Prescribing of long-acting beta-2-agonists/inhaled corticosteroids after the SMART trial
Rottenkolber et al. BMC Pulmonary Medicine
Prescribing of long-acting beta-2-agonists/inhaled corticosteroids after the SMART trial
Marietta Rottenkolber 0 10
Rainald Fischer 2 10
Luisa Ibez 1 6 10
Joan Fortuny 5 10
Robert Reynolds 4 10
Justyna Amelio 3 10
Roman Gerlach 8 10
Martin Tauscher 8 10
Petra Thrmann 7 9 10
Joerg Hasford 0 10
Sven Schmiedl 7 9 10
0 Institute for Medical Information Sciences , Biometry, and Epidemiology , Ludwig-Maximilians-Universitaet , Marchioninistr. 15, D-81377 Munich , Germany
1 Fundacio Institut Catala de Farmacologia, Hospital Universitari Vall d'Hebron , Barcelona , Spain
2 Pneumologische Praxis Muenchen - Pasing , Munich , Germany
3 Amgen Ltd , Uxbridge , UK
4 Pfizer Research & Development , New York , USA
5 Novartis Farmaceutica SA , Barcelona , Spain
6 Departament de Farmacologia, Terapeutica i Toxicologia, Universitat Autonoma de Barcelona , Barcelona , Spain
7 Department of Clinical Pharmacology, School of Medicine, Faculty of Health , Witten/Herdecke
8 National Association of Statutory Health Insurance Physicians of Bavaria , Munich , Germany
9 Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal , Wuppertal , Germany
10 University , Witten , Germany
Background: After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in asthma patients, regulatory actions were taken to promote a guideline-adherent prescribing of LABA only to patients receiving inhaled corticosteroids (ICS). We aim to analyse LABA- and ICS-related prescription patterns after the SMART trial in Germany. Methods: Patients documented in the Bavarian Association of Statutory Health Insurance Physicians database (approximately 10.5 million people) were included if they had a diagnosis of asthma and at least one prescription of LABA and/or ICS between 2004 and 2008. Annual period prevalence rates (PPRs) were estimated and Cochrane Armitage tests were used for time trend analyses. Results: Highest annual PPRs were found for budesonide and the fixed combination of salmeterol/fluticasone. The proportion of concomitant LABA and ICS users increased from 52.0 to 57.6% within the study period, whereas for LABA users without ICS a slight decrease from 6.5 to 5.4% was found. In 2008, the proportion of patients with at least one quarter with a LABA prescription without concomitant ICS was highest in elderly, male patients (20%). In the majority of these patients, a concomitant diagnosis of COPD (i.e. asthma-COPD overlap syndrome [ACOS]) was present. Conclusions: Between 2004 and 2008, we found a moderate increase in guideline-adherent LABA prescribing in a representative German population. Elderly men received a significant number of LABA prescriptions without concomitant ICS probably due to ACOS.
Long-acting adrenergic beta-2-receptor agonists; Inhaled corticosteroids; Asthma; COPD; ACOS; Drug utilisation study; SMART trial; Drug regulatory actions
The Salmeterol Multicentre Asthma Research Trial
(SMART)  was a large randomized controlled trial in
asthma patients evaluating the safety of salmeterol (i.e., a
long-acting beta-2-agonist [LABA]) compared to placebo
in addition to usual asthma care. In 2003, this trial was
prematurely terminated by GlaxoSmithKline due to
recruitment problems and safety issues. In an interim analysis, a
non-significant increase in combined respiratory-related
deaths or life-threatening events was found in patients
receiving salmeterol but for African Americans, this increase
was statistically significant. Furthermore, a significantly
increased risk for combined respiratory-related death or
life-threatening experience (RR = 5.6, 95% CI: 1.2-25.3)
and combined asthma-related deaths or life-threatening
experience (RR = 10.5, 95% CI: 1.3-81.6) was found for
African Americans who had no prescription of an inhaled
corticosteroid (ICS) at baseline. In contrast, if ICS was
present at baseline no significant differences between
patients receiving salmeterol or placebo were found .
Regarding these results as well as previously and recently
published guidelines, LABA should be prescribed only to
patients receiving ICS [2,3].
In 2003, Dear doctor letters were sent out by
GlaxoSmithKline and detailed results of the SMART trial
were added to the respective SPCs of LABA-containing
products [4-6]. After presentation of SMART results to
the public, an intensive and somewhat controversial
discussion occurred between the stakeholders . In
2005, information for health care providers were sent
out by the FDA stating that LABA should be prescribed
to asthma patients only if other medicines, including
low-or-medium dose ICS, do not control asthma [8-10]
and a Black box warning on LABA was imposed by the
FDA [11,12]. In Germany, the national drug regulatory
authority (BfArM) published in August 2003 a
statement  presenting results of the SMART trial and
pointing out the need for a guideline-adherent treatment
. In 2006, it was decided to add warnings similar to
those made by the FDA to product labelling of LABA
compounds in Germany, too .
Taking into account the essential need for a
concomitant ICS usage in patients receiving LABA, fixed
combination of LABA/ICS might be considered as a
meaningful treatment option for patients with asthma
and respective recommendations were made by the FDA
[16,17] and by several guidelines [3,17,18].
Despite the importance of obtaining a reliable picture
of real-life prescription behaviour after the SMART trial
and related regulatory actions, only a few data exists
analysing changes in LABA- and ICS-related prescribing
in detail [19,20]. Hence, we aim to analyse trends in
prescriptions of LABA, ICS, and fixed combination drugs
containing LABA and ICS between 2004 and 2008 using
a German database covering 10.5 million people.
Study type and data source
A drug utilization study was conducted in the database
of the Association of Statutory Health Insurance
Physicians, Bavaria . This population-based database
covers all compulsorily insured persons of the Statutory
Health Insurance. The database has existed since 2001
and covers 85% (i.e., 10.5 million people) of the total
Bavarian population excluding those with a private
health insurance. It compiles, based on accounting
information of Bavarian physicians, the patient
characteristics, diagnoses of both general practitioners and
consultants, all performed medical services, and drug
utilization of all outpatients. Diagnoses and patient
characteristics are documented on a patient-related basis. All
information is updated quarterly; i.e., for each diagnosis
or prescription the quarter is documented in the
database, rather than the actual prescription date.
Prescriptions are only recorded in the database if they are filled
at the pharmacy. The International Statistical
Classification of Diseases and Related Health Problems
terminology (ICD-10-GM) was used for coding diagnoses and
the Anatomical Therapeutic Chemical classification
system (ATC) for coding drugs [22,23]. The study period
included the years 20042008. All analyses were
performed using anonymized administrative data only. Thus
an ethical approval is not needed in Germany. There
was neither a data protection nor a legal basis to ask for
an ethical review or approval. The data of the National
Association of Statutory Health Insurance Physicians of
Bavaria, Munich, Germany (KVB) was routinely
collected on a legal basis. All authors had direct access to
KVB anonymized raw data for statistical analyses. For
this project a written agreement was signed between the
Institute of Medical Information Sciences, Biometry, and
Epidemiology (LMU Muenchen) and the Bavarian
National Association of Statutory Health Insurance
Physicians. Finally, all analyses were performed based on
STROBE (STrengthening the Reporting of
OBservational studies in Epidemiology) guidelines and the
researchers assured that data was handled properly and
stored on secured servers.
Patients having at least one ICD-10-GM diagnostic code
of asthma (J45 (Asthma) and/or J46 (Status
asthmaticus)) documented within the study period and at least
one prescription of the following respiratory drugs
within the study period were included: salmeterol (ATC
code: R03AC12), formoterol (R03AC13), salmeterol and
fluticasone (R03AK06), formoterol and beclometasone
(R03AK27), formoterol and budesonide (R03AK28),
beclometasone (R03BA01), budesonide (R03BA02),
flunisolide (R03BA03), betamethasone (R03BA04),
fluticasone (R03BA05), triamcinolone (R03BA06), mometasone
(R03BA07), and ciclesonide (R03BA08). The index date
was set as the quarter of the year of the first prescription
of a drug of interest in the study period. Patients with an
additional diagnosis of COPD (ICD-10-GM: J44 [Other
chronic obstructive pulmonary disease]) were
considered as patients with asthma-COPD overlap syndrome
Definition concomitant usage of LABA and ICS
If a patient received a fixed combination drug containing
LABA and ICS, the respective quarter of the year was
considered as a quarter with concomitant usage of
LABA and ICS (irrespective of any other drugs).
Concomitant usage of LABA and ICS could also be assured
by prescribing both compounds separately, but in a close
temporal relationship (usually at the same day in clinical
routine). Taking into account a quarterly documentation
of prescribed drugs, a separate prescription of both a
LABA and an ICS compound was considered as
concomitant usage of LABA and ICS if given in one quarter
(irrespective of any other drugs). According to the
pattern of LABA and ICS prescriptions, patients were
assigned to the following five mutually exclusive
categories: concomitant LABA and ICS users, switchers,
non-concomitant LABA and ICS users, LABA users
without ICS, and ICS users without LABA (Table 1).
Switchers were defined as patients with at least one
prescription of concomitant LABA and ICS (fixed dose
or separate prescription) in at least one quarter and at
least one LABA prescription without ICS in at least one
other quarter within a particular calendar year.
In a subgroup analysis, the following further
stratification were performed for the category concomitant
LABA and ICS users: i) patients receiving LABA and
ICS only in fixed inhalers (combined inhaler), ii)
patients receiving LABA and ICS only in separate
inhalers (separate inhalers); iii) patients with
combinations (i.e., patients with at least one
prescription of a fixed LABA/ICS device, and in addition a
separate ICS- or a non-fixed LABA/ICS-prescription
in the same or another quarter of the respective
calendar year; combinations). All assignments to
treatment groups were made on a calendar year basis.
Annual period prevalence rates (PPRs) were calculated
using the number of patients with at least one
prescription of interest during the year of interest
(numerator) divided by the total number of compulsorily
insured Bavarians at midyear of the year of interest
(July, 1; denominator) . Annual PPRs per 10,000
persons were calculated stratified by age (ten-year age
groups [09 years, 1019 years, 2029 years, , 90+
years]), sex, and compound. For the five patient
categories (concomitant LABA and ICS users,
switchers, non-concomitant LABA and ICS users,
LABA users without ICS, and ICS users without
LABA) and the subgroup categories combined
inhalers, separate inhalers, and combinations the
number of patients and proportions were calculated
and stratifications by age, sex, and calendar year were
Table 1 Treatment categories
At least one prescription in at least one quarter
within a particular calendar year
LABA & ICS (fixed or non- LABA ICS
fixed in the same quarter) (no ICS) (no LABA)
X - Possible*
performed. All time trend analyses were performed using
the Cochrane Armitage test. All statistical calculations
were conducted using IBM SPSS Statistics Version 20.0
and GNU R Version 3.0.1 (http://www.r-project.org/).
Period prevalence rates
Within the study period, the highest annual PPRs were
found for budesonide (between 75.6 and 90.6 per 10,000
persons) and the fixed combination of
salmeterol/fluticasone (between 62.1 and 73.1 per 10,000 persons). In
contrast, the lowest PPRs were observed for mometasone
(between 0.1 and 1.8 per 10,000 persons, Additional file 1:
Table S1). From 2004 to 2008, a significant increase in PPRs
was revealed for formoterol, fixed combinations of
salmeterol/fluticasone, formoterol/beclometasone, formoterol/
budesonide, and the ICS beclometasone and budesonide.
For all remaining drugs including salmeterol, a decrease
was found between 2004 and 2008 (all p-values <0.0001;
Figure 1). In addition, a slight decrease was found for
salmeterol/fluticasone (between 2005 and 2008), and for
formoterol and formoterol/budesonide (between 2007 and
Analysis of concomitant LABA and ICS usage
In total, 307,358 patients (approximately 2.9% out of all
insured people) with a documented diagnosis of asthma
or status asthmaticus were treated with at least one drug
of interest in 2008. The highest proportion (57.6%) of
patients was classified as concomitant LABA and ICS
users followed by ICS users without LABA (31.4%,
The proportion of asthma patients classified as
concomitant LABA and ICS users increased from 52.0%
(2004) to 57.6% (2008, p < 0.0001), whereas the
proportion of patients classified as LABA users without
ICS decreased from 2004 onwards (2004: 6.5%; 2008:
5.4%, p < 0.0001). The proportion of switchers
decreased slightly during the study period (2004: 5.4%;
2008: 4.8%, p < 0.0001) and the proportion of
nonconcomitant LABA and ICS users increased slightly
during the study period (2004: 0.55%; 2008: 0.63%, p =
0.0020). For patients classified as ICS users without
LABA, we found a decrease within the study period
(2004: 35.6%; 2008:31.4%, p < 0.0001, Table 3).
The age and sex distribution (for the year 2008) for
each treatment category is presented in Table 2. The
mean age was the lowest in the ICS users without
LABA group with 37.5 (standard deviation (SD): 24.9)
years and the highest in the switchers group with 59.1
(SD: 17.8) years. In each group, more than half of all
patients were females. In the non-concomitant LABA and
ICS users group, the proportion of females was the
*in up to all quarters of a particular calendar year, **except from the quarters
with a LABA only prescription in up to all quarters of a particular
Figure 1 Annual period prevalence rates per 10,000 persons stratified by compound between 2004 and 2008.
The proportion of patients with at least one LABA
prescription without concomitant ICS (combined
analysis of LABA users without ICS, non-concomitant
LABA and ICS users, switchers) was the lowest (1.3%)
in the age group 09 years, increased continuously over
the age groups, peaked in patients aged 8089 years
(19.1%) and was followed by a small decrease for
patients in the age group 90+ years (18.8%, Table 4).
Regarding sex-related differences, the proportion of
patients with at least one LABA prescription without
concomitant ICS was slightly higher in men reaching
more than 20% in men aged over 70 years (7079 years:
20.3%, 8089 years: 21.3%, 90+: 21.4%; Table 4). In
these elderly male patients, a concomitant diagnosis of
COPD (i.e. asthma-COPD overlap syndrome) was
present in 76.8% (Additional file 1: Table S2).
Concomitant LABA and ICS users fixed combination
versus separate inhalers
Out of all concomitant LABA and ICS users, the
proportion of patients receiving LABA and ICS only in a
fixed inhaler device (combined inhaler) was high and
increased significantly from 82.2% to 85.7% within the
study period (p < 0.0001, Table 5).
The fraction of patients receiving at least one
prescription of a fixed LABA/ICS device, and in addition a
separate ICS- or a non-fixed LABA/ICS-prescription
(combinations) decreased from 5.7% to 4.9% (p <
0.0001). On the other hand, patients classified as
concomitant LABA and ICS users receiving LABA and ICS
only in separate inhalers decreased significantly from
12.1% to 9.5% (p < 0.0001, Table 5). The proportion of
those patients with two separate inhalers was highest in
Table 2 Age and sex distribution for the different treatment groups (concomitant LABA and ICS users, switchers,
non-concomitant LABA and ICS users, LABA users without ICS, ICS users without LABA) for the year 2008
Table 3 Proportion of patients stratified by treatment group (concomitant LABA and ICS users, Switchers,
non-concomitant LABA and ICS users, LABA users without ICS, ICS users without LABA) for the years 2004
Concomitant LABA and ICS users
Non-concomitant LABA and ICS users
LABA users without ICS
ICS users without LABA
men and women between ages of 50 and 79 years and
no differences were found for sex (Table 6).
In our study, we found a slightly improved guideline
adherence in asthma patients in terms of i.) a moderate
increase of concomitant LABA and ICS prescriptions
(including both fixed combination drugs and separate
drugs) and ii.) a slight increase of LABA/ICS fixed
combination drugs between 2004 and 2008. Nevertheless, a
relevant number of patients received LABA at least in
one quarter without a concomitant ICS prescription
(2004: 12.5%; 2008: 10.9% [including switchers,
nonconcomitant LABA/ICS users, LABA users without
ICS]) or received non-fixed LABA/ICS treatment (2004:
12.1%; 2008: 9.5% [concomitant LABA and ICS users
receiving LABA and ICS in separate inhalers]). Both issues
were most frequently present in elderly men.
LABA usage & Non-concomitant LABA/ICS usage
For formoterol we found a PPR increase between 2004
and 2007 followed by a slight decrease in 2008 whereas
for salmeterol, a distinct year-by-year decrease was
found between 2004 and 2008. Despite the fact, that the
Table 4 Proportion of patients stratified by age group, sex, and treatment group (concomitant LABA and ICS users,
switchers, non-concomitant LABA and ICS users, LABA users without ICS, ICS users without LABA) for the year
and ICS users
*LABA/ICS treatment categories percentage values were calculated for each age group and sex separately.
Table 5 Concomitant LABA and ICS users stratified by inhaler type for the years 2004 to 2008: Combined Inhalers,
Separate Inhalers, Combinations
Combined inhalers [fixed LABA/ICS]
Separate inhalers [non-fixed LABA/ICS]
German drug regulatory authority has been discussed
LABA in general as a drug class for which concomitant
ICS prescribing is needed , our data cannot exclude a
shift in LABA prescriptions in terms of stopping
salmeterol and initiating formoterol prescribing (without ICS)
in individual patients. For formoterol, an earlier onset of
bronchodilative effects compared to salmeterol is
wellknown  and might explain a switch from salmeterol
to formoterol. However, a lacking prescribing of ICS to
asthma patients receiving formoterol has to be
considered as guideline-violating prescription behaviour, too.
By conducting a combined analysis of formoterol and
salmeterol, we found a PPR increase between 2004 (45.2
per 10,000 persons) and 2008 (50.6 per 10,000 persons;
data not shown). Furthermore, only a small proportion
of patients received LABA without ICS (switchers,
non-concomitant LABA and ICS users and LABA
users without ICS) and the proportion of patients
classified into these categories decreased between 2004 and
Similar to our combined analysis of formoterol and
salmeterol,  a slight increase of the absolute number
of LABA prescriptions was found in Italian asthma
patients between 2006 and 2008. On the other hand, the
proportion of asthmatic children receiving LABA
decreased distinctly between 2001 and 2006 in a Scottish
study . Regarding the United States, the proportion
of treatment visits with a LABA prescription without
concomitant steroids decreased between 2004 and 2008
and reached less than 1% in 2008 . Our data suggest
a higher proportion of patients receiving LABA without
ICS but methodological differences might have
contributed to these discrepant results. Whereas Higashi et al.
 calculated the proportion of visits for a particular
prescription category out of all visits (including visits
without LABA or ICS prescriptions) we analysed the
proportion of a particular patient category based on
prescriptions within one year out of all patients having at
least one prescription of interest not mentioning the
number of treatment visits.
Concomitant LABA/ICS usage & Fixed LABA/ICS
In our study, the proportion of concomitant LABA/ICS
users increased from 52.0% to 57.6% between 2004 and
2008. The observed increase could be related to an
increased prescribing of i.) ICS to patients receiving
LABA, ii.) LABA to patients receiving ICS, or iii.) fixed
LABA/ICS combinations. It is worth mentioning, that
all three potential changes in prescription behaviour
Table 6 Concomitant LABA and ICS users stratified by age group, sex, and inhaler type (Combined Inhalers,
Separate Inhalers, Combinations) for the year 2008*
*Concomitant LABA/ICS treatment categories percentage values were calculated for each age group and sex separately.
would be in accordance to guidelines . Regarding the
proportion of patients with fixed LABA/ICS
combination, we found an increase between 2004 and 2008
(82.2% versus 85.7%) out of all concomitant LABA and
ICS users. In comparison , LABA and ICS were
prescribed concomitantly (fixed combination drug and
separate compounds) in the United States in approximately
20% to 30% of asthma treatment visits. Out of these
patients, 99% received a fixed combination of LABA/
Regarding a compound specific analysis of fixed
combination drugs, we found a PPR increase of between
12.1% (salmeterol/fluticasone) and 49.8% (formoterol/
beclometasone ) within the study period. In
comparison, prescriptions of fixed
salmeterol/fluticasone combination for Italian asthma patients increased
between 2006 and 2008 by 45% whereas for
formoterolcontaining fixed combinations, a much more
pronounced increase by 137% was found . In a
combined analysis of salmeterol- and
formoterolcontaining fixed combinations, more than a doubling
was found for the proportion of children receiving
LABA/ICS in Scotland between 2001 and 2006 .
On a European level , a 50% increase of fixed
LABA/ICS combination drug prescriptions was found
between 2005 and 2009.
Regarding age- and sex-stratified analyses (year 2008),
the highest proportion of patients with at least one
LABA prescription without concomitant ICS (combined
analysis of LABA users without ICS, non-concomitant
LABA and ICS users, switchers) was found in elderly
men. The lack of ICS prescribing in these elderly men
receiving LABA might be related to a relevant COPD
drug burden (i.e. asthma-COPD overlap syndrome).
However, not prescribing ICS to ACOS patients on a
regular base might be reasonable regarding most recent
Gap between guidelines/regulatory decisions and clinical
The knowledge gap between research and clinical
practice is a well-known problem and a wide range of
interventions has been evaluated. To sum up the available
evidence, multifaceted, interactive approaches (e.g.
audits and feedback, workshops, reminders) seems to be
more effective than passive, single interventions (e.g.
educational materials [28,29]). For asthma, several
strategies for improving knowledge translation have been
evaluated. For example, a multiple level intervention was
conducted in Canada including the individual patient,
the practice, and the health system level. By
implementing six guideline-based care elements including e.g.
spirometry measurement, asthma controller therapy, and
self-management action plans, a significant improvement
of relevant clinical endpoints (e.g. reduced number of
urgent / emergent healthcare visits ) was found.
Furthermore, the proportion of patients receiving LABA/ICS
combination therapy increased, but unfortunately, results
for LABA monotherapy were not reported in this study.
Most recently, electronic tools were examined to promote
knowledge translation at physician and patient level, but
further studies are needed to clarify the impact of these
approaches [31,32] in particular regarding their impact on
improving guideline-adherent prescription behaviour.
In Germany, a nationwide disease management
program (DMP) for patients with asthma was implemented
in 2006 including e.g. regular visits, individual action
plans, and regular feedback to coordinating general
practitioners . By analysing annual trends of asthma
treatment for patients included in this DMP between
2006 and 2010, a guideline-adherent prescribing was
found in the majority of patients. Nevertheless, a small
but slightly increasing proportion of patients has
received LABA monotherapy (2006: 2.1%, 2010: 3.5%). As
already discussed for our study, this finding could be
related to a concomitant diagnosis of COPD which was
present in 2.8% to 5.2% of DMP patients .
Regarding the impact of regulatory actions on
prescribing behaviour in daily practice, only a few
wellconducted studies are available. In a systematic review,
no final conclusion regarding the impact of
safetyrelated regulatory actions could be made due to
inadequate study designs and heterogeneity in analyses and
outcome measures . In particular, confounding
factors are of outstanding importance but difficult to adjust
for hampering a valid estimate of the actual impact of a
particular regulatory action. By comparing the impact of
different information included in a Dear doctor letter,
simple information (dose limit) has been considered by
physicians more frequently compared to complex
information (QT prolongation due to drug-drug
interactions) . Taken into account the more or less simple
message of asthma guidelines and SMART-related
regulatory actions, a guideline adherent prescribing of LABA
and ICS seems achievable. Due to confounding factors
(e.g. disease management program for asthma patients)
and the complexity of treatment decision making, we
were unable to quantify the actual impact of the SMART
trial publication and/or SMART-related drug regulatory
actions on prescribing behaviour.
Strengths & limitations
Our study has several strengths worth noting. First, the
database covers a population of about 10.5 million
people and represents 85% of the inhabitants of Bavarian
(the largest federal state of Germany). In addition, we
were able to perform detailed analyses focusing on the
presence or absence of concomitant ICS prescriptions in
asthma patients receiving LABA. Furthermore, due to a
5-year period, we could analyse trends in PPRs as well
as in LABA- and ICS-related prescription behaviour
after the SMART trial. Despite these strengths, there are
also several limitations regarding our study. Firstly, our
analysis was limited to the years 2004 to 2008 and more
recent changes in prescription behaviour should be
taken into account. By comparing nationwide drug
prescription data for the years 2008 and 2013 (irrespective
of indication), for salmeterol a 72.5% decrease (2008:
9.1 Mio. DDD, 2013: 2.5 Mio. DDD), for formoterol a
22.2% increase (2008: 99.1 Mio. DDD, 2013: 121.1 Mio.
DDD), for ICS a slight decrease of 4.0% (2008:
167.6 Mio. DDD, 2013: 160.9 Mio. DDD), and for fixed
combinations of LABA/ICS a distinct increase of 28.7%
(2008: 255.8 Mio. DDD, 2013: 329.2 Mio. DDD) were
found [36,37]. Since our main aim was to conduct a
comprehensive and more detailed analysis of LABA- and
ICS-prescribing in asthma patients after the SMART
trial, we decided to use a period covering most factors
potentially influencing drug prescribing including
publication and dissemination of SMART results and
SMART-related drug regulatory actions. Secondly, the
prescriptions are documented on a quarterly basis in the
database meaning that all LABA and ICS prescriptions
were counted as concomitant if they occurred in the
same quarter irrespective of the actual prescription date.
Hence, the proportion of concomitant LABA/ICS users
is likely to be overestimated in our study. Thirdly, only
patients with compulsory insurance are covered in our
analyses and thus, by excluding patients with a private
health insurance, a socioeconomic bias on our study
results cannot be excluded. Fourthly, this study covers a
Southern region of Germany and hence, generalizability
of results to other German regions or to other countries
is limited as reported for several other studies, too
[38,39]. However, by taking into account methodological
differences, PPRs for LABA, ICS, and fixed combination
of LABA/ICS found in our study showed a similar
pattern and trend compared to national drug consumption
data [36,40]. Fifthly, by using prescription data only,
prescribing quality can only roughly assessed due to missing
individual data important for a clinical decision (e.g.
lacking lung function parameter, detailed clinical history)
and a substantial proportion of patients potentially given
an incorrect diagnosis (i.e. asthma instead of COPD)
By analysing prescription data of a German population
covering 10.5 million subjects, we found a slightly
increased guideline adherence between 2004 and 2008. In
elderly men, the proportion of patients receiving LABA
and ICS non-concomitantly was highest but might be
reasonable taking into account a concomitant diagnosis
of COPD (i.e. ACOS). Due to the complexity of factors
influencing prescription behaviour (e.g. guidelines,
disease management programs), we were not able to
quantify the actual impact of the publication or dissemination
of the SMART trial results and/or related drug
regulatory actions. Further studies are needed to analyse in
detail the impact of milestone trials and related drug
regulatory actions on real-life prescription behaviour.
Additional file 1: Table S1. Annual period prevalence rates per 10,000
persons stratified by compound between 2004 and 2008. Table S2.
Number and proportion of patients with an additional COPD diagnosis
for the year 2008.
ATC: Anatomical Therapeutic Chemical classification system; ICD-10-GM:
International Classification of Diseases and Related Health Problems
terminology (German Modification); ICS: Inhaled corticosteriod; LABA:
Long-acting beta-2-agonist; PPR: Period prevalence rate; SD: Standard
deviation; SMART: Salmeterol Multicentre Asthma Research Trial.
MR, RF, LI, RG, MT, PT, and JH have no conflicts of interest. SS reports
personal fees (Rottapharm Madaus, Cologne, Germany) and reimbursement
of travel costs for an investigator meeting (Bayer HealthCare AG, Leverkusen,
Germany) outside the submitted work. JF is an employee of Novartis. JA is
an employee of Amgen Ltd. RR is an employee and shareholder of Pfizer Inc.
JF, JA and RR belong to EFPIA (European Federation of Pharmaceutical
Industries and Association) member companies in the IMI JU and costs
related to their part in the research were carried by the respective company
as in-kind contribution under the IMI JU scheme.
All authors contributed to the study conception and design. Data extraction
and raw data analysis and interpretation were performed by MR, SS, RF, RG,
MT, and JH. MR and SS wrote the first draft and all authors contributed with
critical comments to the final version. All authors have seen and approved
the final version.
The research leading to these results was conducted as part of the PROTECT
consortium (Pharmacoepidemiological Research on Outcomes of
Therapeutics by a European ConsorTium, www.imi-protect.eu) which is a
public-private partnership coordinated by the European Medicines Agency.
The views expressed are those of the authors only.
The PROTECT project has received support from the Innovative Medicine
Initiative Joint Undertaking (www.imi.europa.eu) under Grant Agreement n
115004, resources of which are composed of financial contribution from the
European Unions Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies in kind contribution.
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