reaction at an early
stage. [24]
review of medicines against asthma, copd and coughs
4
3.2 Medicines against coughing and cystic fibrosis
• The group consists mainly of mucus-reducing medicines.
• Sales 2006: approximately 125 million Skr.
We have examined the following medicines:
Product
Active substance
Dosage form
Acetylcystein
Acetylcysteine
effervescenttablet,
solutionfornebuliser
Bisolvon
Bromhexine
tablet
EfedrinhydrokloridAPL
Ephedrine
capsule,oralsolution
EfedrinhydrokloridiQuillaSimplexAPL
Ephedrine
oralsolution
Lepheton-DesentolAPL
difenhydramine/ephedrine/
Ethylmorphin
oralsolution
Mollipect
bromhexin/ephedrine
oralsolution
Mucomyst
Acetylcysteine
effervescenttablet
Pulmozyme
dornasealfa
solutionfornebuliser
Viskoferm
Acetylcysteine
effervescenttablet
The medicines in this group are older products and documentation is often
lacking. There is no scientific documentation to support the medical effect
for a number of the medicines. Sales comprise two medicines mainly: Mol­
lipect and Acetylcysteine (and their comparable copies).
3.2.1 Acetylcysteine
Older documentation has shown that acetylcysteine has an effect when symp­
toms of COPD patients worsen temporarily. In 2006 the BRONCUS study
was published which questions this effect. [8]. Acetylcysteine is part of the
base treatment for patients with cystic fibrosis.
3.2.2 Bisolvon
Bisolvon is a mucus-dissolving tablet which contains bromhexine. For Bis­
olvon there is older documentation and of uncertain quality, but which in­
dicates that Bisolvon has an effect on phlegm. There is support for Bisolvon
having an effect on cystic fibrosis. The lion’s share of the sales are OTC and
today there is only one product which remains in the reimbursement system.
3.2.3 Mollipect
Mollipect is in part mucus-dissolving (bromhexine) and in part bronchodi­
lating (ephedrine). There is documentation for the mucus-reducing effect of
bromhexine, but at a higher dose than that achieved using Mollipect. Ephe­
drine has a bronchodilator effect but there is no documentation to show that
ephedrine suppresses coughs.
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the pharmaceutical benefits board
3.2.4 Pulmozyme
Pulmozyme contains dornase alfa, which is a recreated human enzyme
(deoxyribonuclease 1 ). Pulmozyme is used to treat cystic fibrosis. In Sweden
there are approximately 500 – 600 patients with this disease and the number
who use Pulmozyme is small.
3.2.5 Cough medicine from Apoteket
Production & Laboratories
A few of the medicines with the ATC code R05 are made by Apoteket Pro­
duktion & Laboratorier (APL). In this review we have examined LephetonDesentol and ephedrine hydrochloride in different concentrations, dosage
forms and mixes.
Lepheton and Desentol are two cough medicines. They are not part of the
Swedish reimbursement scheme separately, however the combination of the
two medicines is reimbursed (Lepheton-Desentol). The indication is: croup
in children (2-14 years) and coughing from various causes where a suppresant
and mucus-reducing effect is needed, for example as in bronchitis (adults and
children over 15 years old).
review of medicines against asthma, copd and coughs
4
4. METHOD
In this section we describe how we collect and evaluate the material which
our position is based on. We evaluate the medical effect, the cost-effectiveness
of the medicine in question and the quality of life for the various diseases.
The report is also reviewed by external experts as a quality control measure.
4.1 Evaluation of medical effect
Our collation of knowledge in regard to medical effect is based, as much as
possible, on existing overviews of knowledge and information from establis­
hed and well-known organisations.
Knowledge overviews from the SBU (Swedish Council on Technology As­
sessment in Healthcare) as well as treatment guidelines from the National
Board of Health and Welfare and Medical Products Agency are taken into
consideration first. We do not further examine the results from the systematic
overview or treatment recommendations.
If there is no systematic overview, or if it does not answer our questions,
then as we must take a stance we must find other sources of reference for
evidence. If there is no systematic overview, then we use direct head to head
studies, in the second instance meta-analyses, following this a collection of
the company’s reference sources and published studies. Lastly, a review of the
literature in question is carried out.
Head to head studies or systematic overviews of head to head studies are ideal
when comparing the effect of medicines. If these are not available however
then we must make indirect comparisons based on, for example, systematic
overviews.
4.1.1 Medical literature in the review
Within the area of asthma and COPD there is much information available.
To a large extent we have used the 2002 report from the SBU – Treatment of
asthma and COPD – report from the National Board of Health and Welfare
– National Board’s healthcare guidelines for asthma and COPD (2004), and
Medical Products Agency treatment guidelines for asthma and COPD from
2002.
We have also utilised the latest international guidelines for asthma and
COPD (GINA och GOLD).
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the pharmaceutical benefits board
The above information and material has been complemented by searches for
newer literature reviews in Cochrane Library and PubMed. We found the
following:
•
•
•
•
Comparison of different inhalation aids [25]
Comparison of different inhaled steroids [26] [27]
Addition of leukotrien receptor antagonist to inhaled steroid [28-31]
Long-acting bronchodilators in comparison to leukotrien receptor antagonist as complement to inhaled steroids [32] [33]
• Sodium cromoglycate when treating children for asthma [34]
• Comparison between sodium cromoglycate and inhaled steroids in asthma treatments of adults and children [35]
• Theophylline as maintenance treatment for COPD [36]
4.1.2 Measures of effect
SBU states in its report on asthma and COPD that there are different views
on how to best evaluate the effect of treatment. Different measures of lung
function and breathing capacity are often used in studies of asthma and
COPD. The connection between lung function and the patient’s experience
of the disease is weak. The SBU uses the following measures of effect: [3]:
•
•
•
•
Fatality from asthma or COPD
Need for increased medication, acute visits or hospitalisation
Health-related quality of life
Symptoms
In our opinion foremost these measures of effect should be used. It is some­
times necessary to make comparisons of various measures of lung function as
often other information is missing.
4.2 Evaluation of health economic data
Summaries of knowledge within health economics are done partly on dif­
ferent grounds than those on medical effect, mainly due to the fact that
the health economic result is largely dependent on local conditions such as
the makeup of the patient population, prices, clinical practice etc. We have
conducted a review of the literature of health economic studies. The search
method used and results are available in appendix 6.
4.3 Evaluation of quality of life
Knowledge on how diseases affect health are founded on in the first instance
knowledge overviews from the SBU, National Board of Health and Welfare
review of medicines against asthma, copd and coughs
4
and Medical Products Agency. Then we have searched for systematic over­
views which take up quality of life for each disease.
We have looked for overviews and analyses which use value as a measure of
effect or general quality of life measures such as SF 36.
We have not searched for the many disease-specific quality of life measures
specific to asthma and COPD.
For both overviews and individual studies a lot of emphasis has been put
on results which arise from the patient’s own assessment and also Swedish
studies.
4.4 Evaluation of facts
The summary of knowledge in regard to medical effect and health econo­
mic documentation which we present in this report has been evaluated by
external experts. These experts have given feedback and answered clinical
questions during the course of the review.
The expert group was formed so as to, as much as possible, cover all of the
areas of knowledge which are covered in the review. The experts have re­
presented asthma treatment for out patients, asthma treatment of children,
asthma with a focus on allergies and other lung diseases where coughing is a
dominant symptom such as COPD.
Feedback on the report has also been sought and received from experts at the
SBU, National Board of Health and Welfare and Medical Products Agency as
well as from Sweden’s county councils and municipalities (SKL), the LFN’s
user council, user organisations and the pharmaceutical companies which
had medicines affected by the review.
4
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
5. HEALTH ECONOMICS
• Medicines against asthma, COPD, coughing and cystic fibrosis turnover approximately 1 700 million Skr per year.
• Sales are dominated by inhaled medicines in powder form
• The diseases cause large costs, both direct and indirect. These are
many times higher than the cost of the pharmaceuticals in question.
• It is cost-effective to treat asthma according to today’s treatment ladder.
However, not all medicines for asthma are cost-effective.
• Treating COPD is also cost-effective but the support for this is weaker.
5.1 Market and sales value
The medicines in this review (ATC codes R03 and R05) had a total sales value
of approximately 1 700 million Skr in 2006. Medicines used for asthma and
COPD stand for over 90 percent of the sales (bronchodilators, inhaled steroids,
combinations of these and anticholinergics).
Table 2: Distribution of sales for medicines in the asthma, COPD and coughs
review.
ATC code
Therapeutic group
R03A
Bronchodilatorsforinhalation
966
R03B
Anti-inflammatorymedicinesfor
inhalationandanticholinergics
536
R03C
Bronchodilatorsinotherdosageforms
R03D
Other
R05C
Mucus-reducing
R05D
Coughsuppressants
R05F
Coughsuppressantsincombination
Total
Sales value in million Swedish krona - 2006
14
88
120
12
58
1 794
Many medicines are available in a number of different dosage forms, but sales
are dominated by inhalation powder. In the last five years some changes have
occurred. Double-action medicines have increased rapidly. Simultaneously it
is possible to observe a decline in sales of anti-inflammatory medicines for in­
halation powder and long-acting bronchodilators, both of which are compo­
nents of the double-action medicines. It is however clear that the increase in
double-action medicines cannot solely be explained by a matching decrease
in its two separate component medicines.
4
review of medicines against asthma, copd and coughs
A probable cause here is the increased use of double-action drugs for COPD.
There are very few generic medicines in these groups. This means that there
is not much room for generic substitution and the price competition it gives
is very small. It is mainly the inhalation devices which prevent the exchange
of medicines, despite the fact that patents on the active substances in many
cases have expired.
35 000 000
30 000 000
Kortverkande
luftrörsvidgare
Short-actingbronchodilators
Långverkande
luftrörsvidgare
Long-actingbronchodilators
Double-actiondrugs
Kombinationer
Inhaledsteroids
Inhalerade
steroider
Anticholinergics
Antikolinergika
Sodiumcromoglycate
Natriumkromoglikat
Antileukotriens
Leukotrienrecept.
Theophyllines
Teofyllin
25 000 000
20 000 000
15 000 000
10 000 000
5 000 000
00
20
20
00
-H
1
20 H2
01
20 H1
01
20 H2
02
20 H1
02
20 H2
03
20 H1
03
20 H2
04
20 H1
04
20 H2
05
20 H1
05
20 H2
06
20 H1
06
-H
2
-
Figure 3: Sales of medicines to treat asthma and COPD between 2000 and
2006, number of doses sold (DDD).
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the pharmaceutical benefits board
5.1.1 Bronchodilators for inhalation
Sales in this group are dominated by the fixed combinations (Seretide and
Symbicort). The distribution between the two competing active substances,
salbutamol/terbutaline and salmeterol/formoterol, is relatively even.
Table 3: Sales value in millions of Swedish krona for 2006 for bronchodilators
(ATC code R03A).
Medicine (active substance)
Sales value (million Skr)
Short-acting bronchodilators
141
salbutamol
56
terbutalin
95
Long-acting bronchodilators
132
salmeterol
41
formoterol
89
Combinations
658
formoterol/budesonide
419
salmeterol/fluticasone
239
The most common dosage form for bronchodilators is inhalation powder,
followed by spray and solution for inhalation. The long-acting bronchodila­
tors and combinations are only available as inhalation powder. The distribu­
tion is shown in table 4.
Table 4: The various dosage forms share of sales for bronchodilators and combina­
tion medicine .
Medicines
Dosage form
Powder
Spray
Solution for inhalation
Short-actingbronchodilators
82%
11%
7%
Long-actingbronchodilators
100%
Combinations
100%
5.1.2 Inhaled steroids and anticholinergics
Inhaled steroids are a large group in terms of sales and stand for almost a fifth
of the total sales for asthma medicines. Powder is the dosage form which sells
the most at 90 percent. Of the four active ingredients on the market in 2006,
budesonide was market leading with 80 percent of sales.
review of medicines against asthma, copd and coughs
4
The two anticholinergic substances ipratropium and tiotropium (Atrovent
and Spiriva respectively) have combined sales of over 200 million Skr.
Sodium cromoglycate (Lomudal) for treating asthma has a turnover of
approximately two million Skr.
Table 5: Sales value in million Skr for 2006 for medicines with the ATC code
R03B.
Medicines
Steroids
beclometasone
Sales value
314
7
budesonide
257
fluticasone
29
mometasone
21
Disodium cromoglycate
Anticholinergics
2
219
ipratropium
56
tiotropium
163
Total
535
5.1.3 Cough medicines
Sales of cough medicines within the benefits system amounted to 70 million
Skr in 2006. Mucus-reducing medicine stood for almost half of that sum, of
which acetylcysteine dominated with about 65 percent of the market.
5.2 Socio-economic costs
Asthma and COPD carry high costs for society. This is partly due to the
inherent medical consequences, and partly because the diseases are relatively
common. The costs for medicines, as noted in chapter 5.1 is approximately 1
700 million Skr per year. This makes up however only a part of the total costs
which these diseases bring on society.
Medicines within the group R05 (cough medicines) sell for a total of 125
million Skr, of which 70 million is within the reimbursement system. Coug­
hing and other problems most probably cause costs both directly in health­
care and indirectly such as in absence from work or decreased productivity at
work. The total socio-economic costs for problems associated with coughing
are however not known.
0
the pharmaceutical benefits board
5.2.1 Direct costs for asthma and COPD
It is not possible to see how much of the costs for pharmaceuticals is made
up of asthma and COPD. On top of the costs for medicines the diseases give
rise to costs in both out and in patient healthcare in the form of visits to the
doctor, emergency visits and hospital stays.
In 1999 Jacobsson et al estimated that the direct costs for asthma and COPD
were 2 200 million Skr [37]. A third of the cost is made up of medicines.
In table 6 and 7 we can see that costs for medicines increased between 1992
and 1999 but that the costs for healthcare in general decreased, especially for
asthma patients.
In 2006 Jansson et al estimated the costs for asthma and COPD to be higher.
[38]. Their calculations are however from a bottom-up study and these kinds
of studies in general give higher costs. A bottom-up study means that a selec­
tion of patients with a certain disease have been interviewed in order to build
an idea of the costs for these patients. Then costs for society as a whole are
extrapolated from this information. In general studies of this type produce
more information, especially to do with factors which cannot be captured in
statistical databases.
5.2.2 Indirect costs for asthma and COPD
Both Jacobsson and Jansson also calculate the indirect costs which the
diseases cost society. In both cases we can see that the direct costs make up
approximately 30 percent of the total socio-economic costs for asthma and
COPD (table 6 and 7).
Table 6: Costs in million Skr for COPD.
COPD
Indirect costs
Jacobsson et al 1992
972
Jacobsson et al 1999
Jansson 1994-1998
969
5 300
Numberofdeaths
209
384
Earlyretirements
763
585
Direct costs
1 121
1 015
Inpatients
474
457
Outpatients
504
392
Medicines
143
166
Total COPD
2 093
1 984
3 800
9 100
review of medicines against asthma, copd and coughs
Table 7: Costs in million Skr for asthma.
Asthma
Indirect costs
Jacobsson et al 1992
Jacobsson et al 1999
Jansson 1994-1998
1 337
798
2 600
Numberofdeaths
159
90
Earlyretirements
1178
708
1 068
1 215
Inpatients
213
69
Outpatients
506
539
Medicines
349
607
2 405
2 013
Direct costs
Total Asthma
1 100
3 700
It is worth noting that Jansson was able to include costs for sick leave due
to asthma and COPD in his interviews. This kind of information cannot be
extracted from sick leave statistics as the disease responsible for the sick leave
is not indicated.
Costs per patient vary greatly depending on how serious the disease is. In
Jansson’s material, individuals with constant and severe asthma symptoms
have up to ten times higher indirect costs than patients with less frequent and
milder symptoms.
The big difference between Jacobsson’s and Jansson’s cost calculations
probably depends on the method used (see above). Jansson has also tried to
estimate the cost due to sick leave.
the pharmaceutical benefits board
5.3 Cost-effectiveness at the different stages of the
treatment ladder for asthma
For asthma there is a well-accepted treatment ladder where the patient begins
with short-acting bronchodilators as needed, and where other medicines are
then added as in figure 4.
5
4
3
2
1
Addition of cortisone in
tablet form.
Inhaled cortisone at a high dose
+ further maintenance treatment.
Inhaled cortisone at a medium-high dose
+ further maintenance treatment.
In the first case long-acting bronchodilators.
Possibly antileukotrien.
Inhaled cortisone at a low – medium high dose
+ short-acting bronchodilators as needed.
Short-acting bronchodilators as needed.
Possibly cromoglycate as a preventative measure.
Figure 4: Medical Products Agency treatment ladder for treatment of asthma in
adults and youths.
We can discern evidence to indicate that the stages in the treatment ladder
are cost-effective.The second and third stage are the most studied and
evidence is therefore most robust for these products.
That treatments in the therapeutic groups in the treatment ladder are cost­
effective (compared to the previous stage in the treatment ladder) does not
however mean that all products in each therapeutic group are necessarily
cost-effective compared to each other.
5.3.1 Stage 1 – short-acting bronchodilators
We have not been able to identify any study which studies cost-effectiveness
of short-acting bronchodilators compared to no treatment at all of asthma
attacks. This is probably due to the group itself being relatively old. The ef­
fect of these medicines in alleviating symptoms is however good. As they also
have a low price we judge these medicines to be cost-effective.
review of medicines against asthma, copd and coughs
5.3.2 Stage 2 – addition of low to medium high dose of
inhaled steroids
We believe there to be good support to indicate that using inhaled steroids
for maintenance treatment is cost-effective.
A retrospective study of the connection between sales of inhaled steroids and
the number of days in hospital care due to asthma between 1978 and 1991
show, amongst other things, that every extra krona spent on inhaled steroids
led to a decrease in costs for emergency healthcare of 1.49 Skr. The article
cannot however with certainty state that the decrease in the number of days
in care was dependent on treatment with inhaled steroids [39].
Paltiel has examined how the addition of inhaled steroids affects the disease
for patients with mild to medium asthma who have only received treatment
with short-acting bronchodilators. For patients who had additional inhaled
steroids the cost per quality adjusted life year was 100 000 Skr (13 500 USD)
[40].
In a Japanese study treatment using budesonide had a lower cost and better
effect compared to placebo [41]. In a multinational study of patients with
mild asthma budesonide was cost-saving from a societal perspective in Swe­
den (and in Canada and Australia) [42].
5.3.3 Stage 3 – addition of long-acting bronchodilators
or antileukotrien.
There is evidence to show that long-acting bronchodilators as an addition
to maintenance treatment using inhaled steroids is cost-effective. This is also
valid when it is administered as a combination medicine. Antileukotrien as
an addition is not cost-effective compared to long-acting bronchodilators at a
group level.
The cost-effectiveness of the addition of formoterol or salmeterol to inhaled
steroids has been studied in a number of studies. A common denominator for
all of these is that they compare formoterol with budesonide or salmeterol
with fluticasone.
In a study where patients were given formoterol as an addition to budesonide
the direct and indirect costs became lower at the same time as the number of
asthma cases decreased for these patients. [43]. In another study the additio­
nal treatment with formoterol led to more symptom-free days and fewer pe­
riods with worsened condition (not significant, and significant respectively).
4
the pharmaceutical benefits board
The cost per symptom-free day gained was between 21 and 85 Skr [44].
The addition of salmeterol to inhaled steroids has been compared in five stu­
dies. Four of these compared treatment with the combination of salmeterol/
fluticasone with only fluticasone [45] [46] [47, 48] and the other compared
salmeterol/fluticasone with budesonide [49]. Three studies showed a cost per
symptom-free day of between 4 and 67 Skr. Price estimated a cost per gained
quality adjusted life year of 1 357 British pounds sterling (approximately
18 000 Skr) [46].
The combination of formoterol/budesonide has been compared with giving
each of the substances separately to Swedish patients. The combination gave
just as good an effect but total costs were lower primarily due to the lower
price of the medicine. [50].
The combination of formoterol/budesonide used for both maintenance and
emergency treatment has also been compared with the combination of salme­
terol/fluticasone with salbutamol as emergency medication. In this analysis
formoterol/budesonide gave somewhat fewer periods of worsened condition
(0.07 per patient and year). The toal costs were only marginally lower and
not significantly so. [51]
For montelukast (antileukotrien) only two cost-effectiveness studies have
been identified where montelukast was used as an inhaled steroid. In both of
these studies montelukast is compared to salmeterol. Salmeterol is better and
cheaper in both of these studies [52] [45].
5.3.4 Stage 4 and 5 – high dose of inhaled steroids and ste­
roids in tablet form
Cost-effectiveness at this stage is difficult to judge. We have only found one
study which examines cost-effectiveness when administering a high dose
of inhaled steroids [53]. This study deals with American patients with very
severe asthma during a one year period. The patients which were also referred
to an asthma centre got a high dose of fluticasone.
An increased dose of fluticasone gave improved lung function, more symp­
tom-free days, less use of steroids in tablet form and less use of healthcare. It
is possible that part or all of the result can be explained by better care at the
asthma centre.
We do not examine steroids in tablet form this time. These medicines will be
reviewed in the review of “Cortisones for systemic use”.
review of medicines against asthma, copd and coughs
5.4 Cost-effectiveness in COPD treatment
COPD does not have as clear a treatment ladder as asthma. The number of
health economic articles of good quality which shed light on the cost-effecti­
veness of various COPD treatments is also limited.
5.4.1 Steroids
We believe that on the whole there is evidence to show that treatment using
inhaled steroids to treat COPD is cost-effective and there is better cost-effec­
tiveness for patients with severe forms of the disease.
We have found three articles on fluticasone [54-56] and an article on inhaled
steroids in general [57]. None of the studies describe Swedish conditions.
In a British study fluticasone gave fewer periods of worsening condition and
higher improvements from breathing than placebo. From a societal perspec­
tive it was in some cases cost-saving [55].
In a Dutch study fluticasone has been compared to placebo. Estimated in
direct costs the cost per gained quality adjusted life year (QALY) was 90 000
Skr (13 000 dollars). When indirect costs were taken into account the total
cost was lower for patients who received fluticasone than for those who got
placebo. Patients with asthma as well as COPD were part of the study [56].
In an analysis based on a European study the cost per QALY was 130 000 Skr
(9 500 British pounds sterling) for fluticasone compared to placebo [54].
A Canadian study has examined the cost-effectiveness of treating COPD
with inhaled steroids. Cost-effectiveness varied depending on how severe the
disease the patients had. For the patient group as a whole the cost was 280
000 Skr (46 000 Canadian dollars) per gained QALY. If only those with the
severest symptoms were treated then the cost was instead 67 000 Skr (11 000
Canadian dollars) [57].
5.4.2 Long-acting bronchodilators
In a British study which compared salmeterol with standard treatment, sal­
meterol showed an improvement in measured lung function and symptom­
free days and nights compared to those patients who received placebo. The
costs for hospital care decreased which partly compensated for the cost of the
medicine [58].
the pharmaceutical benefits board
5.4.3 Combination medicines
A combination of inhaled steroid and long-acting bronchodilators to treat
COPD seems to be cost-effective.
The combination of salmeterol/fluticasone has been studied in Canada. The
cost per gained QALY was in the base analyis 450 000 Skr (75 000 Canadian
dollars). When the authors accounted for the treatment also affecting survival
the cost per gained QALY becomes instead 67 000 Skr (11 000 Canadian
dollars) [59].
Briggs et al compare the combination salmeterol/fluticasone with only admi­
nistering fluticasone. The cost per gained QALY varied between 95 000 and
190 000 Skr (7 000-14 000 British pounds sterling) depending on how large
a dose of steroids the patients had been treated with before the study started
[54].
Löfdahl compares the combination formoterol/budesonide by administering
the substances in different inhalers and with a placebo. The total costs for
healthcare were lowest for those patients who were treated with the combined
substances [60].
5.4.4 Anticholinergics
In a study the combination of ipratropium/salbutamol has been compared
with ipratropium and salbutamol separately. The study is based on American
conditions and can therefore be difficult to compare with the situation in
Sweden. The results indicate that ipratropium and salbutamol have similar
effects. The combination of ipratropium/salbutamol is more expensive than
ipratropium but has a better effect on the number of days without complica­
tions [61].
In a further study on Dutch and Belgian patients tiotropium has been com­
pared to ipratropium. The company has reestimated the result with Swedish
prices for the medicines and other healthcare resources. Treatment with
tiotropium led to fewer periods of worsening condition but to a higher cost
per patient [62].
review of medicines against asthma, copd and coughs
6. DECISIONS
In the table below we summarise the Board’s decisions. Our evaluation un­
derlying each decision is accounted for in section 7. For the medicines which
have been excluded from the benefits system, or where reimbursement has
been limited, there are specific reasons given for each medicine.
Medicine
Dosage form
Decision
Remains
Reason in section:
Out
Limited
Acetylcysteine
effervescenttablet
X
7.2.1
solutionfornebuliser
X
7.2.2
Aerobec
inhalationspray
X
7.1.3
Airomir
inhalationspray
X
7.1.1
Asmanex
inhalationpowder
Atrovent
all
X
7.1.5
Bambec
tablet
X
7.1.2
Beclomet
inhalationpowder
X
7.1.3
Becotide
all
X
7.1.3
Bisolvon
tablet
X
7.1.3
X
7.2.3
Bricanyl
all
X
7.1.1,7.1.2
BricanylDepot
extended
releasetablets
X
7.1.2
BricanylTurbuhaler
inhalationpowder
X
7.1.1
BudesonidArrow
solutionfornebuliser
X
7.1.3
Buventol
inhalationpowder
X
7.1.1
Combivent
solutionfornebuliser
X
7.1.4
EfedrinhydrokloridAPL
capsule,oralsolution
X
7.2.7
Efedrihydrokloridi
QuillaSimplex
oralsolution
X
7.2.7
FlutideDiskus
inhalationpowder
X
7.1.3
FlutideEvohaler
inhalationspray
X
7.1.3
Foradil
inhalationpowder
X
7.1.1
GionaEasyhaler
inhalationpowder
X
7.1.3
Ipramol
solutionfornebuliser
X
7.1.4
Ipratropiumbromid
Arrow
solutionfornebuliser
X
7.1.5
Lepheton-DesentolAPL
oralsolution
X
Lomudal
inhalationpowder
X
7.1.8
Mollipect
oralsolution
X
7.2.4
7.2.6
Medicine
the pharmaceutical benefits board
Dosage form
Decision
Remains
Reason in section:
Out
Limited
Mucomyst
effervescenttablet
X
OxisTurbuhaler
inhalationpowder
X
7.2.1
7.1.1
Pulmicort
all
X
7.1.3
PulmicortTurbuhaler
inhalationpowder
X
7.1.3
Pulmozyme
solutionfornebuliser
X
7.2.5
SalbutamolArrow
solutionfornebuliser
X
7.1.1
Seretide
inhalationpowder
X
7.1.4
Serevent
inhalationpowder
X
7.1.1
Singulair
all
X
7.1.6
Spiriva
inhalationpowder
X
7.1.5
Symbicort
inhalationpowder
X
7.1.4
TeofyllaminIpex
injectionsolution
X
7.1.7
Teovent
oralandrectalsolution
X
7.1.7
tablet
X
7.1.7
Theo-Dur
extended
releasetablets
X
7.1.7
Ventoline
all
X
7.1.1,7.1.2
VentolineDepot
extended
releasetablets
X
7.1.2
Viskoferm
effervescenttablet
X
7.2.1
Xolair
injectionsolution
X
7.1.9
review of medicines against asthma, copd and coughs
7. BACKGROUND TO DECISIONS
When evaluting whether a medicine should be included in the pharmaceu­
tical benefits system the LFN must take the criteria from the law on phar­
maceutical benefits into account [63]. There it is stated that we are to judge
whether a medicine is cost-effective or not, meaning that we weigh the utility
of the medicine against the cost. We shall also consider other principles in
our evaluations: the needs and solidarity principle which means that those
with the greatest medical needs should have more healthcare resources, and
the human value principle which means that healthcare shall respect the
equal value of all people.
Treatment of asthma and COPD is cost-effective
Asthma and COPD are diseases which can have a huge impact on people’s
quality of life. They can also mean an increased risk of dying prematurely,
although the risk has decreased considerably since the introduction of inhaled
steroids and bronchodilators (see section 2). If the medicines are used accor­
ding to current recommendations then there is some evidence in the scienti­
fic literature to indicate that the stages in the treatment ladder for asthma are
cost-effective (see chapter 5).
The health economic evidence in support of medicines used for treating
COPD is somewhat weaker. We estimate that inhaled steroids are cost-effec­
tive compared to no treatment at all as are long-acting bronchodilators and
anticholinergics (see chapter 5).
This does not mean however that all medicines in the above classes are cost­
effective when compared to each other.
Cystic fibrosis is a serious disease
Problems with phlegm in the air passages can be the result of different diseases, from a cold to the constant overproduction of phlegm caused by cystic
fibrosis.
Cystic fibrosis is a serious and chronic disease which leads to large losses in
quality of life and a greatly increased risk of early death. It is therefore urgent
that mucus-reducing medicines are reimbursed for these patients.
0
the pharmaceutical benefits board
Coughing is not a serious disease
In our opinion coughing and phlegm in the air passages as a result of a cold
cause such temporary and mild distress that it is not reasonable to reimburse
medicines used to treat these symptoms. Furthermore, the effect of the medi­
cines is generally rather weak and also badly documented. Patients who want
to use these medicines can of course do so but will have to stand for the costs
themselves.
Infections in the upper respiratory tract can cause great discomfort, but coug­
hing is only part of the symptoms. As we are dealing with temporary discom­
fort the total loss in quality of life is small. [17]
Cost-effectiveness and the value of a range of products
We believe there is a value in having access to alternatives when it comes to
active substances, inhalation devices and dosage forms. It is also valuable if
the same inhalation device is available at a number of stages in the treatment
ladder.
We must carry out a holistic analysis of the pricing situation and the need for
a range of products. The value of adding yet another alternative treatment is
not as big for groups where alternatives already exist.
Amongst the groups of medicines we are evaluating there are a number of
medicines which have an equally good effect for the average patient but
which vary greatly in price. A narrow interpretation of the principle of cost­
effectiveness would mean that many medicines would lose their reimburs­
ment at the present price.
There are however reasons for allowing some differences in price between
different medicines, despite the effect for the patient being the same. In
many areas there is a need for a range of products. People can get different
results from a medicine, even if the medicines are similar. With a number of
alternatives available the chance of as many people as possible getting the best
treatment possible increases.
This allows two different medicines, which have the same effect on average
in clinical tests, to be part of the reimbursement system despite having so­
mewhat different prices. At the same time it is not reasonable that a medicine
with an equal effect should cost a lot more than its alternative.
Inhaled medicines have a large variation in their dose intervals, both when
it comes to the strength and number of dose occasions. This makes it im­
review of medicines against asthma, copd and coughs
possible to set a price limit which covers all products and strengths (see for
example, section 7.1.3).
Within these therapeutic areas there is a greater variation than only the
various active substances. Besides this there are various dosage forms, such as
inhalation powder, solution for nebuliser, inhalation spray, tablets and so on.
There are also a number of different inhalation aids, where some are unique
to a certain active substance, while others can be used for other medicines
too.
We have to make a reasonable evaluation from a holistic perspective. This
evaluation must be made against the backdrop of the specific circumstances
which exist for this therapeutic group. These deliberations are dealt with in
the next section.
7.1 Medicines against asthma and COPD
Included in this group of medicines are short-acting and long-acting bron­
chodilators, anti-inflammatory medicines and combinations of these. Also
other medicines such as anticholinergics, leukotrien receptor antagonists,
anti-allergenics and theophyllines are dealt with in this section.
7.1.1 Bronchodilators for inhalation retain reimbursement
Product
Active substance
Dosage form
Short-acting
Decision on reimbursement
Remains
Airomir
salbutamol
inhalationspray
X
Bricanyl
terbutaline
inhaledpowder,inhalationspray,
solutionfornebuliser
X
Buventol
salbutamol
inhalationpowder
X
SalbutamolArrow
salbutamol
solutionfornebuliser
X
Ventoline
salbutamol
inhalationpowder,inhalationspray,
solutionfornebuliser
X
Out
Limited
Long-acting
Foradil
formoterol
inhalationpowder
X
OxisTurbuhaler
formoterol
inhalationpowder
X
SereventDiskus
salmeterol
inhalationpowder
X
Short-acting bronchodilators
We believe it is important to have a range of products in this group. The
medicines are used to stop an acute narrowing of the air passages and it is
the pharmaceutical benefits board
therefore valuable that the patient be able to choose between different sub­
stances and inhalers.
We have not found any clinical studies which indicate there are any differen­
ces in effect between the medicines. We can however state that there are diffe­
rences in price (see appendix 4). We do not find this difference to be an issue
as this has to do with emergency treatments.
A number of studies have compared the effect of salbutamol administered
with Turbuhaler, Diskus or Easyhaler [64] [65] [66]. In general no clear
differences between the aids have been observed.
For the dosage form ”solution for nebuliser” we can say that the cost per dose
is considerably higher than the price for powder or spray inhalers. A solution
dose for a nebuliser costs approximately 5.40 Skr compared to a dose of spray
or powder which costs approximately 1 Skr.
Due to the nature of the dosage form the nebuliser is only used by patients
who cannot take medicine in any other way. We estimate that treatment for
these patients is cost-effective, as they do not have any other recourse to ease
an acute attack.
Long-acting bronchodilators
In our opinion long-acting bronchodilators should remain in the reimburse­
ment system as there are many health economic studies which point to their
cost-effectiveness in maintenance treatment for asthma in combination with
an inhaled steroid (see chapter 5).
There are differences in price between the substances. The cost per day for
maintenance treatment is between 7.79 and 9.42 Skr (see appendix 4). For
these medicines we believe the price difference is acceptable as it gives us ac­
cess to a number of active substances and inhalation aids.
For the average patient the cheapest medicine is the most cost-effective as in
our estimation the medicines have a similar effect. Oxis at a strength of 4.5
microgrammes looks more expensive than another comparable dose, but we
assume that if a higher dose is needed then the higher strength will be used.
We have not located any studies which can show that one substance is better
than the other for doses which can be compared. 9/12 microgrammes (indi­
cated dose/measured dose) formoterol twice per day seems to be comparable
with 50 microgrammes salmeterol twice per day [67] [68] [69].
review of medicines against asthma, copd and coughs
Two health economic studies have compared the active substances formoterol
and salmeterol for asthma. In one of the studies Oxis Turbuhaler is compa­
red to Serevent Diskus in treating children with asthma. The children who
got Oxis had a lower usage of short-acting bronchodilators but somewhat
higher number of visits to the doctor compared to the children who received
Serevent [70].
In the other study Serevent is compared to Foradil [71]. There are no sig­
nificant differences between the groups in terms of symptom-free days or
quality of life. The average cost was somewhat higher for the group which got
Serevent. The conclusion of the authors was that there was no evidence that
either of the substances was more cost-effective.
Oxis can also be used to ease mild asthma symptoms in the same way as a
short-acting bronchodilator. The cost for Oxis is however considerably higher
than, for example, Bricanyl or Ventoline. Oxis costs about 4 Skr per dose
compared to around 1 Skr for the short-acting medicines.
In a health economic analysis based on an open study, Oxis is compared to
salbutamol (Ventoline) when treating acute asthma symptoms [72]. The pa­
tients who received Oxis had more days without asthma symptoms and fewer
periods when the asthma became worse.
In a British study which compared salmeterol with standard treatment of
COPD salmeterol showed an improvement in measured lung function and
symptom-free days compared to the patients who got placebo. The costs for
hospital care decreased which partly compensated for the cost of the medi­
cine [58].
4
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
7.1.2 Bronchodilators in other dosage forms remain in the
benefits system
Product
Active substance
Dosage form
Reimbursement decision
Remains
Bambec
bambuterol
tablet
X
Bricanyl
terbutaline
oralsolution,tablet,
injectionsolution
X
BricanylDepot
terbutaline
extendedreleasetablets
X
Ventoline
salbutamol
oralsolution,tablet,solution
fornebuliser
X
VentolineDepot
salbutamol
extendedreleasetablets
X
Out
Limited
• Injections and oral solution used to ease acute symptoms.
• Tablets, extended release tablets used for maintenance treatment.
• Used by a limited group of severely ill COPD patients, and children
with cystic fibrosis.
In our opinion these medicines should continue to be included in the phar­
maceutical benefits system. Maintenance treatment with tablets/extended
release tablets is not more expensive than treatment with long-acting bron­
chodilators. Acute treatment with oral solution is somewhat more expensive
than inhalation treatment, but oral solution is not given in the first instance
only when inhalation is not suitable. Use of the oral solution is mainly meant
for children. According to doctors at Stockholm’s CF centret hese medicines
are also part of basic treatment for children with cystic fibrosis.
Despite a large selection of inhalation substances it is only these medicines
which result in successful treatment within out patient care for a limited
group of severely ill COPD patients. This can as an example mean patients
who cannot use an inhaler.
7.1.3 Anti-inflammatory medicines for inhalation
– Asmanex loses reimbursement status
Product
Active substance
Dosage form
Reimbursement decision
Aerobec
beklometasone
inhalationspray
Asmanex
mometasone
inhalationpowder
Beclomet
beklometasone
inhalationspray
X
Becotide
beklometasone
inhalationpowder
inhalationspray
X
Remains
Out
X
X
Limited
review of medicines against asthma, copd and coughs
Budesonid
Arrow
budesonide
solutionfornebuliser
X
FlutideDiskus
fluticasone
inhalationpowder
X
FlutideEvohaler
fluticasone
inhalationspray
X
GionaEasyhaler
budesonide
inhalationpowder
X
Pulmicort
budesonide
inhalationpowder,inhalation
spray,solutionfornebuliser
X
• No differences in effect at comparable doses in treating asthma.
• 30-70 percent difference in price between the cheapest and most expensive alternatives depending on dose.
• Asmanex shall not remain in the reimbursement system.
• Dosage forms mainly used for treating children shall continue to be reimbursed (inhalation spray, solution for nebuliser).
We estimate the products at comparable doses have a similar effect on asth­
ma. At these doses there are large differences in price between the products
(mainly in regard to inhalation powder, see appendix 3). The price difference
varies depending on which dose is compared. The most expensive substances
are between 30 and 70 percent more expensive than the cheapest. We find
the cost in relation to the effect to not be justified for Asmanex Twisthaler.
Inhaled steroids have a well-documented effect and an accepted place in
therapy [4] [3] [1]. Treatment using inhaled steriods as a group can also be
seen as cost-effective (se 5.3.2). That does not however mean that all inhaled
steroids are cost-effective.
Asmanex Twisthaler is not cost-effective
The company has not proven that the increased cost from treatments with
Asmanex actually adds value compared to other inhaled steroids.
Asmanex is 60 to 70 percent more expensive than the cheapest alternative in
all doses which were compared (see appendix 3). We do not find this price
difference to be acceptable and it is not worth paying so much solely for a
range of products as the number of active substances and inhalers in this
group is large. Asmanex shall therefore no longer be part of the pharmaceuti­
cal benefits system.
An advantage which the company pointed out was that simpler dose pro­
cedures combined with just one treatment per day could lead to the patient
being able to better follow the doctor’s prescription. They have not however
shown how important this might be for the results of the treatment, or how
the pharmaceutical benefits board
much this could be worth. The dose advantage applies only to Asmanex 400
microgrammes once per day (comparable to 800 microgrammes budesonide).
At lower doses Giona Easyhaler and Pulmicort Turbuhaler can also be taken
just once a day [73] [74] and at higher doses even Asmanex must be taken
twice per day [75].
Price differences for inhaled steroids in powder form
There are many different strengths for the various medicines in this group.
The amount of medicine the patients need varies also. We use the doses
mentioned below in in the section ”Comparable doses for inhaled steroids for
asthma” as a starting point. Based on these and the approved doses we have
carried out a price comparison (see appendix 3).
To ascertain if a price difference is acceptable for a product a holistic evalua­
tion of all doses must be done. Furthermore, factors such as the need for a
number of active substances and different inhalation aids must be considered.
The differences in price vary greatly depending on how high the dose is. At
the lowest strengths the difference in daily cost is less than one Skr, while at
the highest doses it is eight Skr. The inhaled steroid which is cheapest varies
depending on the patient’s steroids need.
Where Asmanex Twisthaler is available and if you consider all doses then
it generally has a higher price tag. Flutide Diskus also has a price which is
higher than other substances at some strengths. Flutide is however the only
inhaled steroid which is approved for treating COPD [20]. The inhalation
aid Diskus is also used with short-acting and long-acting bronchodilators as
well as combination treatments. It is an advantage that there are a number of
substances which can use the same inhaler.
However, the higher cost of treatment for Flutide Diskus means that other,
cheaper alternatives should be considered first.
Inhaled steroids – spray and solution for nebuliser remains
in the reimbursement system
It is important to keep these substances in the reimbursement system as
these medicines are mainly used for treating small children who cannot use a
powder inhaler. An alternative is to use a solution for nebuliser. The need for
inhaled steroids in these dose forms is therefore judged to be large. For child­
ren steroids are administered early and already for mild asthma which eases
the symptoms well and prevents periods when the condition gets worse.
review of medicines against asthma, copd and coughs
The day cost for inhaled steroids in powder form varies between 2 and 14
Skr. Inhaled sprays are generally not more expensive than powder inhalers.
However, the daily cost for nebuliser solutions is higher. There the cost varies
between 18 and 36 Skr for children and 20 to 40 Skr for adults.
The nature of this type of dose means that the solution for nebulisers is
used by patients who cannot take anything else. We estimate that for these
patients it is cost-effective as the alternative is no treatment at all.
Comparable doses for inhaled steroids for asthma
Collectively the studies and summaries described below support the table in
the Medical Products Agency’s treatment recommendations for asthma (see
table 8). The doses of mometasone have been added based on clinical studies
where mometasone has been compared with other substances after discus­
sions in the project group [27].
Two Cochrane reports have compared inhaled steroids and lend support to
the case that steroids administered in their recommended doses give similar
clinical effects. Fluticasone and mometasone are judged to be comparable at
half of the dose of budesonide and beclometasone. [26, 76]
Table 8: Equal doses of inhaled steroids in powder form.
Active substance
Dose (microgrammes)
Low
Medium high
High
beclometasone
<400
400-1000
>1000
budesonide
<400
400-800
>800
fluticasone
<250
250-500
>500
200-400
>400
mometasone
In the Cochrane report from 2000 [76] a summary is presented of the clini­
cal studies which have compared budesonide to beclometasone. No signifi­
cant difference in effect was observed from budesonide and beclometasone
given at the same dose for the parameters of FEV1, PEF, asthma symptoms
or used amount of rescue medicine. No significant differences in the side-ef­
fects between the substances was either found in the compilation.
In a newly published Cochrane report [26] a summary was presented of the
clinical studies which had compared fluticasone with budesonide or beclo­
metasone to astma. The number of studies which compare powder inhalers
(22 of them) is roughly the same amount as studies which compare sprays
(23 of them).
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
In the summary the following conclusions are evident:
• When fluticasone is compared with budesonide/beclometasone in the
dose relation 1:2, it seems as if fluticasone has a better effect on the
parameters FEV1 and PEF.
• No significant difference for asthma symptoms was observed between
fluticasone and the other substances, ”rescue medicine” and short
acting bronchodilators, or the number of periods when the asthma
has worsened.
• At a dose relation of 1:2 Fluticasone caused more hoarseness than other steroids. It can be said that a similar clinical effect can be expected from fluticasone if
it is administered at half the amount of medicine as compared to budesonide
or beclometasone, and that some variables can be improved further using
fluticasone in the dose (FEV and PEF).
Difference in effect between different inhalers
Studies have been done on the difference in effect between budesonide
administered with Easyhaler and Turbuhaler for asthma symptoms of adults
[77] and children [78]. The different inhalers showed a similar effect on the
measures of effect examined. Turbuhaler was not observed to have an effect
on regulating cortisone use for children. One study examined how budeso­
nide was distributed throughout the lungs with Turbuhaler or Easyhaler [79].
The medical aids had a similar effect on the plasma concentration of bude­
sonide.
In a summary of studies where different inhalation aids for steroids against
asthma were compared [25] it was stated that when individual powder
inhalers were compared to sprays no significant difference was observed.
It should be noted that Asmanex Twisthaler was not part of this comparison.
We have not located any information showing that Twisthaler is better or
worse than other powder inhalers.
review of medicines against asthma, copd and coughs
7.1.4 Combination medicines for inhalation
remain in the reimbursement system
Product
Active substance
Dosage form
Reimbursement decision
Remains
Combivent
salbutamol/ipratropium
solutionfornebuliser
X
Ipramol
salbutamol/ipratropium
solutionfornebuliser
X
Seretide
fluticasone/salmeterol
inhalationpowder
inhalationspray
X
Symbicort
budesonide/formoterol
inhalationpowder
X
Out
Limited
Long-acting bronchodilators and steroids in combination
In our opinion it is important that there is access to both combination
medicines and inhalers. As a whole for asthma and COPD we believe the dif­
ference in price is acceptable.
It has been proven that it is cost-effective to add long-acting bronchodilators
to inhaled steroids for a better effect, mainly for asthma but also for COPD
(see section 5). The pharmaceutical cost is lower with a combination substan­
ce than if the medicines are bought separately. It is however important to first
test the lowest effective dose with each of the medicines before moving to the
combination substance.
We base our price comparison between the substances on the doses which
apply for inhaled steroids and long-acting bronchodilators for asthma (see
section 7.1.1 and 7.1.3).
Both of the combination substances are approved for treatment of COPD.
For COPD the dose between steroid components (fluticasone and budeso­
nide) different to asthma, based on the approved doses for COPD [80, 81].
There are differences in price for the substances. The cost per day for main­
tenance treatment of asthma is between 15 and 20 Skr for standard strength
(see appendix 5). The difference in price is larger for the weaker strength. For
treatment of COPD the difference in price is smaller.
Within the group of combination medicines there are three different
strengths of two different products. The combination medicine which is
cheapest varies based on the patients need for steroids and way to take the
dose. Seretide is cheaper than Symbicort for a fixed dose. For variable doses
and acute and maintenance treatment with Symbicort the cost-effectiveness
can vary.
0
the pharmaceutical benefits board
In two studies, acute and maintenance treatment with Symbicort on a fixed
dose, and Seretide with an addition of Ventoline for acute needs were com­
pared. The patients who received Symbicort lasted longer before getting a
serious deterioration in their asthma and the number of periods where deto­
rioration was evident were somewhat fewer. The difference in the number of
deteriorating periods per patient and year was however only 0.07 [82].
A cost-effectiveness analysis based on this study could only show significant
differences in total cost in one of the four countries studied [51].
In a newly published study where Symbicort was compared with a fixed dose
of Seretide for acute and maintenance treatment roughly the same result
appeared. The study also showed that the total use of steroids was somewhat
lower for Symbicort [83]. Worth pointing out here is that this study compa­
red Symbicort inhalation powder to Seretide inhalation spray.
Anticholinergics and short-acting bronchodilators in combination
In our opinion these medicines are of value for patients who are in constant
need of both of the active substances. It is between 10 and 30 percent chea­
per to use the combination medicine than to use each of the medicines by
themselves.
We stated earlier that solutions for nebulisers are an urgent treatment alter­
native. Combivent/Ipramol is only available as a solution for nebulisers and
contains the same active ingredients as the medicines Atrovent (ipratropium)
and Ventoline (salbutamol).
7.1.5 Anticholinergics stay in the reimbursement system
Product
Active sub­
stance
Dosage form
Reimbursement decision
Remains
Atrovent
ipratropium
inhalationpowder,inhalationspray,
solutionfornebuliser
X
Ipratropium­
bromid
Arrow
ipratropium
solutionfornebuliser
X
Spiriva
tiotropium
inhalationpowder
X
Out
Limited
Ipratropium
In our opinion all dosage forms of the medicine should be included in the
reimbursement system. Ipratropium has a documented effect on lung fun­
ction and breathing difficulties for COPD patients [5]. It may also have an
effect on asthma symptoms [84]. The use of ipratropium for asthma is low,
review of medicines against asthma, copd and coughs
it is mainly used to treat COPD. The disease is debilitating which leads to
patients needing different dose forms the worse the symptoms get.
Spiriva
Spiriva is somewhat more expensive than ipratropium, but there is evidence
that Spiriva is cost-effective in treating COPD [62, 85].
A head to head study between Spiriva and Atrovent showed that the number
of periods with a worse condition for the disease decreased by 24% when tre­
atment with Spiriva was used [86]. The study also stated that time to hospita­
lisation was delayed and that quality of life improved for these patients.
7.1.6 Singulair to remain in the benefits system
Product
Active substance
Dosage form
Reimbursement decision
Singulair
montelukast
oralgranules,
chewabletablet
X
Singulair
montelukast
Tablet
X
Remains
Out
Limited
Singulair, oral granules and chewable tablets for children
Singulair in the form of granules and chewable tablets is useful for children
with infection-triggered asthma [87]. The medicine is easy to take and is
also considered relatively free from side-effects [3]. We believe it is especially
valuable with other dosage forms for children who may have difficulties in
using inhalation devices in the right way.
Singulair, tablets for adults
Singulair tablets have advantages which lead us to conclude they should be
included in the pharmaceutical reimbursement system, despite its higher
price tag. Singulair has an anti-inflammatory effect which differs from the
anti-inflammatory effect achieved through inhaled steroids. This can be
valuable for some patients suffering from a specific type of asthma. It also has
another side-effect profile to both inhaled steroids and long-acting broncho­
dilators.
The treatment cost for Singulair is high compared to adding long-acting
bronchodilators or increasing the dose of steroids for moderate-severe to
severe asthma. In studies Singulair has had a similar effect on symptoms and
lung function as long-acting bronchodilators or an increased dose of steroids.
the pharmaceutical benefits board
That is why we underline the fact that it is important to try treatment using
inhaled steroids and long-acting bronchodilators before using Singulair due
to its prohibitive cost. It is also very important from a cost-effectiveness point
of view that the effect be evaluated and the treatment terminated if positive
results are wanting.
Some patients acheive an excellent effect using Singulair, while others have
no effect at all. The share of patients who do not get an effect is estimated
from clinical experience to be in the region of 30 to 50 percent. In studies
Singulair can exhibit worse results compared to bronchodilators. This is in
part because a demand made to be part of the study is that bronchodilators
have a proven effect, and partly because the effect from Singulair is mainly
anti-inflammatory instead of bronchodilating. [9]
According to the Medical Products Agency’s treatment recommendations
from 2002, adult patients who do not have their asthma under control using
inhaled steroids at a low dose, should add treatment using long-acting bron­
chodilators. It is also stated that leukotrien receptor antagonists (Singulair)
can be used as a complement to inhaled steroids, but that long-acting bron­
chodilators are the first-line choice. If the patient is not free of discomfort
then both long-acting bronchodilators and Singulair can be administered as a
complement to inhaled steroids. The effect from Singulair should be evalua­
ted after four weeks.
When the recommendations were published there were no studies compa­
ring leukotrien receptor antagonists and long-acting bronchodilators. We
have located two systematic reviews which compare the effect of leukotrien
receptor antagonists to the addition of long-acting bronchodilators [32, 33].
One of the studies compares the addition of Singulair to inhaled steroids, to
a doubling of the dose of steroids [88]. We have not found any study which
looks at the effect of adding leukotrien receptor antagonists to both steroids
and long-acting bronchodilators.
The addition of leukotrien receptor antagonists to inhaled steroids is estima­
ted to give a similar effect as an increase of the dose of steroids. When com­
paring the addition of leukotrien receptor antagonists or long-acting bron­
chodilators, the latter were better on all parameters (lung function, number
of exacerbations, acute medication).
For Singulair only two cost-effectiveness studies have been identified where it
is used as a complement to inhaled steroids. In both of these studies Singu­
lair is compared to Serevent. Serevent appears to be the better and cheaper
alternative in both of these studies [52] [45].
review of medicines against asthma, copd and coughs
7.1.7 Theophyllines for acute treatment remains in the reim­
bursement system, maintenance treatment not reimbursed
Product
Active substance
Dosage form
Reimbursement decision
Remains
Out
Teofyllamin
Ipex
theophylline
injectionsolution
X
Teovent
choline
theophyllinate
oralsolution,
rectalsolution
X
Teovent
choline
theophyllinate
tablet
X
Theo-Dur
theophylline
extendedrelease
tablets
X
Limited
• Theophyllines for acute treatment shall remain in the reimbursement system.
• Theophyllines for maintenance treatment are leaving the reimbursement system.
Theophyllines for acute treatment remain in the rimbursement system
Theophyllines in the form of injection fluid and oral and rectal solutions are
mainly used for emergency treatments. The largest use of these is therefore
within inpatient care.
The experts we have used underline that there are patients who get the above
dosage forms of theophyllines on prescription. This is mainly patients with
frequent asthma attacks who are not able to stop the attacks with short-acting
bronchodilators. In these cases the patient can get help to stop the attack by
adding theophylline. Children make up part of this group and pediatricians
are of the opinion that due to this these medicines must be included in the
reimbursement benefits system.
Theophyllines för maintenance treatment
removed from the benefits system
We do not consider it proven that maintenance treatment with theophyllines
is cost-effective. Furthermore, there are more modern medicines which are
better documented both in terms of effect and safety.
The medical effect from theophyllines is hard to judge. There is no literature
which shows that theophylline is cost-effective in comparison with other
more modern medicines.
4
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
There are studies which suggest that theophyllines could have a place in the
treatment of COPD for a limited group of patients [89]. The effect of theop­
hylline on COPD is however rather mild when compared to other substan­
ces. [90]. Also the Medical Products Agency states that theophyllines should
not be a normalised part of maintenance treatment for COPD [5].
Since theophyllines were introduced new medicines have appeared for
maintenance treatment of asthma and COPD, such as inhaled steroids and
bronchodilators. These medicines are better documented both in terms of
effect and safety.
7.1.8 Anti-allergenics - Lomudal
inhalation powder removed from the reimbursement system
Product
Active substance
Dosage form
Lomudal
sodiumcromoglycate
inhalationpowder
Reimbursement decision
Remains
Out
Limited
X
• Treatment using Lomudal inhalation powder costs more than
treatment with other available alternatives. The higher cost is
not compensated for by any clinical or health economic advantages.
• Lomudal inhalation powder is to be removed from the reimbursement system. In our opinion the increased costs inherent in treatment using Lomudal are
not compensated for by clinical or health economic advantages. Lomudal
shall therefore not be part of the reimbursement system. Lomudal does not
have a clear effect on asthma according to recent studies. It may have an
effect on exercise-induced asthma, but in this area there are cheaper options
available.
The medicine is used by a limited group of patients and the market has been
steadily declining over the past years. Possible users are patients who are
afraid of steroid treatments and patients who mainly suffer from exercise­
induced asthma.
The SBU states that the medicine has a good effect on mild to medium
asthma for children over four years old and adults. [3]. The Medical Pro­
ducts Agency estimates that the prevention of symptoms effect gained from
using Lomudal is lower than for inhaled steroids [4]. Newer systematic
reviews have not been able to show any effect besides the placebo effect when
review of medicines against asthma, copd and coughs
it comes to asthma [34]. A systematic review from 2006 showed that inhaled
steroids were better than Lomudal when it came to lung function, number of
exacerbations, asthma symptoms and rescue medication using bronchodila­
tors.[35]
According to treatment recommendations from the Medical Products Agency
from 2002 Lomudal has some effect on asthma triggered by physical exercise.
The most common treatment for exercise-induced asthma is however short­
acting bronchodilators. In our investigation we have not found any studies
which compare the effect of Lomudal for exercise-induced asthma to short­
acting bronchodilators. We can however state that the price per dose is con­
siderably higher for Lomudal than for short-acting bronchodilators available
to us. A dose of Lomudal costs 2.36 Skr while a dose of Bricanyl or Ventoline
costs 0.75 Skr and 1.11 Skr respectively. For regular treatment Lomudal costs
approximately 9.50 Skr per day, compared to low dose inhaled steroids which
cost between 1.50 and 4 Skr per day (see appendix 3).
7.1.9 Other medicines against asthma
- Xolair stays in the reimbursement system
Product
Active substance
Dosage form
Reimbursement decision
Remains
Xolair
omalizumab
injectionfluid
Out
Limited
X
The LFN decided on the 7th of March 2006 that Xolair should be included
in the reimbursement system. The decision is contingent on certain marke­
ting and follow-up conditions (see below). We can state here that we reach
the same conclusion here in this review as we did then.
The decision to grant reimbursement status to Xolair is contingent on the
following conditions:
The company shall in all of its marketing and other information clearly state
that evaluation of patient response to treatment with Xolair is important for
a cost-effective treatment.
The company shall be responsible for the execution of a follow-up of usage of
Xolair in clinical practice. The follow-up shall mainly show how the evalua­
tion of patient response is carried out and how the treatment is concluded
after 16 weeks if the patient has not responded to the treatment.
And experiences from clinical practice on the effect of the medicine and side­
the pharmaceutical benefits board
effects after a longer treatment period than 6 months shall also be followed
up. These follow-up activities shall be reported to the LFN at the latest 31
December 2010.
7.2 Medicines against coughing and cystic fibrosis
These medicines are mainly mucus-dissolving and are used for treating coug­
hing which is not caused by asthma.
Product
Active substance
Dosage form
Reimbursement decision
Remains
Out
Acetylcysteine
acetylcysteine
effervescenttablet
X
Acetylcysteine
acetylcysteine
solutionfornebuliser
X
Bisolvon
bromhexin
tablet
EfedrinhydrokloridAPL
ephedrinehydrochloride
capsule,oralsolution
X
Efedrinhydrokloridi
QuillaSimplexAPL
ephedrinehydrochloride
orallösning
X
Lepheton-DesentolAPL
ephedrine/ethylmor­
phine/difenhydramin
oralsolution
X
Mollipect
bromhexin/ephedrine
oralsolution
Mucomyst
acetylcysteine
effervescenttablet
Limited
X
X
X
Pulmozyme
dornasealfa
solutionfornebuliser
X
Viskoferm
acetylcysteine
effervescenttablet
X
Problems with phlegm in the airways may be the resulty of a number of
diseases, from colds to the constant over-production of phlegm in cystic
fibrosis.
Cystic fibrosis is a difficult chronic disease which leads to great losses in
quality of life, and it is therefore urgent that mucus-reducing medicines are
reimbursed for these patients.
On the other hand we see coughing and phlegm in the airways due to a cold
as resulting in such temporary and mild discomfort, that it is not deemed
reasonable to reimburse medicines for these symptoms. Furthermore, the
effect gained from these medicines is rather weak and also unsatisfactorily
documented.
Upper respiratory infections can cause great discomfort,but coughing is only
part of the symptoms. It is also a temporary ailment resulting in the total loss
in quality of life being very small. [17]
review of medicines against asthma, copd and coughs
In general there is not very much modern documentation on cough suppre­
sants and mucus-reducing medicines. One is then referred to older studies
and few of these stand up to today’s standards in accordance with GCP
(good clinical practice). It is also probable that many substances do not have
any effect other than the placebo effect.
7.2.1. Acetylcysteine, Mucomyst and Viskoferm
– effervescent tablets remain in the reimbursement system
• Effervescent tablets containing acetylcysteine shall not be reimbursed
for formation of mucus caused by a cold.
• Effervescent tablets containing acetylcysteine can give fewer exacerbations for COPD.
• Used for basic treatment of patients with cystic fibrosis.
In our opinion effervescent tablets containing acetylcysteine shall remain in
the pharmaceutical benefits system.
We estimate that there is good reason to reimburse long-term treatment
using acetylcysteine for COPD –patients with chronic bronchitis, as well as
for patients with cystic fibrosis (CF).
Acetylcysteine is used in base treatment of patients with cystic fibrosis and
patients with primary ciliary dyskinesia (PCD). The severity of the disease is
high. These patients also have a great need of medicine and their alternatives
are either totally lacking or severely limited.
We consider coughing and phlegm in the air passages due to a cold as resul­
ting in such temporary and mild discomfort, that it is not deemed reasonable
to reimburse medicines for these symptoms. Neither is there documentation
to support the use of acetylcysteine for this purpose.
The question is whether this usage should be excluded from reimbursement.
In our estimation it would however in this case be difficult to maintain such
a limitation in practice.
There is conflicting information on the clinical effects of acetylcysteine.
According to the SBU’s study from 2000 there is no basis on which to eva­
luate the effect on coughing and expelling phlegm for long-term treatment
of asthma and COPD. They do state however that long-term treatment with
acetylcysteine does give a small decrease in the number of exacerbations for
t h e p h a r m a c e u t i c a l b e n e f i t s b o a r d
patients with chronic bronchitis and that this in turn gives rise to a small
decrease in the number of sick days. [3]
In a study published in The Lancet in 2005 [8] the conclusion is drawn that
acetylcysteine was not better than placebo on any parameter (lung function,
number of exacerbations and so on) except for COPD patients who did not
use steroids.
7.2.2 Acetylcysteine – solution for nebuliser remains in the
reimbursement system
•
Acetylcysteine solution for nebulisers shall remain in the reimbursement system
We find that Acetylcysteine as a solution for nebulisers shall continue to be
reimbursed. This medicine is used in out patient care only by patients with
cystic fibrosis (CF) and patients with primary ciliary dyskinesia (PCD).
The severity of these disease is high. These patients also have a great need of
medicine where their range of possible treatments are either absent, or very
limited.
7.2.3 Bisolvon – reimbursement limited to patients with cyctic fibrosis PCD
•
Reimbursement for Bisolvon tablet is limited to patients with cystic fibrosis or primary ciliary dyskinesia.
Cystic fibrosis and primary ciliary dyskinesia are diseases which lead to great
losses in quality of life. The number of patients is small and most use Bisol­
von for inhalation. The CF/PCD patients who need Bisolvon tablets should
have these reimbursed.
On the other hand we consider coughing and phlegm in the air passages due
to a cold as resulting in such temporary and mild discomfort, that it is not
deemed reasonable to reimburse medicines for these symptoms. Furthermore,
the effect gained from these medicines is rather weak and also unsatisfactorily
documented.
For Bisolvon there is a good deal of older documentation and of uncertain
quality, but which indicates that Bisolvon has an effect on phlegm [91].
There are a number of studies where bromhexine has been evaluated for pa­
tients with cystic fibrosis. One of these [92] shows that bromhexine is equal
review of medicines against asthma, copd and coughs
to other mucus-reducing substances (carbocysteine lysine salt monohydrate)
but there was no placebo component to the study.
A Norwegian study of asthma patients by Heilborn et al from 1976 [93]
did not show any clinical differences but rather a subjective preference for
bromhexine. Valenti et al [94] carried out a study on COPD patients but at
a higher dose (60 mg/day). Improvements to a number of parameters were
found including FEV1 which increased to 138 ml compared to 70 ml for
placebo. The problem with older studies is that the groups studied are often
too heterogenous and badly presented. The dose used in the study by Valenti
was twice as high as that recommended in FASS and due to this we consider
the value of the study to be low.
7.2.4 Mollipect loses reimbursement
•
Mollipect oral solution is removed from the reimbursement system.
We consider coughing and phlegm in the air passages due to a cold as resul­
ting in such temporary and mild discomfort, that it is not deemed reasonable
to reimburse medicines for these symptoms. Furthermore, the effect gained
from these medicines is rather weak and also unsatisfactorily documented.
Our investigation has not concluded that Mollipect is of such importance
for CF treatment that it warrants a limited reimbursement for that patient
group. There are a number of mucus-reducing and bronchodilating medici­
nes which remain within the reimbursement system and are alternatives to
Mollipect.
Mollipect contains a mucus-dissolving (bromhexine) and a bronchodilating
(ephedrine) component. Studies show there can be a small effect on the
stickiness of the phlegm coming from the mucus-dissolving component,
but there is no effect on coughing, breathing difficulties or lung function.
Ephedrine has a bronchodilating effect but no effect on coughing if it is not
related to a narrowing of the air passages. There are other bronchodilators
which are cheaper, better documented and have a better side-effect profile if
there is a need for a bronchodilating effect
0
the pharmaceutical benefits board
7.2.5 Pulmozyme for cystic fibrosis remains in
the the reimbursement system
•
Pulmozyme stays in the reimbursement system.
Studies show that costs in relation to the health gains made using Pulmozyme
seem reasonable when account is taken of the disease and the situation for
the patient group. Pulmozyme is used to treat cystic fibrosis (CF). There is
no comparable medicine on the market, but the treatment cost per patient is
high (111 Skr per day, or 40 000 Skr per year).
An American study indicates that a third of the pharmaceutical costs can be
accounted for in savings made for a lessened need for antibiotics treatment
and contacts with healthcare. [95]. A European study came to a similar con­
clusion, where between 17 and 27 percent of the cost for medicines could be
compensated for by way of savings in the healthcare system in general. [96].
An informal cost-value analysis has been done in England. It was estimated
that the net cost for healthcare (costs minus savings) for treatment using Pul­
mozyme was comparable to 80 000 Skr per patient and year (5 900 Bristish
pounds sterling). The cost per quality-adjusted life year (QALY) was estima­
ted to be approximately 340 000 Skr (25 000 British pounds sterling) [97].
A study carried out by Christopher et al estimated the cost per gained year
of life compared to no treatment to be approximately 720 000 Skr (52 500
British pounds sterling) for all CF patients. The cost per gained year of life
for patients with moderate-severe to severe illness was estimated to be 220
000 Skr (16 000 British pounds sterling) [98].
Suri et al estimate the cost-effectiveness of daily inhalation of Pulmozyme
compared to inhaled salt solution and treatment every second day using Pul­
mozyme. The result was a cost of between 1 500 to 3 000 Skr per 1 percent
improvement in FEV1. What such an improvement is worth in quality of life
is however not indicated [99].
Estimated costs per gained QALY or life year according to the studies above
are not certain and pertain to England. Costs are high, in some calculations
up to 700 000 Skr per gained life year. 340 000 Skr per gained QALY is
within a limit which normally is deemed acceptable. It is however important
to remember that the estimations above are based on a small patient base and
that the quality of life calculations are based on an informal analysis.
review of medicines against asthma, copd and coughs
7.2.6 Lepheton-Desentol loses reimbursement
•
Lepheton-Desentol is removed from the reimbursement system.
We consider coughing and phlegm in the air passages due to a cold as resul­
ting in such temporary and mild discomfort, that it is not deemed reasonable
to reimburse medicines for these symptoms. Furthermore, the effect gained
from these medicines is rather weak and also unsatisfactorily documented.
The effect of Lepheton-Desentol is badly documented. There is no scientific
evidence to indicate that it has any effect in treating croup. According to a
medicines guide in Sweden (Läkemedelsboken) Lepheton-Desentol is not
recommended for treating croup. There cortisone either inhaled or in tablet
form is recommended instead [10]. There is also scientific evidence to back
this up [100].
We have not found any studies on Lepheton and coughing when we perfor­
med a literature search. In various pharmacological educational books for
instance it is stated that Ethylmorphine has the same cough-suppressing
effect as codeine and morphine [101]. There is no modern documentation
in regard to Ethylmorphine.
In FASS Desentol does not have coughing as an indication but instead ”al­
lergic conditions”. On the whole there is nothing to indicate that difenhydra­
min (Desentol) has any cough-suppressing effect in any respectable scientific
journal. Quite the opposite, it is easier to worry over the indicated side-ef­
fects.
7.2.7 Ephedrine hydrochloride loses reimbursement status
•
Efedrinhydroklorid i Quilla Simplex (ephedrine hydrochloride) and
Efedrinhydroklorid (ephedrine hydrochloride) capsules and oral solutions are removed from the reimbursement system.
We consider coughing and phlegm in the air passages due to a cold as resul­
ting in such temporary and mild discomfort, that it is not deemed reasonable
to reimburse medicines for these symptoms. Furthermore, the effect gained
from these medicines is rather weak and also unsatisfactorily documented.
The effect of ephedrine hydrochloride is badly documented. There are other
bronchodilators which are cheaper, better documented and have a better side­
effect profile if there is a need for a bronchodilating effect.
the pharmaceutical benefits board
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review of medicines against asthma, copd and coughs
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(Symbicort) reduces healthcare costs compared with separate inhalers
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Johansson, G., et al., Cost effectiveness of budesonide/formoterol
for maintenance and reliever therapy versus salmeterol/fluticasone
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corticosteroids plus salmeterol or montelukast: effects on resource
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inhaled corticosteroids for chronic obstructive pulmonary disease
according to disease severity. Am J Med, 2004. 116(5): p. 325-31.
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the pharmaceutical benefits board
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single inhaler for COPD compared with each monocomponent used
alone. Pharmacoeconomics, 2005. 23(4): p. 365-75.
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of ipratropium plus albuterol compared with ipratropium alone and
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by Turbuhaler and Diskus. Respir Med, 2000. 94(6): p. 574-7.
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as salbutamol via Turbuhaler in the treatment of histamine-induced
bronchoconstriction. Respir Med, 2000. 94(11): p. 1097-102.
Nightingale, J.A., D.F. Rogers, and P.J. Barnes, Comparison of the
effects of salmeterol and formoterol in patients with severe asthma.
Chest, 2002. 121(5): p. 1401-6.
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in asthmatic patients: onset of action, duration of effect and potency.
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salmeterol in patients with reversible obstructive airways disease.
Respir Med, 1998. 92(6): p. 836-42.
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with asthma. Pharmacoeconomics, 1998. 14(6): p. 671-684.
Lindgren, B., et al., Cost-effectiveness of formoterol and salbutamol
as asthma reliever medication in Sweden and in Spain. Int J Clin
Pract, 2005. 59(1): p. 62-8.
Giona Easyhaler, produktresumé. 2006.
Pulmicort Turbuhaler, produktresumé. 2006.
Asmanex Twisthaler, produktresumé. 2006.
review of medicines against asthma, copd and coughs
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the pharmaceutical benefits board
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review of medicines against asthma, copd and coughs
Appendix 1 – definition of degree
of severity of asthma
National Board of Healthy and Welfare’s classification
of degree of severity for asthma
There are two different ways to classify the degree of severity of asthma.
One way is to estimate the degree of severity before maintenance treatment
is commenced (see below), another way is to examine ongoing maintenance
treatment, symptoms and lung function. The severity scale below is based on
a classification before beginning maintenance treatment.
Intermittentasthmasymptoms
<Onceperweek
Temporaryexacerbations
Nightsymptoms#Twicepermonth
FEV180percentofexpectedvalueor
PEF80percentofexpectedvalue
PEFvariability<20percent
Mildasthmasymptoms
>Onceperweekbut<Onceperday
Symptomscanaffectactivityandsleep
Nightsymptoms>Twicepermonth
FEV180percentofexpectedvalueor
PEF80percentofexpectedvalue
PEFvariability20-30percent
Moderate-severeasthma
Symptomsdaily
Symptomscanaffectactivityandsleep
Nightsymptoms>Onceperweek
Dailyneedofshort-actingbeta-2-stimulants
FEV160–80percentofexpectedvalueor
PEF60–80percentofexpectedvalue
PEFvariability>30percent
Severeasthma
Symptomsdaily
Frequentexacerbations
Frequentnightsymptoms
Limitedphysicalactivity
FEV1#60percentofexpectedvalueor
PEF#60percentofexpectedvalue
PEF-variability>30percent
0
the pharmaceutical benefits board
Appendix 2 – definition of
Degree of severity of COPD
National Board of Health and Welfare severity scale for COPD
severity scale
International consensus documents contain a plan for estimating the severity
scale of COPD. Common to these is extensive reliance on measured values
from FEV1. The purpose is to be able to describe a prognosis and adequate
measures for the various degrees of severity.
Classification of degree of severity
FEV1 indicates values measured after bronchodilator
New stage division in Sweden starting from 2006
(reference www.slmf.se/kol/)
Diagnosis/
classification
Definition
FEV%<70(FEV1/VC)(noteafterbronchodilator)and
PreclinicalCOPD
FEV1>80%ofexpectedvaluewithorwithoutsymptoms(coughing/phlegmproduction)
MildCOPD
FEV150–79%ofexpectedvaluewithorwithoutsymptoms
Moderate-severeCOPD
FEV130–49%ofexpectedvaluewithorwithoutsymptoms
Non-existenceofothernegativefactorsforprognosis*
Moderate-severeCOPD
FEV1<30%ofexpectedvalue
FEV1<50%ofexpectedvalueandexistenceofothernegativefactorsforprognosis*
* Severe chronic hypoxia (PO2 < 7,3 kPa).
Chronic hypercapnia (PCO2 > 6,5 kPa).
Effect on circulation (eg peripheral oedema or tachycardia).
Low body weight.
New GOLD classification
Figure1-2.SpirometricClassificationofCOPDSeverityBasedonPost-BronchodilatorFEV1
StageI:Mild
FEV1/FVC<0.70
FEV180%predicted
StageII:Moderate
FEV1/FVC<0.70
50%#FEV1<80%predicted
StageIII:Severe
FEV1/FVC<0.70
30%#FEV1<50%predicted
StageIV:VerySevere
FEV1/FVC<0.70
FEV1<30%predictedorFEV1<50%predictedpluschronicrespiratoryfailure
FEV1:forcedexpiratoryvolumeinonesecond;FVC:forcedvitalcapacity;respiratoryfailure:arterialpartialpressureofoxygen
(PaO2)lessthan8.0kPa(60mmHg)withorwithoutarterialpartialpressureofCO2(PaCO2)greaterthan6.7kPa(50mmHg)
whilebreathingairatsealevel.
review of medicines against asthma, copd and coughs
Appendix 3 – price comparison for
inhaled steroids in powder form
Thepowdertableisbasedonthelargestpackages.DosesaresourcedfromFASSandpricesaresourcedfrom
theLFN’spricelist070102.Theindexcolumnshowsthepricedifferencerelativetothecheapestalternative
”Beclometason/Budesonide”
~100
~200
~400
~800
~1600+
Productname
GionaEasyhaler
PulmicortTurbuhaler
GionaEasyhaler
PulmicortTurbuhaler
Becotide
FlutideDiskus
BeclometEasyhaler
Becotide
GionaEasyhaler
PulmicortTurbuhaler
FlutideDiskus
AsmanexTwisthaler
Becotide
GionaEasyhaler
BeclometEasyhaler
PulmicortTurbuhaler
FlutideDiskus
AsmanexTwisthaler
Becotide
BeclometEasyhaler
PulmicortTurbuhaler
FlutideDiskus
AsmanexTwisthaler
Strength
100microg
100microg
200microg
200microg
100microg
50microg
200microg
200microg
400microg
400microg
100microg
200microg
400microg
400microg
200microg
400microg
250microg
400microg
400microg
200microg
400microg
500microg
400microg
Substance
Budesonide
Budesonide
Budesonide
Budesonide
Beclometason
Flutikason
Beclometason
Beclometason
Budesonide
Budesonide
Flutikason
Mometason
Beclometason
Budesonide
Beclometason
Budesonide
Flutikason
Mometason
Beclometason
Beclometason
Budesonide
Flutikason
Mometason
NumberAUPeach
200
1,26
200
1,38
183* 1,98
200
1,99
120
1,26
180
1,40
200
1,56
120
1,58
183* 3,30
200
3,39
180
1,99
60
5,12
120
2,65
200
3,02
200
1,56
200
3,39
180
4,21
60
9,03
120
2,65
200
1,55
200
3,39
180
8,10
60
9,03
*Expirydateforforanopenedpackageis6monthsfromopening
Doses
1
1
1
1
2
2
2
2
1
1
2
1
2
2
4
2
2
1
4
8
4
2
2
Dailycost
1,26
1,38
1,98
1,99
2,53
2,80
3,12
3,16
3,30
3,39
3,99
5,12
5,29
6,03
6,24
6,79
8,40
9,03
10,60
12,40
13,57
16,21
18,05
Index
100
109
100
100
128
141
100
101
106
109
128
164
100
114
118
128
159
171
100
117
128
153
170
the pharmaceutical benefits board
Appendix 4 – price comparisons of long­
acting and short-acting bronchodilators
Long-acting bronchodilators
Product name
Substance
Strength
Number
AUP each
Daily cost
Index
Inhalations
Foradil
formoterol
12
180
3,90
7,79
100
2
OxisTurbuhaler
formoterol
9
180
4,19
8,38
107
2
SereventDiskus
salmeterol
50
180
4,70
9,41
121
2
OxisTurbuhaler
formoterol
4,5
180
3,42
13,69
176
4
Short-acting bronchodilators
Product name
Substance
Strength
Number
Skr/dose
BricanylTurbuhaler
terbutalin
0,25mg/dos
200
0,76
BricanylTurbuhaler
terbutalin
0,5mg/dos
200
0,81
BuventolEasyhaler
salbutamol
0,1mg/dos
200
0,71
Inhalation powder
BuventolEasyhaler
salbutamol
0,2mg/dos
200
0,81
VentolineDiskus
salbutamol
0,2mg/dos
180
1,12
VentolineEvohaler
salbutamol
0,1mg/dos
200
0,31
Airomir
salbutamol
0,1mg/dos
200
0,3
AiromirAutohaler
salbutamol
0,1mg/dos
200
0,61
Inhalation spray
review of medicines against asthma, copd and coughs
Appendix 5 – price comparison of combi­
nation medicines (inhaled steroids + long­
acting bronchodilators)
beta
stimulants
formoterol/
salmeterol
steroid
bude­
sonide/
flutica­
sone
SeretideDiskusmite
50
100
180
1058,50
5,88
11,76
100
SymbicortmiteTurbuhaler
4,5
80
120
557,00
4,64
18,57
158
4
SymbicortmiteTurbuhaler
4,5
80
360
1577,00
4,38
17,52
149
4
SeretideDiskus
50
250
180
1386,00
7,70
15,40
100
2
SymbicortTurbuhaler
4,5
160
360
1800,50
5,00
20,01
130
4
9
320
180
1800,50
10,00
20,01
130
2
SymbicortTurbuhaler
4,5
160
120
631,50
5,26
21,05
137
4
SeretideDiskusforte
50
500
180
1912,50
10,63
21,25
100
2
SeretideEvohalermite
25
50
120
402,00
3,35
13,40
4
SeretideEvohaler
25
125
120
517,00
4,31
17,23
4
SeretideEvohalerforte
25
250
120
701,50
5,85
23,38
4
SymbicortTurbuhalerforte
Number
AUP
AUP
each
Equi­
valent
price
In­
dex
Inhala­
tions
2
4
the pharmaceutical benefits board
Appendix 6 – Health economic literature
asthma and COPD
SUMMARY ASTHMA
A search for articles published at the earliest in 1999 and which had a health
economic perspective on pharmaceutical asthma treatment was carried out in
the autumn and winter of 2004. Articles which had to do with Swedish con­
ditions have been included even if their publication date was prior to 1999.
An updated search was carried out on the 17th of August 2006.
This led to a further 11 articles being added to the previous 38 articles. This
report is based on these 49 articles. For maintenance treatment of asthma for
adults a large number of the articles lent support to the group of inhaled ste­
riods and long-acting b2-agonists giving a good effect in terms of both cost
and medical effect. Leukotrien receptor antagonists seemed to perform worse
than both inhaled steroids and b2-agonists, however the number of articles
examining this group was considerably less than than was the case for inhaled
steroids and b2-agonists. The information available is not extensive enough
to draw a conclusion for the group short-acting b2-agonists.
The number of head to head comparisons with various inhalation aids is also
too small to allow any conclusions to be drawn.
review of medicines against asthma, copd and coughs
ABBREVIATIONS
AK
ICS
LTRA
LABA
SABA
Anticholinergics
Inhaledcorticosteroids
leukotrienreceptorantagonists
Long-actingbetaagonists
Short-actingbetaagonists
BAM
BEC
BUD
BUD/FOR
FOR
FLN
FP
IPB
LSAB
MON
NAK
PIR
RSAB
SAB
SAM
SAM/FP
TEO
TER
TRI
ZAF
ZIL
Bambuterol Beclometasone
Budesonide SymbicortTurbuhaler
Formoterol Flunisolid Fluticasone Ipratropium Levsalbutamol
Montelukastsodium
Disodiumcromoglycate
Pirbuterol Racemisksalbutamol
Salbutamol Salmeterol Seretide
Theofylline
Terbutaline Triamcinolon
Zafirlukast Zileuton
BID
CEA
CMA
CUA
EFD
FEV1
HMO
ICER
KOL
MCO
MDI
PEF(R)
SFD
STW
Twiceperday
Cost-effectivenessanalysis
Cost-minimisationanalysis
Cost-utilityanalysis
EpisodeFreeDays
ForcedExpiratoryVolumein1second
HealthMaintenanceOrganization
Incrementalcosteffectivenessratio
Chronicobstructivelungdisease
ManagedCareOrganization
MeteredDoseInhaler
PeakExpiratoryFlow(Rate)
SymptomFreeDays
SuccessfullyTreatedWeeks
LABA
ICS
ICS
PulmicortTurbuhaler
LABA
ICS
ICS
AK
SABA
LTRA
OxisTurbuhaler(fastaction)
SABA
SABA
LABA
LABA
MaxairAutohaler,Betaagonist
SABA
ICS
LTRA
LTRA
BricanylTurbuhaler
the pharmaceutical benefits board
SUMMARY
1
GENERAL
95
1.1
The search
95
1.2
Quality of the articles
95
1.3
Perspective
96
1.4
Cost-drivers
97
1.5
Quality of life
97
2
HEALTH ECONOMIC TERMS
3
REVIEW OF THE THERAPEUTIC GROUPS
99
100
3.1
Short-acting b2-agonists
100
3.1.1
Salbutamol
100
3.1.2
Terbutaline
100
3.1.3
Summary short-acting b2-agonists
101
3.2
Long-acting b2-agonists
101
3.2.1
Formoterol
101
3.2.2
Salmeterol
104
3.2.3
Saummary long-acting b2-agonists
107
3.3
Inhaled corticosteroids
108
3.3.1
Beclometasone
108
3.3.2
Budesonide
108
3.3.3
Flunisolid
112
3.3.4
Fluticasone
112
3.3.5
Triamcinolon
117
3.3.6
Non-specific inhaled steroids
118
3.3.7
Summary inhaled cortico steroidd
119
3.4
Leukotrien-receptor-antagonists
120
3.4.1
Montelukast sodium
120
3.4.2
Zafirlukast
120
3.4.3
Summary leukotrien receptor antagonists
121
3.5
Cromoglycate
121
3.6
Combination substances
122
3.6.1
Seretide (salmeterol/fluticasone)
122
3.6.2
Symbicort (formoterol/budesonide)
123
3.7
Various inhalation aids
123
3.7.1
Maxair Autohaler
123
3.7.2
CFC free beclometasone
124
3.8
Variable doses compared to fixed doses
125
3.8.1
Symbicort
125
4
REFERENCES
127
review of medicines against asthma, copd and coughs
GENERAL
The search
A literature search was carried out in the Pubmed and Cochrane databases
during the autumn/winter of 2004. On the 17th of August a further search
was performed to find any articles published in the interim. The searches
were performed in order to find articles concerning asthma, coughing and/or
COPD from a health economic perspective .1 Besides the targeted search
words,2,3 all articles published prior to 1999 and which did not treat Swedish
conditions were excluded from the search. No time parameter was used for
analysis of Swedish conditions. In total 49 articles have been summarised in
the table which is the basis for this health economic report.
Quality of the articles
Performing a literature search on health economic aspects of asthma, coug­
hing and COPD is in some ways more rewarding than doing a similar clini­
cal search, as the volume of articles is more manageable. At the same time
as this can simplify the search somewhat it can also mean the act of making
decisions becomes more difficult, as the limited volume of the articles may
not be enough to answer the questions being put to them.
An example of a weakness which is prevalent in practically all articles is the
measure of effect. The LFN normally uses the measure of effect ”quality
adjusted life year”, which measures changes in both sickness and mortality.
In the asthma articles we located it is mainly the measures FEV1 och PEF,
”change in lung capacity”, which is used, or or other measures such as symp­
tom-free days which can be traced from these same measures. The frequency
of the usage of the measure lung capacity in health economic reviews and
problems associated with this is dealt with in the SBU report (Boman G,
2000) which mentions that part of the explanation for this choice of measure
is that it can benefit the product in question. This criticism can of course be
aired towards any measure of effect, and is in itself a good reason to lament
the lack of fixed and generally accepted guidelines as to choices of measures
of effect.
1InPubMedthefollowingquerystringwasusedtoidentifyarticleswhichdealtwithasthma,coughingand/orCOPD:
asthmaORcopdORcough.Thisgave35258hits.
Tofurtheridentifyarticleswithonlyhealtheconomiccontentweused:”CostsandCostAnalysis”[MeSH]OR”Economics,
Pharmaceutical”[MeSH].Whenfocusedbetwee1999and2004thisgave110905hits.
BycombiningthesetwosearchesusingAND,thenusingthetimeparameterabovewegenerated641hits.
2TheCochranesearchwasperformedintheNHSEEDdatabasewiththeterms:”asthmaORcopdORcough”.
Thisledto298hits.
3Thesamesearchstringwasusedtofindarticleswhichhadbeenaddeduptothe17thofAugust,2006.
Thissearchledto282hitsinPubMedand151hitsinCochrane.
the pharmaceutical benefits board
Our ambition has been to cover all relevant published literature, even cases
where quality has been in question have been included. The main reasons
for articles being considered irrelevant/not of interest have been, in order of
frequency, that they have not weighed effects of treatment against costs, that
they have not examined any of the diseases in question, or that they have not
been published in English, Swedish, Norwegian or Danish.
A weakness with the studies was that they have often been for relatively short
periods of time, a typical value being 12 weeks. Many of the articles mention
the difficulty of the short time horizon and point out that it is not possible
then to say if the effect is retained over a longer period of time.
The authors claim that in many cases it is not possible to get an overview of
the long-term consequences of the substances’ short-term effects, but that
a long-term perspective would probably lead to better cost-effectiveness for
those substances which are already in the short-term more cost-effective than
their competitors. Another weakness with the short time-perspective is that
it is difficult to illuminate side-effects which often appear after use over a
longer period of time.
All articles except for two are either completely or partly funded by a com­
pany, or written by at least one person who was employed by a company at
the time of writing. None of the articles sent to the LFN by companies have
been included, unless they were already judged to be relevant in this literature
review.
Perspective
Most studies only contain direct costs. It would be desirable to have more
studies which also covered indirect costs, such as decreases in production.
For asthma treatment, it is likely that a medicine which is equal to another
when direct costs are taken into account but clinically better, would increase
its cost-effectiveness relative to its competitor medicines by including indirect
costs in calculations. The reason for this is that clinical inferiority should
result in increased decreases in production due to, as an example, increased
absence due to sick leave.
The share held by indirect costs of the total costs varies from country to
country and between studies. In the four Swedish studies which include indi­
rect costs, the share is between 11 and 25 percent (Stallberg et al, 2003) and
43-68 percent (Berggren & Ekstrom, 2001). According to the SBU direct
costs in healthcare for asthma in Sweden were approximately 1.1 billion Skr
in 1991, at the same time as the indirect costs amounted to 1.9 billion Skr
(Boman G, 2000). Based on this it is clear that excluding indirect costs unde­
review of medicines against asthma, copd and coughs
restimates the clinical advantages of a better medicine, and furthermore this
is visible in studies where both indirect and direct costs are accounted for.
Cost drivers
Besides indirect costs it is mainly the medicines themselves which are the cost
drivers in the studies. This is an effect of the medicines leading to good treat­
ment results where in many cases the patients become free from symptoms.
To get a patient who earlier had not been treated properly under control,
leads generally to cost savings as hospital visits and loss in production are
expensive effects of asthma. The effect of these cost savings are that the cost
of medicine’s share of total costs increases. Therefore it follows that it is not
only the sometimes high costs of medicines which make pharmaceutical costs
such a large part of the total costs, especially for patients with milder forms of
asthma.
An example which shows that patients with severe asthma stand for a large
part of the costs is mentioned in an article, where 0.8 percent of asthma pa­
tients in an American MCO stood for 20.6 percent of the total asthma-rela­
ted costs (Lyseng-Williamson & Plosker, 2003). In health economic analyses
the medicines studied stand for approximately 60 to 75 percent of the direct
costs. As a result the price of the medicines can be a deciding factor in the
health economic outcomes for the studies.
The dose used can also play a key role. In cases where an increased dose has a
relatively small effect, the higher dose leads to a higher cost which is not fully
realised by a higher comparative effect.
Quality of life
One of the greatest advantages of a measure of effect which measures both
quality of life and mortality is that it gives an opportunity to compare asthma
treatment with other treatments in healthcare. A health economic analysis
which bases itself on a study with quality of life as a measure of effect therefo­
re makes it possible to compare for example asthma and high blood pressure.
For this reason these types of studies are of interest.
The search was not carried out with the express purpose of finding articles
which discussed changes in utility value in asthma treatment without simul­
taneously executing a health economic analysis. Three articles used quality
adjusted life years as a measure of effect.
In the study by Paltiel et al (2001) interviews were carried out with 100
American asthma patients. In a Markov model the authors found that inha­
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led steroids as a complement to as-needed medicines over a 10-year period
led to 84 quality adjusted months. The comparable number without inhaled
steroids was 81.2 months. The incremental direct cost per QALY was 13 500
USD.
Another article which used QALY as a measure of effect was by Price et
al (2002b). The quality of life measures used in the analysis were mainly
sourced from an abstract where 100 patients with mild to moderate asthma
were interviewed (Stahl et al 1999). The authors found that treatment using
Seretide led to an incremental direct cost per QALY of 1 357 British pounds
sterling.
Finally, quality adjusted life years were used in an article by Marchetti et al
(2004). The utility values were sourced from Asthma Symptom Utility Index.
The incremental utility of the best treatment according to the analysis (be­
clometasone extra fine) led, over a period of two months, to approximately
1.5 quality adjusted life days compared to the treatment with worst results
(beclometasone). From a societal perspective beclometasone extra fine was a
dominant alternative for both moderate and severely ill asthma patients.
Besides these articles some have used the Asthma Quality of Life Question­
naire in order to produce utility values. One article used St George’s Respi­
ratory Questionnaire. Although these articles measure utility values from a
treatment they do not give the possibility to compare directly with treatments
of other diseases, as is the case with quality adjusted life years.
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HEALTH ECONOMIC TERMS
The most frequently occurring health economic analysis is cost-effectiveness
analysis (CEA). In short this means that the measure of effect achieved, such
as symptom-free days (SFD) for a substance is divided by the total costs
(Number of SFD/Cost).
In a comparison of two substances, A and B, it is also normal to calculate
an incremental cost-effectiveness ratio (ICER). To do this the incremental
effect of a substance A (EffectA-EffectB) is divided by the difference in costs
(CostA-CostB). The lower the incremental cost-effectiveness ratio is in com­
parison to above, the better A is performing. In cases where substance A is
both better and cheaper than B then it is said that, A dominates B and ICER
normally is not calculated. If it is anyway calculated then it is negative. For
positive ICER it is a normative question if the substance is cost-effective.
It is important to underline that the cost-effectiveness ratios calculated in the
various analyses are in many cases not directly applicable to Swedish con­
ditions. Types of costs, relative prices and treatment traditions differ from
country to country and also vary within time within countries.
A special variety of cost-effectiveness analysis is cost utility analysis (CUA),
where the measure of effect is the value accorded to the patients from a
certain treatment. As quality of life calculations have not been made in very
many of the articles found, CUA is not either a major part of the analysis.
A further variant of CEA is cost minimisation analysis (CMA). This is used
when the substances do not differ in effect. Instead of looking at the effect
the costs only are calculated, and the substance which has the lowest costs is
therefore the most cost-effective.
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REVIEW OF THE THERAPEUTIC GROUPS
Short-acting b2-agonists
Salbutamol
Lindgren et al (2005) compared salbutamol 200 µg with the long-acting
beta agonist formoterol 4,5 µg. Besides other rescue medications patients
could use any other medicine at all. The huge RELIEF study, a multinational
open parallel group study with a total of 18 124 patients with varying degrees
of severity of asthma, formed a basis for the health economic analysis.
The patients were followed for 6 months and health economic data was
applied retrospectively. Formoterol led to fewer exacerbations and more
symptom-free days. All of these differences were significant. The average total
direct cost per day was in Sweden 2.49 euro for formoterol and 2.35 euro for
salbutamol. Salbutamol’s lower costs were mainly as a result of lower phar­
maceutical costs, 0.19 euro compared to 0.54 for formoterol. The difference
in cost was largest for patients with mild asthma. The incremental cost per
prevented exacerbation in Sweden was comparable to 0.62 euro per day
(95% CI: 0.11-1.57).
Terbutalin
Berggren et al (2001) compared the short-acting beta agonist terbutaline 500
µg (Bricanyl Turbuhaler) with the long-acting beta agonist formoterol 4,5 µg
(Oxis Turbuhaler). Both of the medicines are used as needed. A 12-week long
multinational (Sweden, Norway, Greece and the Netherlands) double-blind
RCT with parallel groups formed the foundation for the results. The study
population consisted of 362 patients with moderate to severe asthma which
was reversible on using inhaled steroids. 182 patients were randomised for
formoterol and 180 for terbutaline.
26 patients in the formoterol and 43 in the terbutaline group had at least one
severe asthma attack during the 12-weeks of the study period. For both mor­
ning and evening measurements of PEF formoterol showed the better results
(eleven, compared to eight litres per minute).
Based on baseline data the average number of serious exacerbations was 1.62
times more for the terbutaline group than for the formoterol group (95% CI:
1.02 till 2.58). It has been mentioned that formoterol performed better in
the quality of life index SF-36, but no figures have been presented.
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Formoterol cost 3.50 Skr per inhalation and terbutaline 0.77 Skr. Based on
the FACET study it was assumed that a serious asthma attack lasted on avera­
ge 6.82 days. With an average monthly salary of 17 900 Skr a serious asthma
attack led to indirect costs of approximately 4 000 Skr.
The average total cost per patient day was 40.32 Skr for formoterol and
44.16 Skr for terbutaline. In the formoterol group the indirect costs stood for
almost half of the total costs and in the terbutaline group for approximately
two-thirds. The size of the indirect costs was therefore of great importance
for the cost-effectiveness calculation below. A higher salary or longer attack,
leads to greater advantages for formoterol. If we only look at direct costs then
formoterol led to nine Skr higher daily costs than terbutaline.
The incremental total cost per prevented asthma attack for formoterol ins­
tead of terbutaline treatment, goes from (95% CI) minus 1 890 Skr (cost-sa­
ving) to 716 Skr. The waiting value is under zero, which means that formote­
rol is both cost-saving and dominant here.
Summary short-acting b2-agonist
There is data that indicates that formoterol despite its higher price can be a
cost-effective alternative as a complementary treatment at the second stage in
the treatment ladder.
Long-acting b2-agonists
Formoterol
Andersson et al (2001b) took the clinical results from a one-year long ran­
domised and placebo-controlled FACET study and applied them to Swe­
dish cost conditions, amongst other things. Formoterol 24 µg per day was
examined as a complementary treatment to budesonide 200 µg and 800 µg
respectively per day. The study population consisted of 852 asthma patients
18-70 years old who had used inhaled steroids for at least 3 months.
As a primary measure of effect the frequency of mild and severe asthma at­
tacks was used and the number of symptom-free days and episode-free days
was also reported.
The addition of formoterol 24 µg decreased the number of mild exacer­
bations by approximately 40 percent and the number of severe by 26 per­
cent. The decrease in the number of mild attacks was about as big for both
formoterol groups. The group which got formoterol and budesonide 800 µg
decreased the number of severe attacks by 44 percent to 0.5 per year, while
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the group which got formoterol as a complement to 200 µg budesonide de­
creased the number of attacks by 28 percent to 1.3 per year. The other three
measures of effect were also improved significantly for both of the formoterol
groups.
In the Swedish analysis formoterol was cost-saving compared to placebo for
both budesonide doses, for both direct and indirect costs.
The inclusion of indirect costs led immediately to even more advantageous
results for the formoterol group. At 200 µg budesonide with the addition
of formoterol the total costs in Sweden were 3 258 euro per patient year
compared to 4 441 euro using only budesonide. The indirect costs share of
total costs were 34 percent and 39 percent respectively. At the higher dose of
budesonide the total annual cost was 2 258 euro including formoterol, and
3 002 euro excluding formoterol. The indirect cost’s share was 36 and 27
percent respectively. In Great Britain and Spain this relationship was roughly
the same, however costs in total were higher than in Sweden which was due
to much higher costs per asthma attack.
Campbell et al (2000) examined eformotorol Turbuhaler 12 µg, salmeterol
50 µg via pMDI and salmeterol 50 µg via Diskus, based on an eight week
long prospective open RCT with 454 people. All medicines were used twice
per day. The patients had mild to moderate asthma and according to doc­
tors were in need of long-acting beta stimulants. Eformoterol gave 32.8
symptom-free days, salmeterol pMDI 28.0 and salmeterol Diskus 24.1 (this
difference was significant compared to eformoterol, p<0.02).
Total direct costs after eight weeks were lowest for the eformoterol group (77
British pounds sterling) and highest for the group which used pMDI (82
pounds). Cost per symptom-free day was 4.22 pounds for eformoterol, 5.94
pounds for Diskus and 5.26 pounds for pMDI. Pharmaceutical costs made
up more than 97 percent of the total costs. This high share can probably be
explained by the patients increasing the dose and therefore being relatively
well-treated.
Everden et al (2002) compared formoterol 12 µg twice daily taken via
Turbuhaler with salmeterol 50 µg twice daily via Accuhaler. The patient po­
pulation consisted of 6-17 year old asthma patients who still had symptoms
despite treatment with short-acting b2-agonists and inhaled steroids.
73 were randomised to formoterol and 72 to salmeterol in an open study
over 12 weeks.
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The primary measure of effect was the number of symptom-free days wit­
hout using short-acting b2-agonists. Compared to salmeterol, formoterol
decreased the use of SABA at four, eight and 12 weeks (p=0.04) and night
symptoms over 12 weeks (p=0.05). The average number of symptom-free
days without SABA use was 39 percent in the formoterol group and 30
percent in the salmeterol group (p=0.034).
The average daily direct cost per patient was 1.39 pounds in the salmeterol
group and 1.15 pounds in the formoterol group (p<0.001). Average cost
per symptom-free day was for formoterol 2.97 pounds (95% CI: 0.85-1.97)
and for salmeterol 4.69 pounds (95 % CI: 0.98-2.53). The savings arose as a
result of lower cost of acquisition in the formoterol group and lower use of
aid medicines.
The result from the OPTIMA study, a twelve month long prospective
double-blind multinational RCT with a total of 1 272 patients was applied
to Swedish conditions by Jönsson and colleagues (Jonsson et al, 2004). The
study examined formoterol 4,5 µg twice daily as a complementary treatment
to budesonide 100 µg or 200 µg twice daily for a population with mild
asthma. Total societal costs were lowest for the group which only got 100 µg
budesonide (4 355 Skr) and highest in the group which got 100 µg bude­
sonide with formoterol as a complement (5 893 Skr). The other two groups
had total costs similar to the higher costs.
The share of symptom-free days was highest for the patients who had got
complementary treatment and 200 µg budesonide (75.2 percent) and lowest
for those who had only got 100 µg budesonide (69.0 percent). The differen­
ces between 200 µg budesonide and the two groups with complementarý
treatment was not significant, but the authors did not account for how the
difference compared to 100 µg budesonide was significant.
If the number of serious exacerbations per year is also considered then com­
plementary treatment led to a better clinical outcome than only budesonide.
The difference was significant compared to budesonide as a monotherapy.
The incremental cost per symptom-free day for complementary treatment
was 82.78 Skr for the lower budesonide dose and 20.67 Sk for the 200 µg
dose.
Rutten-van Molken et al (1998) compared formoterol 12 µg twice daily via
Aerolizer with salmeterol 50 µg twice daily via Diskhaler. Pooled results from
a six month long open study using patients from Italy, Spain, France, Swit­
zerland, Great Britian and Sweden lay the foundation for the results.
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In total 482 patients over the age of 18 who had been diagnosed as having
had asthma for at least one year were part of the study. Only costs which
could be related to asthma were included in the study, which included indi­
rect costs.
The average number of episode-free days was 97 in the formoterol group and
95 in the salmeterol group. Neither was there any significant difference when
it came to improved quality of life as measured using St George’s Respiratory
Questionnaire for the number of patients who achieved at least a 4% increase
in quality of life (64 percent in formoterol and 62 percent in the salmeterol
group). Differences were also insignificant when it came to loss of produc­
tion, use of rescue medication and use of healthcare resources.
The average and median costs were lower in the formoterol group, but
differences were not statistically significant. In both groups the median cost
per episode-free day was approximately 9 USD, and the median cost per
patient who reached a clinically significant improvement in quality of life was
approximately 1 300 USD in the formoterol group and 1 370 USD in the
salmeterol group.
No cost effect ratios were calculated, as there was no significant difference in
cost nor in effects.
See also (Lindgren et al, 2005) under the section Salbutamol for a compari­
son between formoterol and salbutamol as a rescue medication.
Salmeterol
Under this section you can also find comparisons between the combination
salmeterol/fluticasone (Seretide) and fluticasone without salmeterol.
See Campbell et al (2000) and Everden et al (2002) under the section
Formoterol for two comparisons of salmeterol and formoterol.
Johansson et al (1999) has compared Seretide 50/100 µg twice daily with
fluticasone 100 µg twice daily with clinical data from a twelve week long
North American double blind placebo-controlled RCT. 87 patients took
part in the seretide group and 85 patients in the fluticasone group. Swedish
cost and treatment conditions were applied retrospectively on the results.
The average number of episode-free days was 35.6 percent in the seretide
group and 28.0 percent in the fluticasone group (p=0.134). The share of
symptom-free days was 44.1 percent and 34.9 percent respectively. This dif­
ference was not significant either (p=0.096), however the difference in the
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share of successful treatment weeks, defined as at least five percent improve­
ment of PEF compared to the baseline, was significant. Seretide had 65.0
percent successful treatment weeks compared to 33.0 percent for fluticasone
(p<0.00001).
The treatment cost per patient and day in the seretide group was 14 Skr
compared to 8 Skr in the fluticasone group. The cost per successful treatment
week was 151 Skr for Seretide and 169 Skr for fluticasone, which resulted in
an incremental cost-effectiveness ratio of 133 Skr (95% CI: 89 to 215). The
cost per symptom-free day was 31 Skr and 25 Skr for each treatment respec­
tively, and the cost per episode-free day was 39 Skr and 34 Skr. ICER was 45
and 47 Skr respectively for these two measures.
Palmqvist et al (1999) compared Seretide 50/250 µg twice daily with fluti­
casone 250 µg twice daily. In a North American placebo-controlled double
blind RCT 160 patients were divided equally between Seretide and fluticaso­
ne. The average share of episode-free days was 43.5 percent and 25.2 percent
(p=0.00004), the average share of symptom-free days was 55.2 percent and
37.1 percent respectively (p=0.0017). The average share of successful treat­
ment weeks, according to the same criteria as (Johansson et al, 1999) above,
was 74.5 percent and 35. 1 percent respectively (p<0.00001). The average
treatment cost per patient and day was 20.9 Skr in the seretide group and
20.2 Skr in the fluticasone group. The average cost per episode-free day was
37.8 Skr in the seretide group and 54.5 in the fluticasone group.
The incremental cost-effectiveness ratio was 3.9 Skr (95% CI: -27.8 to 37.2).
The average cost per episode-free day was 48.1 Skr for Seretide and 80.1 Skr
for fluticasone, with a resultant ICER of 3.9 Skr (95% CI: -25.4 to 35.9).
The cost per successful treatment week was 196.3 and 404.5 Skr respectively
and an ICER of 12.6 Skr (95% CI: -82.2 to 93.1).
Pieters et al (1999) compared Seretide 50/500 µg twice daily to fluticasone
500 µg twice daily. A 28-week long multinational double blind placebo-con­
trolled RCT formed the basis of the result. 167 patients were randomised to
Seretide and 165 to fluticasone. The average share of episode-free days was
29 percent in the seretide group and 24 percent in the fluticasone group.
(p=0.068) and the average share of symptom-free days was 39 percent and
29 percent respectively (p=0.012). The average share of successful treatment
weeks (five percent increase of PEF) was 57.5 percent and 33.6 percent
respectively (p=0.001). The average direct cost per patient and day was 30.0
Skr in the seretide group and 23.4 Skr in the fluticasone group. The average
cost per episode-free day was 98.8 Skr for Seretide and 94.2 for fluticasone.
The waiting value for ICER was 120 Skr. The average cost per symptom-free
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day was 74.7 Skr for Seretide and 77.2 Skr for fluticasone, ICER was 66.8
Skr (95% CI: 17.5 to 318.2). The average cost per successfully treated
patient was 365 and 488 Skr respectively, ICER: 192 Skr (95% CI: 58 till
437).
Price, M. J. et al (2002b) compared Seretide 50/100 µg twice daily to fluti­
casone 100 µg twice daily. The authors used data from a twelve week long
double blind placebo-controlled RCT in order to establish the transition
probabilities to the Markov model. The share of successful treatment weeks
was 66 percent for seretide and 47 percent in the fluticasone group (95% CI:
Seretide gave 10 percent to 26 percent more successful treatment weeks). The
pharmaceutical cost per week was 7.96 pounds for Seretide and 2.38 pounds
for fluticasone. The average total direct cost per week was 15.77 pounds in
the seretide group and 11.83 pounds in the fluticasone group. ICER per suc­
cessful treatment week was 20.83 pounds (95% CI: -10.97 to 17.51). The
article used utility values which had been produced by other authors through
interviews with 100 asthma patients who at the time of the interview were
undergoing inhaled steroid treatment. On a scale of 100 degrees a serious
asthma attack was considered to have a utility value of 26, a mild attack a uti­
lity value of 62 and the patient’s general health status to be 81. The authors
assumed that controlled asthma gave a utility value of 99. Based on these
figures the result was that Seretide, during a twelve week period, gave an in­
cremental utility increase of 0.03 compared to fluticasone. The incremental
cost per QALY was 1 357 pounds. See Rutten-van Molken et al (1998) under
the section Formoterol for a comparison of salmeterol and formoterol.
In Stempel et al (2002) salmeterol and montelukast sodium were examined
as a complementary treatment to inhaled steroids in a retrospective study
of data from an MCO. The patients were 4-65 years old, had used inhaled
steroids without long-acting beta agonists for a twelve-month period and
then had the complementary treatment with either salmeterol (n=703) or
montelukast sodium (n=216), after which they were followed for another
twelve months.
The number of patients who demanded at least one emergency visit sank by
22.3 percent in the salmeterol group and by 6.5 percent in the montelukast
sodium group. The number of patients who demanded hospitalisation sank
by 61.4 percent in the salmeterol group and increased by 9.5 percent in the
montelukast sodium group. The usage of SABA decreased by 42 percent in
the salmeterol group and by 21 percent in the montelukast sodium group
(p<0.0001 for all differences).
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The total cost of healthcare during the year was 3466 USD in the salmeterol
group compared to 4 346 USD in the montelukast sodium group(p<0.001).
Asthma-related healthcare costs were 952 USD and 1 522 USD respectively
(p=0.004). Salmeterol as a complementary treatment was therefore the domi­
nant alternative.
O’Connor et al (2004) compared Seretide (fluticasone 100 µg/salmeterol 50
µg) twice daily to fluticasone 100 µg twice daily with montelukast sodium
10 mg as a complement. 447 patients were randomised to each treatment in
a twelve-week long double blind study. The patients were at least 15 years
old and did not have full control of the disease using only inhaled steroids.
The number of patients who had at least a 12% improvement of FEV1 were
54 percent (95% CI: 26-38) in the seretide group, and 31 percent (95% CI:
26-38) in the fluticasone/montelukast sodium group (p<0.001). Seretide also
led to a higher number of symptom-free days, but the difference was not sig­
nificant (31 percent and 27 percent respectively). The average direct cost per
day was 3.64 USD (95% CI: 3.60-3.68) in the seretide group and 4.64 USD
(95% CI: 4.56-4.73) in the fluticasone/montelukast sodium group. Seretide
was therefore the dominant alternative.
Pieters, W. R. et al (2005) made the same comparison as O’Connor above,
but based on clinical results and with Dutch cost conditions. The clinical
data was collected from a twelve-week long multinational double blind RCT.
This group also consisted of patients who did not have full control of their
asthma using inhaled steroids without a long-acting beta agonist. The sere­
tide group had a significantly higher number of symptom-free weeks (63.3
percent to 39.0 percent in the montelukast sodium group, p<0.001) and
significantly more symptom-free days (48.0 and 42.5 respectively, p=0.003).
As total direct costs were also lower in the seretide group (1 938 USD) com­
pared to the fluticasone/montelukast sodium group (2 246 USD), Seretide
was the dominant alternative.
Summary long-acting b2-agonists
Formoterol performed well in all comparisons. In comparison to the short­
acting beta agonists terbutaline and salbutamol formoterol was a cheaper and
clinically better alternative. Also in two studies the substance was a clinically
more effective alternative compared to not using any complementary treat­
ment to budesonide. In one study it was expensive, and in the other cheaper.
Both of these studies looked at Swedish cost conditions and took a societal
perspective.
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In three different studies formoterol 12 µg twice daily was compared to s
almeterol 50 µg twice daily as a complementary treatment to inhaled steroids.
In two cases formoterol was the dominant alternative, while in the third
study it was clinically better but more expensive than salmeterol.
The combination substance Seretide (salmeterol/fluticasone) was compared
in three analyses with only fluticasone. In all analyses Seretide gave a clinical­
ly better effect at a higher cost compared to fluticasone. These analyses were
based on Swedish conditions. The result was the same in another analysis
carried out on British conditions.
Seretide 50/100 µg was compared in two studies to montelukast sodium 10
mg as a complement to fluticasone 100 µg. Seretide was the dominant alter­
native in both analyses.
Finally a study which compared bambuterol and salmeterol found that bam­
buterol was cheaper and not significantly worse from a statistical standpoint.
The health economic analysis however lacked in a few areas.
Based on these articles there is clear evidence that the group of long-acting
b2-agonists are cost-effective for maintenance treatment of adult asthma
patients with moderate and serious asthma.
It is not possible to ascertain with the same degree of certainty if the same
holds true for children or sufferers of mild asthma. According to the SBU
there appears to be strong evidence in scientific studies that long-acting beta
agonists have a beneficial effect on adult asthma patients for maintenance
treatment (Boman G, 2000, SBU report, page 25).
Inhaled corticosteroids
Beklometason
Marchetti et al (2004) have examined beclometasone extra fine (EF) 400 µg
per day (800 µg for severe asthma) compared to beclometasone 1 000 µg
per day (1 500 µg), fluticasone 400 µg per day (1 000 µg) and budesonide
800 µg per day (1 600 µg). The data used for the Markov model was sour­
ced from six different clinical studies. Beclometasone EF led to most quality
adjusted days, measured using the Asthma Symptom Utility Index, both for
moderate and severely ill asthma patients. Compared to other substances the
incremental effect was between 1.24-2.33 and 0.55-1.54 quality adjusted
days for each stage of sickness over a two-month period. The ranking of the
review of medicines against asthma, copd and coughs
substances in falling order based on their effect was beclometasone EF, bude­
sonide, fluticasone and beclometasone. Total societal costs were lowest in the
beclometasone EF group for both moderate and severely ill asthma patients,
and the substance was therefore the dominant alternative. Cost savings were
from 28 euro (compared to budesonide) to 47 euro (fluticasone) for pa­
tients with moderate to severe asthma and from 4 to 67 euro for the severely
ill asthma patients.
Budesonid
Andersson et al (2001a) has compared budesonide to disodium cromoglycate
for maintenance treatment of asthma for Swedish children in the ages of five
to eleven years old in a 1-year long randomised open RCT. The 138 children
included in the study had unstable asthma and had earlier not been treated
using steroids or cromoglycates, but had been treated using a beta agonist
at least three times a week. 69 patients were randomised to budesonide 200
µg twice daily and the other 69 to disodium cromoglycate 20 mg three times
daily. The average daily usage in the study was 465 µg for budesonide and
45.8 mg for disodium cromoglycate.
In the study the objective was to acheive control of the asthma using all
means available, including changing therapy. Three of the children in the
budesonide group stopped their treatment with budesonide compared to 32
children in the cromoglycate group (of which 29 completed the treatment
with budesonide). There was no significant difference between the groups in
the number of symptom-free days (76 percent in the budesonide group and
75 percent in the cromoglycate group), however of those who changed from
cromoglycates to budesonide the number of symptom-free days increased by
14 percent after the change (p<0.01). The number of children whose asthma
was controlled during the last month was higher in the budesonide group
for six out of seven variables.
Both direct and indirect costs were included in the study. The daily dose
of budesonide cost 4 Skr and the cromoglycate dose 8.73 Skr. The authors
assumed that budesonide was not worse than cromoglycates and carried out
a cost-minimisation analysis. The total average costs were 17 436 Skr in the
cromoglycate group and 13 240 Skr in the budesonide group, a non-signifi­
cant difference of 4 195 Skr (95% CI: -2 340 to 10 731). The lower cost of
acquisition for budesonide and the lower indirect costs were the main reasons
for the cost savings.
In a meta-analysis of seven studies (published between 1994-1997) Barnes et
al (1999) compared budesonide 400 to 1600 µg per day with fluticasone 200
to 800 µg per day for treatment of children and adults with mild to severe
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asthma. There were 1 980 patients in the studies and they were from four to
twelve weeks long.
A significantly higher number of patients who received fluticasone reached at
least fifteen percent improvement in PEFR (49 percent compared to 41 per­
cent of the budesonide group, p<0.001). The number of successful treatment
weeks was also higher in the fluticasone group: 47.1 percent compared to
34.1 percent (p<0.001). The number of symptom-free days was also higher
for fluticasone patients (41.7 percent compared to 38.7 percent, p=0.036).
The number of episode-free days was 31.0 percent for the fluticasone group
and 26.7 percent for the budesonide group (p<0.003).
The average daily direct cost per patient in the fluticasone group was 7.78
GBP and in the budesonide group 12.33 GBP, a difference which mainly
arose due to higher costs for hospital visits in the budesonide group, but flu­
ticasone was cheaper for all types of measured costs. The authors had no data
on primary and emergency healthcare use, and instead estimated these based
on existing data.
As fluticasone was both cheaper and clinically better it was the dominant
alternative.
Utilising data from the same meta-analysis as above, Stempel et al (2000)
compared the substances from an American perspective. For natural reasons
the clinical results were similar to those obtained in the Barnes study, but had
a marginal difference. The number of symptom-free days was 44 percent in
the fluticasone group and 40 percent in the budesonide group. The number
of episode-free days was 32 percent and 27 percent respectively (p<0.001 for
both differences). Analysis of the sub-groups showed that fluticasone was bet­
ter than budesonide regardless of patient age and earlier medication.
The average total cost per day was 2.25 USD for the fluticasone group and
3.00 USD for the budesonide group. Just like in Barnes et al (1999) flutica­
sone was the dominant alternative.
Buxton et al (2004) examined budesonide treatment (200 µg per day for
patients below the age of 11 and 400 µg for others) for patients between 5
and 66 years old with mild asthma who had not earlier used inhaled steroids
as treatment. Data was collected from the START study, a three-year multi­
national double-blind RCT of 7 241 patients. The primary measure of effect
was the number of symptom-free days. The addition of budesonide resulted
in 14.1 extra symptom-free days (<0.001), led to 69 percent fewer days in
review of medicines against asthma, copd and coughs
hospital care, 67 percent fewer emergency healthcare visits, 36 percent fewer
doctor visits and 37 percent fewer lost days at school or work (all differences
p<0.005 or less). Health economics was estimated for a number of countries,
including Sweden. Total costs were not accounted for, but incremental costs
were. From a societal perspective the cost per symptom-free day was negative
(-33.5 Skr; 95% CI: -59.7 till -7.1). When only the direct costs are taken
into consideration ICER was 23.9 Skr (11.6-38.9).
The same data has been applied to the USA (Sullivan et al, 2003), with the
result being that the total costs to society increased by on average 0.14 USD
per day when adding budesonide to treatment, and the incremental cost­
effectiveness ratio was 11.30 USD (95% CI: 8.60 14.90).
From the same meta-analysis Weiss et al (2006) have carried out a sub-group
analysis of children between the ages of 5 and 10. Clinical results for the
children were somewhat worse than for the entire population, but in general
significantly better than treatment without inhaled steroids and were also
cost-saving from a societal perspective.
See Marchetti et al (2004) under the section Beclometasone for a comparison
of budesonide, fluticasone, beclometasone and beclometasone extra fine.
Miyamoto et al (1999) compared budesonide 200, 400 or 800 µg per day
to placebo in a Japanese six week long RCT. The population comprised 218
patients in total suffering from mild to severe asthma and they were roughly
evenly distributed to the four therapeutic groups. 20 patients did not com­
plete the study, for these a linear extrapolation was performed on existing
data. In cases where data was missing zero cost was assumed and freedom
from symptoms. Not even in a sensitivity analysis was this assumption aban­
doned.
Compared to placebo all budesonide doses were significantly better when it
came to the number of symptom-free days (budesonide between 46 percent
and 55 percent, compared to 32 percent for placebo) and the number of epi­
sode-free days (budesonide 44 percent to 53 percent, compared to 29 percent
for placebo).
The average total societal costs per day were 2 518 yen for placebo, 750 yen
for 200 µg budesonide, 635 yen for 400 µg budesonide and 1 226 yen for
800 µg budesonide. All budesonide doses displayed significant cost savings
compared to placebo. Costs for emergency visits, hospitalisation and losses
in productivity were much higher in the placebo group. The cost for bude­
4
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sonide is not included in the costs, as the medicine was not priced in Japan
at the time of the study. At Apoteket 800 µg budesonide inhalation powder
from Astra Zeneca costs almost seven Skr per day when purchasing 200
doses at 400 µg, equal to approximately 100 yen. The addition of the cost
of budesonide should therefore hardly change the dominance of budesonide
over placebo. The health economic analysis here suffers from other methodo­
logical weaknesses meaning that the result should be interpreted with some
degree of caution, even if the addition of the budesonide cost by itself would
not change the result.
See Rosenhall et al (2003) under the section Combination substances for
a comparison of Symbicort (budesonide and formoterol-combination) to
budesonide and formoterol in separate inhalers.
Flunisolid
In a German study based on two parallel RCTs Volmer et al (1999) compa­
red flunisolid 500 µg twice daily to fluticasone 250 µg twice daily. One study
was open and six weeks long (n=332), and the other was a double-blind eight
week long study (n=308). The patients were between 18 and 70 years old and
suffered from mild asthma.
There was no significant difference in either of the studies in regard to the
number of patients who reached at least a ten-percent increase in PEFR.
In the open study this improvement was acheived by 56.8 percent of the
fluticasone patients and 39.6 percent of the flunisolid patients. Comparable
figures from the blind study were 55.3 percent and 44.5 percent respectively.
There was not either any significant difference in the percentual increase in
the number of symptom-free days. In the open study the fluticasone group
increased the number of symptom-free days by 30.2 percent compared to
21.1 percent in the flunisolid group. In the blind study the numbers were
25.7 percent and 20.0 percent respectively. At the end of the open study the
number of symptom-free days were 36.4 percent in the fluticasone group and
28.5 percent in the flunisolid group. Comparable figures for the blind study
were 35.1 percent and 31.1 percent respectively. Therefore, fluticasone was
on the whole better, however not significantly so. All differences were greater
in the open studies, both in absolute and relative terms, compared to the
double-blind studies.
The average total direct costs per day were 3.72 German marks in the open
studies and 2.97 German marks in the blind studies. For flunisolid compara­
ble costs were 3.36 German marks and 2.75 German marks.
review of medicines against asthma, copd and coughs
The average daily cost per successfully treated patient was 6.51 German
marks for fluticasone and 8.43 German marks for flunisolid in the open
study, and 5.37 German marks and 6.16 German marks respectively in the
blind study. The daily cost per further symptom-free day compared to the
baseline was 12.35 German marks in the open study for fluticasone and
15.94 German marks for flunisolid. In the blind study the costs were 11.65
German marks and 13.78 German marks respectively. The daily cost per
symptom-free day was 10.24 German marks in the open study for fluticasone
and 11.80 German marks for flunisolid. In the blind study the costs were
8.53 German marks and 8.86 German marks respectively. No incremental
cost-effectiveness ratios have been estimated.
Fluticasone
Armstrong & Malone (2002) examined in a retrospective study of data over
three years how costs in an MCO changed on usage of fluticasone compared
to the leukotrien-receptor-antagonists montelukast sodium, zafirlukast and
zileuton. 57 patients received fluticasone and 290 patients received one of the
three LTRA substances.
Patients in the LTRA group used SABA more than the fluticasone patients
(10.07 and 4.63 prescription; p<0.0001). At the start of the study the average
value for pharmaceutical costs in the LTRA group was 322 USD and for the
fluticasone group 230 USD (p=0.036). At the end of the study total average
asthma-related costs were 1 092 USD in the LTRA group and 511 USD in
the fluticasone group (p=0.0001). In both groups approximately 20 percent
of the patients had been diagnosed as having COPD.
See Barnes et al (1999) under the section Budesonide for a comparison of
fluticasone and budesonide.
Bisgaard et al (2001) compared fluticasone 50 µg or 100 µg through Baby­
haler twice daily to placebo. The patients were between 12 and 47 month­
old infants. The randomised double-blind international studies were twelve
weeks long. 237 patients got active treatment and 77 got placebo.
Compared to placebo the dose of 100 µg resulted in significant improve­
ments in eight of the ten parameters examined (p<0.05). The lower dose
was significantly better in five of the ten parameters. There was no signifi­
cant difference between the two doses. The trend for all parameters was that
both doses were better than placebo, except for the measure symptom-free
days where the lower dose was a few tenths of a percentage point worse than
placebo. The placebo group had a considerably higher use of healthcare than
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both of the fluticasone groups (30 visits compared to 21 in the lower dose
and 15 in the higher). This greater use of healthcare also impacted costs. To­
tal direct costs per patient day were 13.85 Dkr at the lower does, 14.39 Dkr
at the higher, and 20.81 Dkr for placebo. Fluticasone was cost-saving and
better from a clinical perspective, therefore the incremental cost-effectiveness
ratios were negative compared to placebo, with the exclusion for the cost per
SFD for the lower dose. In this latter case the incremental cost per symptom­
free day was 1 505 Dkr compared to placebo.
Bukstein et al (2001) examined in a retrospective study of compensation
demands for a two-year period in an HMO how asthma-related costs dif­
fered between montelukast sodium and fluticasone patients. 229 fluticasone
and 114 montelukast sodium patients with mild asthma were examined one
year after starting their respective therapies. Four percent of the fluticasone
patients changed within a year to an LTRA substance, none of the montelu­
kast sodium users changed substance. In the montelukast sodium group the
patients got on average 0.19 more prescriptions of SABA compared to pre-in­
dex. The comparable increase in the fluticasone group was 0.66 (p=0.03). On
average total asthma-related costs in the fluticasone group increased by 342
USD compared to 268 USD in the montelukast sodium group (p=0.39).
The montelukast sodium group had a considerably higher rate of adherence
to medication compared to the fluticasone group (41 percent, and 15 percent
respectively throughout the year).
See Marchetti et al (2004) under the section Beclometasone for a comparison
of beclometasone, beclometasone extra fine, budesonide and fluticasone.
Menendez et al (2001) compared fluticasone 88 µg twice daily to zafirlukast
20 mg twice daily. 231 patients, at least twelve years old, who had only
been treated with short-acting beta agonists were randomised to fluticasone
and 220 to zafirlukast treatment in a double-blind and placebo-controlled
RCT. Eight fluticasone and fourteen zafirlukast users experienced at least one
exacerbation and were therefore excluded from the study. A further 23 and
36 patients respectively discontinued the study, mainly due to side-effects
and the need for oral steroids. 53 percent of the fluticasone patients and 37
percent of the zafirlukast patients achieved an at least twelve precent increase
in FEV1 (p=0.001). The average number of symptom-free days was 33.4
percent for the fluticasone group and 19.3 percent for the zafirlukast group
(p<0.001). The fluticasone group also had a lower daily usage of SABA with
2.17 inhalations, compared to 3.33 in the zafirlukast group (p<0.001). The
average treatment cost per day was lower in the fluticasone group: 1.84
USD, compared to 2.89 USD in the zafirlukast group. Approximately 70-80
review of medicines against asthma, copd and coughs
percent of this cost originated from the pharamceuticals. Fluticasone was
both cheaper and more effective than zafirlukast.
Orsini et al (2004) compared fluticasone 44 µg twice daily to montelukast
sodium 5 or 10 mg per day. The authors carried out a retrospective investiga­
tion of data from an insurance database and found 400 fluticasone and 777
montelukast sodium patients over four years old who had been followed for
the twelve months before and after the prescription of each medicine. The
patients who used fluticasone had a 62 percent lower risk of having an asth­
ma-related hospital visit (p=0.13). The probability of them changing asthma
treatment or needing further treatment was 44 percent (p<0.001). Cost data
existed for only 261 and 538 patients respectively. Total costs for asthma
medicines were 245 USD (95% CI: 243-247) in the fluticasone group and
501 USD (500-503) in the montelukast sodium group. Total asthma-related
healthcare costs were 430 USD (426-434) and 769 USD respectively (766­
772), and the total healthcare costs (not only asthma-related) were 2 908
USD (2 883-2 933) and 4 105 USD respectively (4 071-4 139). All compa­
rable differences were significant (p=0.01).
Pathak et al (2002) compared fluticasone 44 or 110 µg, montelukast sodium
5 or 10 mg and zafirlukast 20 mg. In this retrospective investigation data was
collected from four MCOs. 284 fluticasone patients, 302 montelukast so­
dium patients and 195 zafirlukast users were followed for nine months. The
number of patients who had an asthma-related emergency visit decreased in
the fluticasone group (från 3.5 percent to 3.2 percent), but increased in both
the montelukast sodium group (from 2.3 percent to 3.0 percent) and the
zafirlukast group (from 4.6 percent to 7.2 percent). The number of patients
who had asthma-related hospitalisations also decreased in the fluticasone
group (3.2 percent to 1.8 percent) but increased in both the montelukast
sodium group (from 1.7 percent to 3.0 percent) and in the zafirlukast group
(6.2 percent to 6.7 percent). In absolute numbers however this refers to very
few observations, between 5 and 14 patients. The average cost of treatment
for the nine-month period increased for all three groups. In the fluticasone
group the original unadjusted cost was 445 USD (median cost 90 USD),
and this increased to 576 USD (95% CI: 413-738; median cost 528 USD),
an increase of 29 percent (487 percent). In the montelukast sodium group
costs increased from 355 USD (120 USD) to 902 USD (95% CI: 689-1
116; median cost 967 USD), an increase of 154 percent (706 percent). In the
zafirlukast group costs increased from 838 USD (118 USD) to 1 417 USD
(95% CI: 775-2 060; median cost 1 359 USD), an increase of 69 percent
(1052 percent). Both adjusted and unadjusted postindex costs were signifi­
cantly lower in the fluticasone group (p<0.0001).
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Stanford et al (2000) compared fluticasone 250 µg twice daily to triamcino­
lon 200 µg four times daily. Cost data was applied afterwards to clinical data
from two 24-week long double-blind placebo-controlled RCTs.
53 percent of fluticasone patients and 32 percent of triamcinolon patients
achieved an at least twelve percent improvement of FEV1 (p<0.001). The
average increase in the number of symptom-free days compared to pre-index
was 18.0 percent in the fluticasone group and 9.6 percent in the triamci­
nolon group (p<0.02). A significantly higher number of triamcinolon users
discontinued the study, 93 of 202 (46 percent), compared to 62 of 195 (32
percent) fluticasone users (p<0.05). The cost of acquisition for fluticasone
was higher than for triamcinolon (2.18 USD compared to 1.85 USD). The
average daily cost was also higher for the fluticasone group (2.52 USD and
2.38 USD respectively). The cost per symptom-free day was 14.01 USD in
the fluticasone group and 24.88 USD in the triamcinolon group. The incre­
mental cost-effectiveness ratio was 1.70 USD per symptom-free day. The cost
per patient who acheived an at least twelve percent improvement of FEV1
was 4.76 USD for the fluticasone group and 7.43 USD for the triamcinolon
group, and ICER was 0.68 USD per day.
Stempel et al (2001a) compared fluticasone 44 µg to montelukast sodium 5
or 10 mg in a population consisting of 4-64 year old asthma patients. In the
fluticasone group there were 318 patients and in the montelukast sodium
group there were 575 patients. The authors carried out a retrospective study
of data from an HMO and followed the patients for nine months. 17.3 per­
cent of the fluticasone users got complementary treatment with a leukotrien
inhibitor or inhaled steroid. For the montelukast sodium patients this figure
was 38.1 percent (p<0.001). Direct costs for asthma care during the nine­
month period were 1 025 USD for the montelukast sodium group and 694
USD for the fluticasone group (p<0.001). Controlled for differences in the
baseline between the two groups a regression showed that fluticasone resul­
ted in a 46 percent decrease in costs compared to montelukast sodium.
Stempel et al (2001b) compared fluticasone 44 µg to non-specified doses of
beclometasone, triamcinolon, budesonide and flunisolid. In a retrospective
analysis of insurance data one year after and six months before indexing, 131
users of fluticasone, 598 of beclometasone, 91 of budesonide, 967 of triamci­
nolon and 169 users of flunisolid were studied. The population consisted of
12-64 year old asthma patients.
All pharmaceuticals had significantly higher asthma-related healthcare costs
compared to fluticasone (p<0.03). Beclometasone had 24 percent higher,
triamcinolon 45 percent higher, flunisolid 45 percent higher and budesonide
review of medicines against asthma, copd and coughs
34 percent higher. Furthermore, budesonide, triamcinolon and flunisolid
patients had significantly higher total healthcare costs: 53 percent, 43 percent
and 39 percent respectively (p 0.005). The annual savings for asthma-related
healthcare would be between 199 and 433 USD if all patients instead had
been treated with fluticasone. Total healthcare costs would decrease by bet­
ween 1 188 USD and 2 245 USD.
See Stempel et al (2000) under the section Budesonide for a comparison of
fluticasone and budesonide.
In a retrospective review of insurance data Stempel (2000) compared flutica­
sone doses of 44 µg and 100 µg to triamcinolon. The authors also compared
fluticasone doses of 44 µg, 100 µg and 200 µg to zafirlukast. In the compari­
son to zafirlukast 1 101 fluticasone patients were involved and 392 zafirlukast
patients. In the comparison to triamcinolon 857 fluticasone patients and 4
142 triamcinolon patients were involved. The use of fluticasone led to a 62
percent decrease in the number of emergency care visits compared to a 32
percent decrease for the zafirlukast group. The number of hospitalisations
decreased by 70 percent and 20 percent respectively. According to the aut­
hors the first difference was significant, as was most probably the second one.
What is clear is that the change in both asthma-related and healthcare-rela­
ted costs was significant. Fluticasone brought about a decrease in monthly
asthma-related costs of 13 USD (-22 percent) and zafirlukast increased the
costs by 13 USD (+21 percent), (p<0.001). Total healthcare costs decreased
by 21 USD (-6 percent) for fluticasone patients and increased by 74 USD
(+24 percent) for zafirlukast patients (p<0.02).
In comparison to triamcinolon, using fluticasone led to a 59 percent decrease
in the number of healthcare visits compared to a 38 percent decrease for the
triamcinolon group. The number of hospitalisations decreased by 64 percent
and 29 percent respectively (p<0.01). For fluticasone use asthma-related
healthcare costs decreased by 126 USD (-64 percent) per year, compared to a
decrease of 47 USD (-29 percent) per year for triamcinolon treatment. Total
healthcare costs decreased by 324 USD (-9 percent) and increased by 375
dollar (+13 percent) respectively.
Fluticasone was therefore not only more effective, but also cheaper than both
zafirlukast and triamcinolon.
See Volmer et al (1999) under the section Flunisolid for a comparison bet­
ween fluticasone and flunisolid.
0
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Wenzel et al (2001) compared treatments with fluticasone at high doses (880
µg twice daily) combined with treatment at a national asthma centre, and
without treatment at a national asthma centre. Using a 1-year long prospec­
tive open study, use of resources within healthcare was compared both before
and after entry to the asthma centre. The study population consisted of 18
patients, at least twelve years old with severe chronic asthma. FEV1 increased
by 15.2 percent (from 54.6 percent to 62.9 percent). Use of steroids de­
creased from 31.5 to 19.5 grammes, a decrease of 38 percent. Furthermore,
the number of school/work days with symptoms, the number of days absent
from school/the workplace, the number of asthma-related healthcare visits
and the number of days in hospital care decreased (p<0.05 for all). Average
direct costs decreased by 25 percent, from 1 466 USD per patient month to
1 101 USD. The inclusion of indirect costs led to an even greater cost saving,
from 1 891 USD to 1 112 USD (-41 percent).
Triamcinolon
See Stanford et al (2000) under the section Fluticasone for a comparison of
fluticasone and triamcinolon.
See Stempel (2000) under the section Fluticasone for a comparison of flutica­
sone to triamcinolon and zafirlukast.
Non-specified inhaled steroids
Gerdtham et al (1996) carried out a retrospective examination of the re­
lationship between sales of inhaled steroids in Sweden and the number of
emergency care days at hospitals as a result of asthma between 1978 and
1991. Regional data was used in the study which covered approximately 70%
of Sweden’s population. Between 1978 and 1985 the number of emergency
care days as a result of asthma was around 17 to 18 days per thousand people.
From 1985 the trend was clearly declining. In 1991 the number of days in
care was nine, which was approximately half as many as in 1985. Sales of ICS
increased exponentially from 1978 onwards. In 1985 sales were three DDD
per thousand people and in 1991 sales had quadrupled. The authors found a
significantly negative correlation in all models between sales of ICS and the
number of days in care (p<0.001). The co-efficient in the main model was
-1.49. An increase in sales of one DDD per thousand people led thereby to a
decrease of 1.49 days in care per thousand people. The average daily cost for
a day in hospital in 1991 was 2 640 Skr. The average annual cost for DDD
inhaled steroids in 1991 was 2 620 Skr. Taken together this meant that for
each krona invested in an ICS treatment, the result was a decrease in healt­
hcare costs of 1.49 Skr (95% CI: 1.07 to 1.92). It is not possible to draw the
conclusion from the article that there is a causal relationship between increased
review of medicines against asthma, copd and coughs
ICS sales and the decrease in healthcare use, for example increased information
to patients and better inhalation devices can have decreased morbidity.
Paltiel et al (2001) examined what effect the addition of inhaled corticos­
teroids had compared to treatment using only fast-acting bronchodilators.
The authors had collated transition probabilities from 76 articles published
between 1966 and 1999 for the Markox model. In the model patients who
were only treated using bronchodilators were assigned 81.2 quality-adjusted
months of life (QALM) in a simulation over 10 years. With the addition of
ICS QALM increased to 84.0 (+3.4 percent). At the same time the number
of days with symptoms decreased from 36.7 percent to 21.7 percent. Dis­
counted direct costs for patients increased from 5 200 USD to 8 400 USD
for the patients who received ICS treatment. The incremental cost per QALY
was 13 500 USD and per symptom-free day was 7.50 USD. These costs were
a bit lower if ICS was only administered to patients with moderate asthma
instead of being also given to mild asthma patients.
Summary inhaled corticosteroids
The two inhaled steroids which there are most analyses of are budesonide
and fluticasone. For other inhaled steroids the information available is too
scarce to draw any conclusions.
Two studies comparing budesonide to placebo both arrived at the same
conclusion that budesonide was the dominant alternative. A Swedish study
on indirect costs which compared budesonide to disodium cromoglycate also
found that budesonide was the dominant alternative.
Two studies using data from the same meta-analysis found that fluticasone
200-800 µg per day was the dominant alternative to budesonide. Finally, af­
ter beclometasone extra fine, budesonide was the best alternative for patients
with moderately severe asthma, both in terms of costs and effect in a study
which also compared beclometasone and fluticasone. The result for severely­
ill asthma patients was somewhat worse in the same study, but still better
than for normal beclometasone.
Seven of the fifteen articles which examined fluticasone are retrospective cost
studies, which have lower value when it comes to evidence than randomised
perspective clinical studies. The effect data used in these types of analyses
are mainly to do with decreased care or pharmaceutical usage. In all seven
comparisons fluticasone was connected to lower costs and at least as good an
effect as the alternatives which in all cases except for one (inhaled steroids)
were leukotrien-receptor-antagonists. It is important to note that not all dif­
ferences were significant.
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The other eight comparisons were based on clinical studies. In the two cases
where comparison was not to do with active treatment fluticasone was the
dominant alternative. The result was the same for the comparison for mon­
telukast sodium. In comparisons to flunisolid and triamcinolon, fluticasone
was a clinically better alternative, but at a higher cost. Two comparisons were
made to budesonide only, and also here fluticasone was dominant. In the
comparison with beclometasone, beclometasone extra fine and budesonide,
fluticasone was in terms of both cost and effect the third best alternative for
moderately severe asthma patients. For severely ill asthma patients it was the
best alternative after beclometasone extra fine.
Compared to other pharmaceutical groups, inhaled steroids as maintenance
treatment seems satisfactory in terms of both cost and effect. This is suppor­
ted by the SBU who found strong evidence indicating that inhaled steroids
had a positive effect on both symptoms and quality of life for maintenance
treatment of both children and adults, with however only weak support for
improved survival. For emergency use this limitation did not apply, neither
for adults nor children (Boman G, 2000).
Leukotrien-receptor-antagonists
Montelukast sodium
Borker et al (2005) compared Seretide (fluticasone 100 µg/salmeterol 50 µg) twice daily to montelukast sodium 10 mg taken once per day. 426 patients who needed additional treatment with short-acting beta agonists were divi­
ded equally into two groups in a twelve-week long double-blind randomised study. Seretide led to significantly higher number symptom-free days (44 percent vs 26 percent) and a higher number of successfully treated patients (73 percent vs 46 percent). Incremental direct cost was 0.49 USD (95% CI: -0.19 to 0.87), which led to an ICER per symptom-free day of 2.87 USD (95% CI: -1.08 to 6.65) and an ICER per successfully treated patient of 1.79 USD (95% CI: -0.72 to 3.86).
See Bukstein et al (2001) under the section Fluticasone for a comparison of fluticasone and montelukast sodium. Under the same section the same comparison has also been carried out by Orsini et al (2004) and Stempel et al (2001a).
See Pathak et al (2002) under the section Fluticasone for a comparison of fluticasone with montelukast sodium and zafirlukast.
See Sheth et al (2002) under the section combination substances for a com­
parison of montelukast sodium and salmeterol/fluticasone.
review of medicines against asthma, copd and coughs
See Stempel et al (2002) under the section Fluticasone for a comparison
of fluticasone and montelukast sodium as an add-on treatment for inhaled
corticosteroids.
Zafirlukast
In a retrospective study of insurance data Klingman et al (2001) compared
treatment before and after using zafirlukast. 599 patients were examined
six months before and six months after the start of treatment. 203 of these
were followed for twice that amount of time. The number of patients with
one emergency care visit decreased from 7.2 percent to 4.8 percent in the
six month group and from 10.3 percent to 9.9 percent in the twelve-month
group. The number of patients who had been prescribed short-acting b2-ago­
nists decreased from 81.1 percent to 71.8 percent, and from 91.1 percent to
773 percent respectively. The number of patients who had been hospitalised
decreased from 11.9 percent to 7.8 percent in the six-month group, and from
17.7 percent to 14.3 percent in the twelve-month group. All changes were
significant in the six-month group (p<0.05), but in the twelve-month group
only the change in the prescription of SABA was significant.The average
cost for zafirlukast was 251 USD in the six-month group. Total direct costs
decreased by 101 USD. In the twelve-month group the cost for zafirlukast
was 386 USD. Total costs decreased by 11 USD.
See Menendez et al (2001) under the section Fluticasone for a comparison of
fluticasone and zafirlukast.
See Pathak et al (2002) under the section Fluticasone for a comparison of
fluticasone to montelukast sodium and zafirlukast.
See Stempel (2000) under the section Fluticasone for a comparison of flutica­
sone to triamcinolon and zafirlukast.
Summary leukotrien-receptor-antagonists
Four of the seven articles which analysed montelukast sodium were retro­
spective insurance database studies where montelukast sodium was compared
to fluticasone and in one case also to zafirlukast. In all cases fluticasone was
associated with lower costs and in at least three of the cases it was better,
measured against the chosen measures of effect. In the database study which
compared salmeterol and montelukast sodium as a complement to inhaled
steroids, salmeterol was the dominant alternative. In the two articles based
on clinical data Seretide was a clinically better alternative, but at a somewhat
higher cost.
4
the pharmaceutical benefits board
In the two database studies whcih compared fluticasone to zafirlukast, flutica­
sone was the dominant alternative. In one of these,montelukast sodium was
also used as a comparator and it performed roughly the same as zafirlukast.
A third database study found that using zafirlukast led to a decrease in costs.
Finally, fluticasone was a clinically better, but more expensive alternative in
an analysis based on a clinical study.
The SBU found strong evidence in its review of medical literature that leu­
kotrien-receptor-antagonists had a positive effect for maintenance treatment
of both adults and children (Boman G, 2000).
Cromoglycate
See Andersson et al (2001a) under the section Budesonide for a comparison
of disodium cromoglycate and budesonide.
Combination substances
Seretide (salmeterol/fluticasone)
See Borker et al (2005) under the section Montelukast sodium for a compari­
son of Seretide and montelukast sodium.
Lundback et al (2000) compared Seretide 50/250 µg twice daily with
budesonide 800 µg twice daily. In a 24-week long prospective double-blind
parallel group study, 180 patients were randomised to the seretide group and
173 to the budesonide group. The patients had symptoms despite treatment
with inhaled steroids. The number of episode-free days was 38 percent in the
seretide group compared to 25 percent in the budesonide group. The number
of symptom-free days was 47 percent and 35 percent respectively. 67 percent
of the seretide patients and 43 percent of the budesonide patients achieved an
at least five-percent improvement of PEF measured in the morning compared
to baseline. All differences were significant (p<0.001). Direct asthma-related
costs were similar, with 19.6 Skr per patient day for Seretide and 18.5 for
budesonide. The cost per episode-free day was 51 Skr for Seretide and 75.1
for budesonide. ICER was 31.6 Skr (95% CI: -38 till 114). The cost per
symptom-free day was 42 and 53 Skr respectively, and ICER 9.2 Skr (95%
CI: -12 till 48).
In Sheth et al (2002) Seretide 50/100 µg is compared to montelukast sodium
10 mg. 423 patients who had long-term asthma and symptoms when treated
with beta agonists were randomised evenly to two groups in a twelve-week
long double-blind study. The Seretide group had 46.8 percent symptom-free
days compared to 21.5 percent in the montelukast sodium group (p<0.001).
review of medicines against asthma, copd and coughs
The montelukast sodium group had also significantly more exacerbations (11
percent compared to 0 percent, p<0.05). Total average cost per day was 3.55
USD in the seretide group and 3.12 USD in the montelukast sodium group
(p<0.001). The average cost per symptom-free day was 5.03 USD in the sere­
tide¬ group (95% CI: 4.61 5.50) and 8.25 USD in the montelukast sodium
group (95% CI: 6.98 9.93). This resulted in an incremental cost-effectiveness
ratio of 1.69 USD (95% CI: 1.01 2.48).
Lyseng-Williamson et al (2003) have summarised some quality of life studies
where Seretide is compared to salmeterol and fluticasone in separate inhalers,
budesonide, montelukast sodium and placebo. In all cases Seretide raised
quality of life significantly more than the comparator alternatives (Asthma
Quality of Life Questionnaire). The average incremental cost per QALY was
1 357 GBP for Seretide 50/100 µg compared to fluticasone 100 mg.
On the whole Seretide performed better clinically than both budesonide and
montelukast sodium, but at a higher cost.
Symbicort (formoterol/budesonide)
Rosenhall et al (2003) compared Symbicort (formoterol 9µg/budesonide
320 µg) twice daily (delivered dose) with formoterol 9 µg and budesonide
320 µg twice daily (delivered dose) taken using separate inhalers. A twelve­
month long open prospective parallel group study of Swedish adult asthma
patients formed the foundation for the results. 217 people used Symbicort
and 103 used separate inhalers. The cost for combination substances was
21.43 Skr per day and for the separate inhalers it was 23.37 Skr per day. The
combination group had 1.14 days absence from work compared to 1.37 for
the group with separate inhalers. The number of emergency care visits was
0.1 and 0.34 respectively, the number of doctor visits was 0.27 and 0.42
respectively, and the number of nurse visits was 0.22 and 0.13 respectively.
Total direct costs were 8 915 Skr in the combination group compared to 10
510 Skr in the group with separate inhalers (15 percent lower, p=0.0004).
Indirect costs were also lower in the combination group: 1 384 Skr to 1 673
Skr (17 percent lower, p=0.69). Total costs were 10 299 Skr and 12 183 Skr
(p=0.043). The main cost drivers were pharmaceuticals, this share of the total
costs was 76 percent in the combination group and 70 percent in the group
with separate inhalers.
the pharmaceutical benefits board
Various inhalation devices
Maxair Autohaler
In a retrospective study of American insurance data over two years Langley
(1999) compared the two beta agonists salbutamol (press-and-breathe-inha­
lator) and pirbuterol (breathing-driven Maxair Autohaler). Patients 65 yeasr
and older and patients with COPD were excluded from the population.
The pirbuterol group consisted of 10 333 patients and the salbutamol group
consisted of 2 924 patients. According to the author there were two substan­
ces similar enough to carry out a study of different inhalation devices.
The monthly asthma-related healthcare costs for the Maxair Autohaler
group was 45.77 USD compared to 54.83 USD for the salbutamol group
(p<0.0001). Of these costs medicines accounted for approximately 17 per­
cent in both groups (7.83 USD and 9.80 USD). Also when non-asthma-rela­
ted healthcare costs were taken into account Maxair was significantly cheaper
(159.74 USD to 190.88 USD, p<0.0002). In a regression model the author
found that a change from a press-and-breathe-inhalater to Maxair would
result in an almost twelve percent decrease in costs. No measures of effect or
indirect costs were included in the study.
CFC-free beclometasone
Malone & Luskin (2003) compared beclometasone taken with an CFCdriven inhaler (80 µg) with an inhaler driven by hydrofluoroalkane-134a
(approximately half the CFC dose). Of 291 CFC users 218 were randomised
to change to an HFA inhaler and 73 to continued treatment using an CFC
in a 1-year long prospective open RCT. The median value for the number of
symptom-free days won compared to the baseline was 22 percentage points
for the HFA group (from 28 percent to 50 percent) compared to 14 per­
centage points for the CFC group (15 percent to 30 percent, p=0.03 for the
difference in the number of symptom-free days at the end of the study).
Median cost for beclometasone was 378 USD in the HFA group compared
to 640 USD in the CFC group (p<0.001). Total median costs were 668 USD
and 977 USD respectively (p<0.001). The cost per symptom-free day was
4.07 USD in the HFA group and 8.86 USD in the CFC group. The HFA
inhaler was the dominant alternative and the incremental cost-effectiveness
ratio was negative, -5.77 USD (95% CI: -68.08 to -4.08).
Price, D. (2002a) has also compared beclometasone via a CFC or HFA-dri­
ven inhaler. Data was collected from the same study as Malone and Luskin
used above. Price et al however also use the patients who were not from the
review of medicines against asthma, copd and coughs
USA, which is why the population is a little bigger: 354 in the HFA group
and 199 in the CFC group. The HFA users got 50 or 100 µg beclometa­
sone and CFC users 50, 100 or 250 µg. The number of symptom-free days
were as a median 42 percent in the HFA group and 20 percent in the CFC
group (p=0.006). The number of patients who improved their health-related
quality of life significantly (0.5 point change in AQLQ-points) compared to
baseline was 44 percent in the HFA group and 36 percent in the CFC group
(p=0.019). The share of patients who had significantly worsened their health­
related quality of life was 9 percent and 20 percent respectively.
The average total direct healthcare-related cost per year of treatment was 226
GBP in the HFA group and 231 GBP in the CFC group. The waiting value
for ICER per patient per week was minus 0.14 GBP for total healthcare costs
and minus 0.09 GBP for medicines only. No confidence interval was presen­
ted.
HFA beclometasone was not clinically better than CFC beclometasone
(significantly better in one case) and displayed in one case significant cost
savings, and in the other was not more expensive.
Variable doses compared to fixed doses
Symbicort
Bruggenjurgen et al (2005) examined how health-related quality of life
changed for 3 297 patients with mild asthma who were treated with bude­
sonide/formoterol 160 µg/4,5 µg either two puffs per day or one to four
puffs per day depending on the degree of severity. The result of the study was
gathered from a twelve week long prospective open RCT. The study found
no significant difference in change of quality of life measured using AQLQ
(0.18 for patients with variable, and 0.20 for those with a fixed dose). The
study did not either find any difference in the number of symptom-free days
(48 percent and 49 percent respectively). From a German societal perspective
variable doses led to significantly lower costs per patient (277 euro compared
to 340 euro for the group with fixed doses, p<0.001). Medicines stood for
approximately 60 percent of total costs and few patients experienced exacer­
bation. It is likely the patients were somewhat over-treated, which would lead
to unnecessarily high medical costs for patients who could not decrease their
intake of medicine. This theory is supported by the fact that the sub-group
who had most severe asthma had significantly more symptom-free days for
fixed doses compared to variable doses.
the pharmaceutical benefits board
Price, D. et al (2004) had the same approach as Brüggenjürgen and associa­
tes, but looked at direct costs in Great Britain. Of the 782 patients who were
randomised to variable doses, 1.2 percent (95% CI: -3.7 to 6.3) achieved
an at least 0.5 points improvement of AQLQ (Mini-Asthma Quality of Life
Questionnaire). The comparable result for the 771 patients using fixed doses
was 5.7 percent (95% CI: 0.4-10.9). The difference between the groups was
not significant (-4.4 percent [95% CI: -12% till 2%]). Based on these condi­
tions the authors chose to conduct a cost minimisation analysis. Carrying out
a cost minimisation analysis with this confidence interval seems somewhat
odd. There was no significant difference between the substances, but there
was a clear trend. Direct costs per patient and day were 1.13 GBP for the
group with variable doses compared to 1.31 GBP for the group with fixed
doses. In both groups Symbicort stood for roughly 90 percent of the total
direct costs.
Studies by Ställberg and associates (Stallberg et al, 2003) carried out an
analysis which was similar to the one in Bruggenjurgen et al, 2005, but was
from a Swedish societal perspective. The patients were also able to get the
lower dose of 80 µg budesonide. Data was collected from a six month long
Swedish randomised open parallel group study of 1 034 patients. 6.2 percent
of patients who could take one, two or four puffs per day had some form of
exacerbation, compared to 9.5 percent of the rest of the patients (p<0.049).
When use of rescue medication is considered and the number of nights with
disturbed sleep, the group with the fixed dose was better (p=0.011). Total
cost per patient and half-year was significantly lower in the group with vari­
able doses (355 euro, of which direct costs made up 75 percent) than in the
group with a fixed dose (454 euro, direct costs 89 percent). The difference
was significant for both total and direct costs (p<0.,001).
On the whole variable doses seem to lead to cost savings.
review of medicines against asthma, copd and coughs
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the pharmaceutical benefits board
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T Volmer, A Kielhorn, H H Weber & K J Wiessmann. Cost effectiveness of
fluticasone propionate and flunisolide in the treatment of corticosteroid­
naive patients with moderate asthma. Pharmacoeconomics 1999; 16(5 Pt 2):
525-31.
review of medicines against asthma, copd and coughs
COPD
Introduction
The purpose of this literature review was to identify cost-effectiveness analy­
ses which had been done on medicines used for treating COPD.
The search
The search was carried out on 23rd November 2006 in PubMed and
Cochrane’s NHS EED-section. The number of hits was 303 and 83 respec­
tively. The search terms used in PubMed were ”copd AND (”Costs and Cost
Analysis” [MeSH] OR ”Economics, Pharmaceutical” [MeSH]” and limited
to articles in English, Swedish, Danish or Norwegian. In Cochrane we used
only copd as a search term. In both databases the search was limited to artic­
les published 1999 or later.
Of the total of 386 articles, twelve were cost-effectiveness studies of medici­
nes used for treating COPD. This report is based on these studies.
We also carried out a search based specifically on Swedish conditions. This
search was limited to articles published at the latest 1998. None of the 94
hits had their starting point in Swedish cost conditions.
Measure of effect
In principle in health economic analyses there are three types of measures of
effect:
Lung capacity – often measured as an improvement of FEV1 .
Exacerbations – how many exacerbations have the patients in each group?
Quality of life – expressed as the number of patients who improve quality of
life by at least four points measured using St George’s Respiratory Questionn­
aire (SGRQ), or expressed quality-adjusted life year (QALY).
Most articles use more than one measure of effect. Generally it is difficult to
judge cost-effectiveness of lung capacity.
Usability
Only one of the eleven health economic analyses used Swedish cost condi­
tions (Lofdahl et al, 2005). Other analyses were based on British, American,
Canadian or Dutch costs. As relative costs and treatment traditions differ
from country to country the results from these other studies are of limited
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value. That the same clinical starting point can give differing cost-effective­
ness results for different cost conditions is clear in Oostenbrink et al (2005).
In this article the effect of three different treatment alternatives is examined.
Although the clinical effects were the same in both countries in Canada the
alternatives were cost-neutral, while in the Netherlands there was a difference
of 170 euro between the most expensive and cheapest substance over a period
of a year.
All articles except for one (Sin et al, 2004) used only direct costs. This is
explained in the articles as that COPD patients in general are so old that
they have already retired. According to two cost-of-illness studies on Swedish
conditions this assumption seems to be unfortunate. Jacobson et al (2000)
estimate the indirect costs for COPD to be 1.7 billion Skr in 1991. This was
57 percent more than the direct costs. In the other study the average indirect
cost per COPD patient was estimated at almost 8 000 Skr (Jansson et al,
2002). 90 percent of this cost was made up of costs for early retirement.
Corporate connections
All articles had a connection to some company, either because one of the
authors was employed at the company, or that the company had either partly
or wholly financed the study.
Medicines
Under the following headings there are short summaries of each health
economic analysis. Studies comparing short-acting beta agonists come first,
followed by long-acting beta agonists, inhaled steroids, anti-cholinergics and
finally combination products.
The comparison made is described under the first suitable heading. A com­
parison between a short-acting beta agonist and a long-acting beta agonist is
described under the section Short-acting beta agonists. Under Long-acting
beta agonists there is a cross-reference to Short-acting beta agonists.
Short-acting beta agonists
Salbutamol
Friedman et al (1999) compared Combivent with its constituent substances
ipratropium and salbutamol separately. Data for clinical effect was collected
from two 85 day long double-blind randomised studies with a total of 1 767
patients. Both studies were designed identically.
review of medicines against asthma, copd and coughs
At the end of the study Combivent had improved lung function significantly
better than its alternative comparators. There was no significant difference
between salbutamol and ipratropium. Direct costs were highest in the salbu­
tamol group (269 USD) and lowest in the ipratropium group (156 USD).
For Combivent patients the cost was 197 USD.
Based on the presented effects it is difficult to judge if salbutamol is a cost­
effective alternative as the measure of effect (percent change in FEV1-value
and improvement of FEV1 after four hours) is not used in any other studies.
In the MPA’s recommendations for treatment of COPD short-acting beta
agonists are not recommended for regular treatment.
Long-acting beta agonists
Unspecified long-acting beta agonists
Gagnon et al (2005) examined how the use of long-acting beta agonists,
inhaled steroids, the combination of both and finally not using any of these
options at all was correlated to costs and life span. Using a 3-year long ob­
servation study of 1 154 COPD patients who were part of an HMO, the aut­
hors found that patients who had had treatment with both steroids and beta
agonists on average lived 2.7 years. This was on average 0.10 years more than
patients who had got inhaled steroids and 0.07 years more than patients who
had received long-acting beta agonists. The difference was not statistically
significant. The difference compared to patients who had not received any of
these medicines was 0.29 years. This difference was statistically significant.
Costs were highest in the group which had only received inhaled steroids
(35 170 USD), next came the group who had also been treated using long­
acting beta agonists (33 780 USD), followed by those who had not received
any of these medicines (28 030 USD) and finally those who had been treated
using long-acting beta agonists (27 380 USD). None of the differences were
statistically significant.
Long-acting beta agonists were therefore cheaper and better than treatment
alternatives which did not use beta agonists. The incremental cost-effective­
ness ratio for combination treatment was 91 430 USD per gained year of life.
Observation studies do not give any clear indications as to causality. It is the­
refore not possible based on this study to say that treatment with long-acting
beta agonists leads to lower costs or more years of life, just that in this study
they were correlated to lower costs.
Formoterol
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Hogan et al (2003) compared formoterol 12 µg twice daily, formoterol 24
µg twice daily and ipratropium 40 µg four times daily. The twelve-week long
double-blind randomised study comprised 780 COPD patients. All medi­
cines improved FEV1 more than placebo. The largest increase was in the
group which got 12 µg – dose of formoterol (223 ml more than placebo),
followed by the 24 µg-dose (194 ml) and ipratropium (137 ml). The 12 µg
group improved on SGRQ points by 6.6 points compared to the baseline.
The 24 µg group increased by 4.8, in other words a lower increase than the
lower dose. The ipratropium group improved by only 1.1 compared to the
placebo group’s increase of 1.5. The health economic analysis only examined
pharmaceutical costs, including costs for rescue medication. Other costs were
assumed to be the same. As total pharmaceutical costs were lower in the 12
µg group (215 USD) than in the 24 µg group (419 USD), the latter was
dominated. In the same way the ipratropium group (76 USD) was domina­
ted by the placebo group (39 USD). The incremental cost-effectiveness ratio
per point improvement in SGRQ was 32 USD, when using formoterol 12 µg
BID, compared to placebo. Compared to ipratropium ICER was 25 USD.
Twelve weeks seems too short a time for studying the health economic effects
for treatment of a chronic disease such as COPD.
A health economic analysis by Lofdahl et al in 2005 compared Symbicort
(budesonide/formoterol) to each component in single therapy based on 1
022 patients in a large one-year study. The doses delivered were 160 µg for
budesonide and 4.5 µg for formoterol, both in single and combination th­
erapy. The medicines were administered as two puffs twice a day. The FEV1­
value for the COPD patients was max 50 percent of that expected.
The relative risk of an exacerbation using Symbicort was 0.75 (95 % CI:
0.59-0.95) compared to formoterol and 0.86 (0.68-1.10) compared to
budesonide. The study used Swedish cost conditions. As total direct costs
were lower for Symbicort (2 518 euro) than for budesonide (3 194 euro) or
formoterol (3 653 euro), Symbicort was according to the study the dominant
alternative from a Swedish perspective. Differences in cost were not however
significant. It is worth noting that in terms of cost and effect formoterol was
worse than placebo, however not significantly so.
Based on both of these studies formoterol 12 µg seems to be the dominant
alternative to the 24 µg dose. If change in quality of life is considered from
the first study then formoterol seems to also be a cost-effective alternative to
ipratropium. In the Swedish analysis by Lofdahl et al from 2005 formoterol
is dominated by both Symbicort and budesonide.
review of medicines against asthma, copd and coughs
Salmeterol
In Jones et al (2003) salmeterol 50 µg twice daily as a complementary tre­
atment was compared to normal COPD treatment without beta agonists.
The comparison was made to placebo. In the sixteen-week long double-blind
study which the results were based on, 229 patients were randomised to
salmeterol and 227 to placebo. The patients had an FEV1 value of max 70
percent of the expected value. The number of patients who improved their
FEV1 value by at least 15 percent was 32 percent in the salmeterol group
compared to 15 percent in the placebo group (p<0.001). The number of
patients who improved their SGRQ points by at least four was 59 percent
and 38 percent respectively. The difference of 22 percentage points was sta­
tistically significant (95 % CI: 8-35). Average direct costs were 192 GBP in
the salmeterol group and 102 GBP in the placebo group (difference 90 GBP,
95 % CI: 20-154). Costs which arose due to study protocol are also included
in these costs. The resultant ICER was 4.62 GBP (1.08-10.40) when the
FEV1criterion was considered and 4.44 GBP (1.85-11.78) when the SGRQ
criterion was considered.
Oostenbrink et al (2005) compared tiotropium 18 µg once per day with on
the one hand ipratropium 40 µg four times daily, and on the other hand
salmeterol 50 µg twice daily. The health economic analysis was carried out
partly from a Dutch perspective and partly from a Canadian one. Clinical
data was collected from six different studies. Approximately 70 percent of the
almost 1 900 patients got tiotropium and approximately 10 percent ipratro­
pium. The studies which compared these two medicines were one year long.
The other 20 percent of the patients got salmeterol in six month long studies.
During a period of one year tiotropium led to 8.42 quality adjusted months
(QALM), compared to 8.17 for salmeterol and 8.11 for ipratropium. The
differences were not significant. Tiotropium gave fewer exacerbations than
salmeterol (-0.17; not significant). Salmeterol in turn gave fewer exacer­
bations than ipratropium (-0.12). The difference between tiotropium and
ipratropium was probably significant.
In regard to direct costs there were no significant differences between the
different alternatives in either of the countries. In the Netherlands treatment
with ipratropium was 128 euro more expensive than using salmeterol. Salme­
terol was 42 euro more expensive than treatment using tiotropium. Tiotro­
pium was therefore the dominant alternative, at the same time as salmeterol
dominated ipratropium. In Canada the various treatment alternatives were
cost-neutral.
40
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The article by Oostenbrink and associates which is recounted under the sec­
tion Ipratropium used some of the same clinical data as above.
According to the article by Oostenbrink et al (2005) salmeterol dominates
ipratropium, but is at the same time dominated by tiotropium. In Jones et al
(2003) salmeterol is more expensive but better than placebo.
Inhaled steroids
Non-specified steroids
Sin et al (2004) used a Markov model to examine four differing strategies for
use of inhaled steroids (ICS). Strategy a meant that no COPD patient, regardless of the degree of severity , would get treatment using ICS. Strategy b
meant that all patients would be treated with ICS. In strategy c patients with
an FEV1 value of max 50 percent of the expected value. In the last strategy,
d, ICS was given to patients whose FEV1 value was max 35 percent of the
expected value. Data for clinical effects was collected from approximately 15
published articles. Treatment with ICS was assumed to decrease the risk of
exacerbations by 30 percent and the risk of death by 16 percent per quarter.
Over three years treatment of all COPD patients gave 2.75 QALYs. This was
0.04 QALYs more than if no patient had been treated using ICS. For the two
other strategies the number of QALYs was 2.72. The reason that the average
QALY value did not differ between these two groups most probably is becau­
se the authors assumed that 93 percent of the patient cohort was made up of
patients with an FEV1 value more than 50 percent of the expected value.
Therefore strategies b and c meant that only seven percent of the patients
were treated. The incremental societal cost compared to not treating any
patient was 3 612 USD for strategy b, 922 USD for strategy c and 774 USD
for strategy d. Compared to strategy a the ICER therefore becomes 90 300
USD for strategy b, 92 200 USD for strategy c and 77 400 USD for strategy
d. The authors show considerably lower incremental cost-effectiveness ratios
but it is unclear how they have arrived at these.
See the section Non-specified long-acting beta agonists for a comparison of
non-specified long-acting beta agonists and inhaled steroids together, separa­
tely or treatment without any of the alternatives.
According to both of these studies inhaled steroids seem to be an expensive
alternative, when we consider its effect compared to placebo. According to
Sin et al the addition of long-acting beta agonists is a better alternative. It is
however difficult to ascertain how this may be applied to Swedish circums­
tances. The article by Gagnon et al does not offer any answers to the question
regarding cause between treatment and effect.
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4
Budesonide
See the section Formoterol for a comparison of Symbicort to budesonide and
formoterol as single therapy.
According to this study budesonide was both worse and more expensive than
Symbicort, but a better and cheaper alternative to formoterol.
Fluticasone
Two articles have analysed taking fluticasone compared to placebo. A further
article has compared the effect of discontinuing fluticasone treatment.
One of the articles (Ayres et al, 2003) examined how fluticasone performed
as a complement to normal bronchodilating treatment. The article collected
data from a half-year long double-blind randomised study with a total of 281
patients who had moderate to severe COPD. Fluticasone was significantly
better than placebo when the number of patients who improved their FEV1
by at least ten percent was considered (32 percent compared to 19 percent in
the placebo group, p>0.02), but there was not a significant difference in the
number of patients who were free of exacerbations during the entire study
period (63 percent and 58 percent respectively). The fluticasone group had
somewhat higher direct costs than the placebo group, but lower total costs
when indirect costs were also included (3.65 GBP and 4.06 GBP respecti­
vely). Fluticasone was therefore the dominant alternative, also when the 95
percent confidence interval for ICER showed a zero overlap.
In the study other medicines against COPD were administered without any
changes in dose. In the placebo group in everyday clinical use these doses
would probably have been raised as the patient showed symptoms. The cost­
related advantage enjoyed by fluticasone would thereby be amplified, at the
same time as the clinical advantage would decrease.
Patients with moderate to severe COPD were also examined in the other
article which looked at using fluticasone for treatment (Briggs et al, 2006).
The ISOLDE study, a three-year long randomised double-blind study
(n=742) formed the foundation for the clinical results. The study suffered
from a high number of drop-outs in both groups - 53 percent in the placebo
group and 43 percent in the fluticasone group – at the same time as there
was only full information in regard to quality of life for 37 percent of the
patients. The lack of information concerning quality of life means that there
is uncertainty in the effect measured in QALYs.
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Over the three-year period fluticasone resulted in 0.06 (95 % CI: -0.01 to
0.14) more years of life than placebo. The number of gained QALYs using
fluticasone treatment was 0.12 (0.00-0.25) based on the patients where the
data was complete in regard to quality of life. In the health economic ana­
lysis, which only looked at direct costs, fluticasone over three years was con­
nected with significantly higher costs than placebo (2 494 GBP and 1 341
GBP respectively). Costs were driven primarily by the medicine studied. The
incremental cost per gained year of life was 20 000 GBP. The comparable
cost per gained QALY was 9 600 GBP.
As it is not possible to see how costs are distributed in the study by Briggs et
al it is not either possible to pinpoint what causes costs for formoterol treat­
ment to be approximately one British pound higher per day than formoterol
treatment, at the same time as formoterol treatment is in principle cost-neu­
tral compared to in Ayres et al.
The structure of the study in the third article (van der Palen et al, 2006) was
somewhat different to the other articles. The patients were treated for a four
month period with 500 µg fluticasone twice daily. After this period they were
randomised to either continue the treatment for a further 6 months or, to
continue using placebo. The study was double-blind. Continued treatment
using fluticasone resulted in 0.87 attacks, to be compared with the placebo
group’s 1.37. Total costs were 511 euro and 456 euro respectively. The cost
per prevented attack was 110 euro.
In all three studies fluticasone gives a better effect than placebo, but in two of
the cases at a higher cost.
Anti-cholinergics
Ipratropium
Oostenbrink et al (2004) compared tiotropium to ipratropium based on two
of the one-year studies also used in Oostenbrink et al (2005). The health
economic analysis was carried out parallel to the clinical study and comprised
519 patients with an FEV1 value of max 65 percent of the expected value.
Tiotropium led to significantly fewer exacerbations than ipratropium (0.74
compared to 1.01). Also the difference in the number of patients with at
least a four point improvement in quality of life (SGRQ) was significantly to
the advantage of tiotropium (17 percent, 95 % CI: 7-30). In contrast to the
other comparison between tiotropium and ipratropium, tiotropium in this
health economic analysis was a more expensive alternative. Total direct costs
were 1 721 euro and 1 541 euro respectively. The incremental annual cost
review of medicines against asthma, copd and coughs
4
per successfully treated patient was 1 084 euro. ICER per prevented exacer­
bation was 667 euro.
See also the section Salmeterol for a comparison of ipratropium, tiotropium
and salmeterol, and the section Salbutamol for a comparison of Combivent
with its constituent substances in single therapy.
According to these studies Ipratropium is a clinically inferior alternative to
tiotropium. Under both Dutch and Canadian cost conditions ipratropium
was dominated by tiotropium and by salmeterol. In the comparison with
tiotropium, ipratropium was worse and cheaper.
When compared to Combivent and salbutamol, ipratropium was clinically
worst but also cheapest. The measures of effect are difficult to evaluate and
therefore cost-effectiveness is also difficult to ascertain.
Tiotropium
See the section Salmeterol for a comparison between tiotropium, ipratropium
and salmeterol.
See the section Ipratropium for a comparison between tiotropium and
ipratropium.
According to these health economic analyses tiotropium seems to be a cost­
effective alternative to both ipratropium and salmeterol.
Combination treatment
Non-specified steroids and long-acting beta agonists
See the section Long-acting beta agonists for a comparison of long-acting
beta agonists, inhaled steroids, treatment with both, and not using either of
these medicines. In this study combination treatment leads to better results
than the comparator alternative. ICER compared to treatment with only
long-acting beta agonists (91 430 USD) is however relatively high.
Combivent (ipratropium/salbutamol)
See the section Salbutamol for a comparison of Combivent to ipratropium
and salbutamol as single therapy. The measures of effect in this study make it
difficult to judge if Combivent is a cost-effective alternative. The effect is best
with Combivent, but it is not possible to judge if it is worth the increased
cost compared to ipratropium.
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Seretide (salmeterol/ fluticasone)
In an article by Spencer et al (2005) combination treatment (salmeterol 50
µg and fluticasone 500 µg) taken twice daily was compared to placebo. The
average FEV1-value for the patient group was approximately 45 percent of
what was expected and they responded badly to salbutamol. The Markov
model was applied over 25 years. Transition probabilities were collected from
the 1-year long Tristan study (n=1 465). In a post hoc analysis of the Tristan
study it emerged that Seretide, besides decreasing the number of exacer­
bations, also affected survival. Without this survival benefit the number of
QALYs in the model over 25 years was 4.08 in the placebo group and 4.21 in
the seretide group. The average life span was 8.95 years. Including the effect
on survival Seretide increased the number of QALYs to 6.07. The average life
span then became 14.43 years. The difference was not significant compared
to placebo, excluding or including the mortality effect.
In the scenario without the survival benefit the cost for treatment with Sere­
tide was 25 780 CAD compared to 16 415 CAD. This gave an ICER of 74
887 CAD (95 % CI: 21 985-128 671). With a mortality benefit direct costs
increased to 38 560 CAD in the seretide group. ICER then became 11 125
CAD (8 710-).
Excluding the mortality benefit the cost per gained year of life was relatively
high. If the assumption in regard to mortality benefit is correct then Seretide
is a cost-effective alternative.
Symbicort (budesonide/formoterol)
Please see the Section Formoterol for a comparison of Symbicort to budeso­
nide and formoterol as an isolated therapy.
In this Swedish study Symbicort was the dominant alternative compared to
budesonide and formoterol separately.
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4
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Läkemedelsförmånsnämnden (LFN)
Sundbybergsvägen 1
Box 55, 171 11 Solna, SWEDEN
Telephone: +46 8 56 84 20 50, Fax: +46 8 56 84 20 99
[email protected], www.lfn.se