CLINICAL CARE

Combination
therapies for asthma
Mark Greener

ABSTRACT
Combination inhalers are one of the five most expensive drug groups in the UK. Expenditure may
rise further following the launch of several new combinations for asthma, chronic obstructive
pulmonary disease (COPD), or both. Despite clear advice, healthcare professionals (HCPs) often
prescribe combination therapies inappropriately, which potentially undermines efficacy, increases
costs, and may contribute to asthma mortality. Nevertheless, health care professionals need a
diverse formulary to tailor treatment to each patient, and address the related issues of poor
adherence and poor inhaler techniqueboth of which undermine outcomes and drive up costs.
Meanwhile, commissioning groups seem to be missing several opportunities to reduce expenditure
on drugs for asthma, while maintaining or improving outcomes.

Mark Greener
Pharmacologist
now working as a
freelance medical writer
Email: markgreener@
virginmedia.com

12 

Despite regularly updated and internationally

influential management guidelines (Scottish
Intercollegiate Guidelines Network (SIGN),
2014), relatively high public and professional
awareness, and a wide and growing
armamentarium, 1167 people died from
asthma in the UK during 2011 (Asthma
UK, 2014)about one death every 8 hours.
Tragically, optimising treatment would
potentially avoid up to 90% of deaths from,
and 75% of hospital admissions for, asthma
(Asthma UK 2014).
Optimising treatment could also reduce the
considerable economic toll imposed on the NHS
by asthma managementabout 1 billion a year.
Indeed, 5.4 million people in the UK currently
receive treatment for asthma (Asthma UK, 2014).
Against this background, commissioners and
healthcare professionals (HCPs) need to improve
outcomes, while minimising inappropriate
and wasteful use of medicines (Primary Care
Commissioning (PCC), 2012).

At first sight, the growing number of

combination inhalers seems to help HCPs
and commissioners balance these competing
imperatives. Certainly, combination inhalers
are popular among prescribers. During
2010, the Health and Social Care Boards
in Northern Ireland spent 49 million on
respiratory drugs, with combinations of
inhaled corticosteroids (ICS) and long-acting
bronchodilators accounting for 47% of the bill.
Indeed, combination inhalers are among the
top five most-expensive drug groups across all
NHS regions in the UK (Sweeney et al, 2014).
Commissioners may need to consider whether
this bill will rise in the wake of the launch of
several new combinations for asthma, chronic
obstructive pulmonary disease (COPD) or both.
Furthermore, HCPs often prescribe
combination therapies inappropriately (Sweeney
et al, 2014), which potentially undermines
efficacy, increases costs and might contribute
to some asthma deaths (Royal College of

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Key Words: Asthma combination inhalers chronic obstructive pulmonary disease

CLINICAL CARE

Physicians, 2014). Meanwhile, commissioning

groups seem to be missing opportunities to
reduce expenditure on drugs for asthma, while
maintaining or improving outcomes (PCC, 2012).

A double whammy
Essentially, two major features drive asthma:
inflammation and hyper-responsiveness of the
airways. Asthmatic inflammation, for example,
increases mucus production by the airways.
The walls become oedematous, while the ring
of smooth muscle around the airways thickens.
Eventually, inflammation scars the airways.
ICS (such as beclomethasonealso called
beclometasonebudesonide or fluticasone)
dampen this inflammation (Alangari, 2014) and
so prevent asthma attacks. HCPs can prescribe
several other oral and inhaled anti-inflammatory
drugs, but ICS remain the most widely used
preventer.
In addition, asthmatic airways are hyperresponsivein other words, they are twitchy
and narrow (bronchoconstrict) excessively when
exposed to a range of triggers. This natural
response evolved to keep potentially harmful
substances away from the delicate lung lining.
However, the narrowing of their hypersensitive
airways can trigger an attack, especially if the
lungs are inflamed. During asthma attacks, the
narrowing limits airflow into the deep areas
of the lung where oxygen and carbon dioxide
exchange. Symptoms can range from a mild
cough, to profound breathlessness, to a feeling
of suffocationand even death (Greener, 2011).
Hyper-responsible lungs can narrow in response
to a range of allergic (such as pollens, animal
dander, mould and the faeces of dust mites) and
non-allergic triggers (including viral infections;
irritants such as smoke and dust; cold air and
exercise) (Alangari, 2014).

14 

The balance of nervous inputs determines

airway diameter. The adrenergic system opens
the airways when noradrenaline or adrenaline
binds to 2 adrenergic receptors in the ring of
muscle. This switches on pathways inside the
cell that open the airway, a bit like the way your
ignition key switches on your cars engine. Drugs
that stimulate these receptors (called agonists)
open the airways (Greener, 2011).
Some beta-agonists (such as salbutamol) are
short-acting and open the airways for between
four and six hours. Short-acting beta-agonists
rapidly relive asthma attacks. Long-acting 2agonist (LABAs) can keep the airways open for
up to 12 hours. LABAs (such as salmeterol and
formoterol) can prevent nighttime symptoms
and prevent asthma attacks (Greener, 2011;
Cazzola et al, 2012).
As mentioned above, airways sometimes
narrow to protect the lungs. Cholinergic
nerves release acetylcholine, which stimulates
muscarinic receptors and, in turn, triggers
bronchoconstriction. This means that drugs that
block muscarinic receptors (called antagonists
or anticholinergics) open the airways (Cazzola
et al, 2012). Traditionally, HCPs prescribed
anticholinergics for COPD rather than asthma
although between 10% and 15% of patients have
both conditions (Price et al, 2013). However,
Spiriva Respimat (tiotropium) is now approved
as an add-on maintenance bronchodilator for
adults with asthma who experienced one or
more severe exacerbations in the previous
year despite receiving maintenance ICS (at least
800g budesonide daily or equivalent) and
LABA (Boehringer Ingelheim, 2014).

The appeal of combinations

HCPs should use a dose and combination of
anti-inflammatory drugs and bronchodilators
tailored to each patients asthma severity to
rapidly control symptoms and optimise peak flow
(a measure of lung function). HCPs maintain
control by moving up and down the treatment
steps outlined in the British Guideline on the
Management of Asthma. This approach aims to,
for example, prevent daytime symptoms, nighttime wakening due to asthma and acute attacks,
while minimising asthmas detrimental effect on

British Journal of Healthcare Management 2015 Vol 21 No 1

2015 MA Healthcare Ltd

Commissioning groups seem to

be missing opportunities to reduce
expenditure on drugs for asthma while
maintaining or improving outcomes

 2015 MA Healthcare Ltd

CLINICAL CARE

activities (including exercise) and lung function

(SIGN, 2014).
Despite the benefits, between 30% and 70%
of patients do not comply with their asthma
treatment, which, not surprisingly, undermines
outcomes and increases health-care costs
(Lindsay and Heaney, 2013). The British
guidelines note that it is generally considered
that combining ICS and LABA in a single inhaler
improves compliance (SIGN 2014).
In addition, studies during the 1990s suggested
that LABAs used alone (monotherapy) might
increase deaths among people with asthma.
A meta-analysis reportedbased on 54 placebocontrolled studiesthat salmeterol monotherapy
increased mortality from asthma in patients not
prescribed ICS 7.3 fold. In 127 studies, HCPs
also prescribed ICS, but in separate inhalers.
Salmeterol still doubled (odds ratio 2.1) the risk
of death from asthma. Further studies confirmed
that ICS seem to protect against salmeterols
harmful effects (Weatherall et al, 2010).
But, as we have seen, adherence with asthma
drugs may be poor (Lindsay and Heaney, 2013).
So, theres no guarantee that people take the
ICSwhich probably accounts from the doubling
in deaths in people prescribed ICS in a separate
inhaler. Indeed, none of the 22600 patients died
from asthma in 63 studies in which patients
received salmeterol and fluticasone propionate
in a single inhaler (Weatherall et al, 2010).
Combining ICS and a LABA in a single device
does not influence efficacy compared to two
drugs given by two inhalers (SIGN, 2014).
In other words, combination inhalers ensure
that patients do not take LABA without ICS
(SIGN, 2014) allowing people to benefit from
prolonged bronchodilation without the increased
risk of mortality. Yet despite well-established
risks, the National Review of Asthma Deaths,
which included 195 people thought to have
died from asthma between February 2012 and
January 2013, found evidence of inappropriate
prescribing of LABAs. For instance, 14% were
prescribed a single-component LABA (ie an
inhaler that does not also include ICS) at the
time of death. At least five (3%) patients were on
LABA monotherapy without ICS (Royal College
of Physicians, 2014). Commissioners should

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audit prescribing to ensure that no one is using

long-acting bronchodilators without ICS (PCC,
2012) and that everyone taking LABA/ICS uses a
combination inhaler.

The place of combination

treatment
The British Guideline on the Management
of Asthma states that HCPs should prescribe
LABA (and, therefore, combination therapies)
to patients over the age of five years only when
ICS monotherapy does not adequately control
symptoms (SIGN, 2014).
Despite this clear guidance, an analysis of
prescription data in Northern Ireland in 2010
found that 67% of patients taking an ICS/LABA
combination had not received ICS monotherapy
in the study year or the last six months of
2009. Indeed, 52% had not received ICS even
extending the window to the whole of 2009.
Moreover, HCPs do not seem to start ICS/LABA
because of persistent symptomsjust 17% of
users received short-acting beta-agonists in the
previous six monthsor severe exacerbations
(5% received oral steroids). On the other hand,
41% of the inappropriate ICS/LABA prescribing
occurred from January to March, which the
authors suggest could reflect...a propensity to
viral infection with more prominent symptoms
(Sweeney et al, 2014).
Against this background, commissioners need
to ensure that HCPs use ICS/LABA combination
inhalers only after ICS monotherapy fails to
adequate control symptoms and after checking
adherence and inhaler technique (SIGN, 2014).
Indeed, PCC (2012) remark, Considerable
savings could be made if inhaled corticosteroids
are used first and are sufficient to achieve control
of patients asthma.
In addition, the British Guideline stresses that
HCPs should check adherence and ensure that
patients use their inhaler properly before moving
to another treatment, including ICS/LABA
combinations (SIGN, 2014). Inhalers can be
remarkably difficult to use. Any sceptics should
ask a HCP to let them try using a placebo inhaler.
In turn, incorrect use can markedly reduce the
proportion of drug that reaches the lung. For
instance, poor co-ordination between actuation

15

and inhalation using metered dose inhalers

(MDIs) reduced the amount of drug deposited
in the lung from about 23% to 7% (Chrystyn
and Price, 2009).
Such problems are common: between 32%
and 96% of patients make errors when using
MDIs. Indeed, 28% to 68% do not use their MDI
or dry powder inhaler (DPI) sufficiently well
to benefit from the drug (Chrystyn and Price,
2009). Against this background, the National
Institute for Health and Care Excellence (NICE)
quality standard states that people with asthma
should be given specific training and assessment
in inhaler technique before starting any new
inhaler treatment (NICE 2013). HCPs should
also regularly check inhaler technique (SIGN 2014).

Spare the formulary

The proliferation of inhalers and combinations
might tempt commissioners to limit formularies.
Certainly, some patients can use simple MDIs
and DPIs. However, each inhaler has advantages
and disadvantages (see Chrystyn and Price,
2009). Choosing the most appropriate inhaler
for each patient can help optimise asthma
management. Commissioners could encourage
HCPs to consider whether they are using the
most appropriate inhaler for that person before
changing the dose of ICS or adding other
treatments (Chrystyn and Price, 2009) including

16 

ICS/LABA combination inhalers.

Indeed, some inhalers are not interchangeable
and HCPs should prescribe by brand. In
part, the dose depends on particle size: on
average, smaller particles penetrate deeper
into the lungstherefore, the dose of the
steroid can be less. The patient breathes
the rest out or swallows drug deposited in
the mouth and throat. For example, in 2014
Chiesi launched Fostair NEXThaler, which
combined beclomethasone and formoterol, for
maintenance treatment of asthma in adults. The
difference in particle sizes means that 250g
beclomethasone administered using a standard
inhaler is therapeutically equivalent to 100g
beclomethasone in a Fostair product such as the
NEXThaler (MIMS, 2014).
In other words, commissioners need to
carefully balance the costs, benefits and
characteristics of each inhaler when considering
formularies. A formulary needs to include a wide
enough range of devices to meet the diversity
of patients. After all, patients who find using a
particular inhaler uncomfortable or difficult are
more likely to make critical handling errors,
which potentially undermine asthma control
and, in turn, increase demand for consultations
and other services (Bjrnsdttir et al, 2013).
As Bjrnsdttir et al (2013) comment: savings
achieved in acquisition costs may result in a

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CLINICAL CARE

CLINICAL CARE

greater net loss because of increased

healthcare consumption, caused by decreased
asthma control.
In any case, commissioners are not making
the most of existing opportunities to reduce
costs. The British Guideline emphasises that
HCPs should review patients regularly and if
their asthma is well-controlled, step downfor
example, switching combination inhalers for
ICS monotherapy. However, stepping down is
often not implemented leaving some patients
overtreated (SIGN, 2014). Commissioners
could also audit use of high-dosegreater than
1000g beclometasone or equivalent whether
as monotherapy or in combinationto see how
many patients might be considered for step down
or referral to a specialist. This may reduce sideeffects and offers a real opportunity to reduce
the cost of prescribing (PCC, 2012).
Despite considerable innovations in drugs
and devices, asthma continues to impose
heavy morbidity, mortality and financial
burdens. However, the plethora of combination
treatments, inhalers and other treatments in the
armamentarium allows HCPs to tailor treatment
to each patient with unprecedented accuracy.
Yet, there is not, and probably never will be,
a magic bullet that controls asthma optimally
in every patient. Commissioners, clinicians,
patients and their carers need to collaborate to
allow as many people with asthma as possible to
live as normal a life as possible. BJHCM

2015 MA Healthcare Ltd

Conflict of interest: Mark Greener

receives or has received royalties on
several books on asthma most recently
Coping with Asthma in Adults (Sheldon
Press 2011). He has worked as a
consultant for several pharmaceutical
companies on communications and
health economics around asthma and
COPD, but has held no such positions in
the last four years.

References
Alangari AA (2014) Corticosteroids in the treatment of
acute asthma. Ann Thorac Med 9(4): 18792
Asthma UK (2014) Asthma facts and statistics. Available
at: www.asthma.org.uk/asthma-facts-and-statistics.

British Journal of Healthcare Management 2015

Vol 21 No 1

(accessed 22 December 2014)

Bjrnsdttir US, Gizurarson S and Sabale U (2013)
Potential negative consequences of non-consented
switch of inhaled medications and devices in asthma
patients. Int J Clin Pract 67(9): 90410
Boehringer Ingelheim (2014) Asthma: Spiriva
(tiotropium) Respimat becomes the only
LAMA licensed in asthma care http://www.
boehringer-ingelheim.co.uk/news/medical_
journalistpressreleases/asthma_spiriva_
tiotropiumrespimatbecomestheonlylamalicensedinast.
html (accessed 22 December 2014)
Cazzola M, Page CP, Calzetta L, Matera MG (2012)
Pharmacology and therapeutics of bronchodilators.
Pharmacol Rev 64(3): 450504
Chrystyn H and Price D (2009) Not all asthma inhalers
are the same: Factors to consider when prescribing an
inhaler. Prim Care Respir J 18(4): 24349
Greener M (2011) Coping with Asthma in Adults. Sheldon
Press, London
Lindsay JT, Heaney LG (2013) Nonadherence in difficult
asthmafacts, myths, and a time to act. Patient
Preference and Adherence 7: 32936
National Institute for Health and Care Excellence (2013)
NICE Quality statement 4: Inhaler technique. Available
at: www.nice.org.uk/guidance/qs25/chapter/qualitystatement-4-inhaler-technique (accessed 22 December
2014)
Price D, Yawn B, Brusselle G, Rossi A (2013) Risk-tobenefit ratio of inhaled corticosteroids in patients with
COPD. Prim Care Respir J 22(1): 92100
Primary Care Commissioning (2012) Designing and
commissioning services for adults with asthma: A good
practice guide. Available at: www.pcc-cic.org.uk/article/
designing-and-commissioning-services-adults-asthmagood-practice-guide (accessed 22 December 2014)
MIMS (2014) Fostair NEXThaler: extrafine dry powder
inhaler launched for asthma. www.mims.co.uk/more/
NewDrugs/article/1313881/fostair-nexthaler-extrafinedry-powder-inhaler-launched-asthma/ (accessed 22
December 2014)
Royal College of Physicians (2014) Why asthma kills:
The National Review of Asthma Deaths (NRAD).
Available at: www.rcplondon.ac.uk/sites/default/
files/whyasthma-still-kills-full-report.pdf (accessed 23
December 2014)
Scottish Intercollegiate Guidelines Network (2014) British
guideline on the management of asthma. Available
at: https://www.brit-thoracic.org.uk/documentlibrary/clinical-information/asthma/btssign-asthmaguideline-2014/ (accessed 22 December 2014)
Sweeney et al J, Patterson CC, ONeill S et al (2014)
Inappropriate prescribing of combination inhalers in
Northern Ireland: retrospective cross-sectional cohort
study of prescribing practice in primary care. Prim Care
Respir J 23(1): 7478
Weatherall M, Wijesinghe M, Perrin K, Harwood M,
Beasley R (2010) Meta-analysis of the risk of mortality
with salmeterol and the effect of concomitant inhaled
corticosteroid therapy. Thorax 65(1): 39-43

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