Introduction
Asthma and chronic obstructive pulmonary disease (COPD) are the most common obstructive
airway diseases. Figures from 2005 indicate the prevalence of asthma in German social
health insurance to be approximately 6 % [1 ]. It estimated that in Germany the prevalence of COPD is 7.5 % [2 ]
[3 ]. Moreover, a considerable proportion of patients in routine care are suffering from
both asthma and COPD.
There are a number of current guidelines for the management of asthma and COPD in
Germany including the ‘Nationale Versorgungs Leitlinien’ (NVL) for asthma and COPD
and guidelines produced by the German respiratory Society [4 ]
[5 ]
[6 ]
[7 ]. These guidelines are consistent with the principal international standards of the
Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) [8 ]
[9 ].
The treatment strategies for both asthma and COPD employ a stepwise approach, and
the range of medications shows considerable overlap. Although there are some differences
in treatment goals, the prevention and treatment of symptoms and exacerbations are
common aims for both conditions [4 ]
[5 ].
NVL guidelines for asthma, and those of GINA, recommend a low-dose inhaled corticosteroid
(ICS) as the initial controller medication at treatment Step 2. In the NVL guideline,
there is an important controversy over the escalation of therapy at Step 3; the majority
recommendation of the NVL was for doubling the ICS dose, however, the German Respiratory
Society voted for the early addition of a long-acting β2 agonist (LABA), either in separate inhalers, or in a combined delivery device (fixed-dose
combination) ([Fig. 1 ]) [4 ]. The decision to adjust step-up (or step-down) treatment is made on the level of
patient’s asthma control [4 ]
[8 ].
Fig. 1 NVL guideline: medication for the long-term therapy of asthma in adults [4 ]. ICS = inhaled corticosteroid, LRTA = leukotriene receptor antagonist, DAL/DGP = Deutsche
Atemwegsliga/Deutsche Gesellschaft für Pneumologie (German Airways League/German Respiratory
Society), RABA = rapid-acting beta-agonist. Adapted; from: Nationale VersorgungsLeitlinien
Asthma: Available at: http://www.versorgungsleitlinien.de/themen/asthma .
Despite the availability of effective treatments and full reimbursement, a high proportion
of patients has asthma that is not well controlled. In Germany, it was estimated from
the European National Health and Wellness Survey that almost two-thirds (65.3 %) of
people with asthma were uncontrolled [10 ], according to the criteria of the Asthma Control Test (ACT) [11 ].
The current NVL (2007) recommendations for the pharmacological treatment of COPD are
based on four stages defined by airflow limitation with the option of introducing
an ICS to long-acting bronchodilator therapy at Grade III (where FEV1 < 50 %), in patients with repeated exacerbations ([Fig. 2 ]) [5 ]. However, the label of the salmeterol plus fluticasone fixed-dose combination is
for FEV1 < 60 % [12 ]. In the most recent GOLD guideline (2011), published after the Delphi research was
conducted, the approach to pharmacological treatment of COPD has changed and is now
based on a combined assessment of severity of COPD, which includes the risk of exacerbations
and symptoms assessed by validated questionnaires. Assessment of airflow limitation
should be used as a complementary tool beside the patient’s history, to assess exacerbation
risk [9 ].
Fig. 2 NVL guideline; therapy for stable COPD [5 ]. * Avoid inhalation of irritants (especially tobacco smoke), ** vaccination against
influenza and pneumococcal disease, *** beta2 -agonists and/or anticholinergics (antimuscarinics); theophylline is third choice.
**** ambulatory or inpatient rehabilitation and/or non-drug measures such as physical
exercise, physiotherapy and patient education. Adapted; from: Nationale VersorgungsLeitlinien
COPD: Available at: http://www.versorgungsleitlinien.de/themen/COPD .
COPD exacerbations, particularly those that lead to hospitalisation account for the
greatest proportion of costs [5 ].
This paper reports on research we conducted using a modified Delphi process with a
panel of physicians in primary and secondary care in Germany, who regularly manage
patients with asthma and COPD. The aim of this Delphi panel was to investigate real-life
clinical practice in the use of ICS/LABA in the management of asthma in primary and
secondary care in Germany. It aimed to investigate whether such treatments are employed,
based on the clinical judgement of experienced physicians and how the real clinical
use matches the guidelines.
Methods
This research was commissioned by GlaxoSmithKline (GSK) to Double Helix Consulting
(DHC) who recruited participants, performed all research, conducted the analysis and
drafted the manuscript in accordance with a structure devised by the leading author.
The Delphi process
The study used a modified Delphi process to develop a series of consensus statements
on the use of combination ICS/LABA therapy in patients with asthma and/or COPD derived
not only from the guidelines, but also the routine practice by experienced GPs and
specialists.
The Delphi process is a validated consensus development methodology that enables a
group of experts to deal with a complex problem through a structured group communication
process. The process was devised by Dalkey and Helmer at the RAND Corporation in the
1950s [13 ]. Its name is taken from the Oracle at Delphi in Ancient Greece. The method has been
successfully employed in business and military applications, and now Delphi processes
are increasingly used in published biomedical studies. There is evidence that the
technique has been utilised in several hundred published papers [14 ]. Furthermore, most guidelines are developed by a modified Delphi process, for example,
the asthma and COPD guidelines of the German Respiratory Society [4 ]
[5 ].
The method is based on the assumption that group judgments can be more valid than
individual judgments. It uses an iterative process of questioning; in each round of
the Delphi process, individual judgments are collected and summarised by an independent
facilitator, who presents them for the next round, with the goal of achieving consensus,
as results are shared and responses are adjusted. It is not necessary to achieve ‘perfect’
consensus; the goal is to identify as many statements as possible to which the highest
number of panellists can agree within a pre-specified range.
Traditional focus groups or advisory boards can be difficult to manage, anonymity
can be violated, ‘vocal’ versus ‘reserved’ participants, and power dynamics could
skew the outcomes of such groups. Delphi survey methods can be used in scenarios where
accurate information is unavailable, or would be resource-prohibitive to obtain and
human opinions are critical.
A workshop with an interdisciplinary team devised a questionnaire on the use of ICS
and LABA that could be put to a panel of physicians. In the first round of the process
panellists completed the questionnaire, which comprised three sections; 36 questions
on the number of asthma patients attending the physician’s practice each month; 30
questions on the number of COPD patients seen; and nine questions on the prescribing
and use of ICS/LABA combination therapy as separate inhalers and in fixed-dose combination
inhalers, i. e., fluticasone/salmeterol or budesonide/formoterol. The questions on
asthma and COPD patients asked about the characteristics of these patients with regard
to disease severity, signs and symptoms, and the therapeutic choices made.
The questionnaire, which drew on the experience of primary care physicians and pulmonologists
regularly involved in the management of asthma and COPD patients, was used to develop
25 radical statements concerning the early use of ICS/LABA combination therapy.
The second stage was a mediated meeting of approximately 4 hours duration by online
videoconference with participants visible to each other by web cam on 24 November
2011. The discussion aimed to arrive at consensus on the 25 statements addressing
issues raised in the questionnaire. For the current study it was specified that a
majority of 7 out of 10 was necessary for consensus to be arrived at, and statements
were modified where necessary to achieve consensus.
Constitution of panel
The panel comprised ten physicians, four pulmonologists and six general practitioners
(GPs), in clinical practice in Germany, who were regularly involved in the management
of outpatients with asthma or COPD. The physicians were recruited from different locations
across Germany, to provide a snapshot of clinical practice in the management of obstructive
airways disease across the country both in primary and specialist care ([Table 1 ]).
Table 1
Physicians recruited for Delphi process consensus panel
Physician
Clinical role
Location
Average No. Patients Month
Patients prescribed ICS/LABA fixed-dose combination
Prescribing step-up according to GINA/GOLD guidelines
Asthma
COPD
1
GP
Rhein-Neckar
40
150
75 %
Yes
2
GP
Berlin
45
35
80 %
Yes
3
GP
Hannover
80
150
60 %
Yes
4
GP
Heidelberg
40
80
70 %
Yes
5
GP
Coburg
40
40
80 %
Yes
6
GP
Munich
20
40
30 %
Yes
7
Pulmonologist
Frankfurt
NR
NR
NR
NR
8
Pulmonologist
Ulm
NR
NR
NR
NR
9
Pulmonologist
Schwedt
NR
NR
NR
NR
10
Pulmonologist
Frankfurt
NR
NR
NR
NR
NR = information not requested at time of recruitment. Pulmonologists were assumed
to treat to the guidelines.
Pulmonologists were recruited by DHC, at random from a GSK list of pulmonologists
practicing in Germany. There was no pre-selection of potential participants, and the
physicians had no financial or other connections with GSK or DHC.
GPs were recruited by a third party specialist recruitment agency based in Germany,
commissioned by DHC. These physicians had no financial or other connections with GSK
or DHC.
When recruiting GPs it was established that they regularly managed asthma and COPD
patients in their practices, and that they followed the principles of current German
guidelines (both NVL and the German Respiratory Society), and of the international
GOLD and GINA guidelines ([Table 1 ]). At recruitment the GPs reported that they saw between 20 – 80 asthma patients
a month and 35 – 150 COPD patients ([Table 1 ]). At recruitment, pulmonologists were not asked about their patient numbers.
Results
In the results of the questionnaire, GPs reported that they saw 20 – 83 asthma patients
a month at their practices and pulmonologists reported that they saw between 20 – 250
asthma patients. GPs saw an average of 40 – 150 COPD patients a month at their practices
and pulmonologists saw an average of 100 – 200 COPD patients ([Table 2 ]). The GPs reported that 30 – 75 % of patients had uncontrolled asthma at the time
of presentation, and the pulmonologist reported that 50 – 70 % of their asthma patients
were uncontrolled. GPs reported that approximately 29 % of their COPD patients had
moderate COPD and 12 % had severe or very severe COPD. The pulmonologists estimated
that 45 % of their COPD patients had moderate COPD and 23 % had severe or very severe
COPD ([Table 2 ]). Physician usage of medication is summarised in [Table 2 ].
Table 2
Physician background – from questionnaire
Physician
Speciality
Average No. Patients Month
Asthma patients prescribed ICS/LABA fixed-dose combination
COPD patients prescribed ICS/LABA
Asthma
COPD
N
Controlled
Uncontrolled
N
Mild[1 ]
Moderate[1 ]
Severe or very severe[1 ]
1
GP
40
70 %
30 %
150
60
30
10
40 %
NS
2
GP
35
70 %
30 %
45
25
18
2
80 %
50 %
3
GP
83[2 ]
25 %
75 %
144[2 ]
70[2 ]
50[2 ]
24[2 ]
70 %
35 %
4
GP
50
60 %
40 %
100
60
30
10
70 %
10 %
5
GP
40
70 %
30 %
40
10
20
10
20 %
30 %
6
GP
20
30 %
70 %
40
25
10
5
25 %
10 %
7
Pulmonologist
250
30 %
70 %
200
100
60
40
150 /month
30
8
Pulmonologist
30
67 %
33 %
100
20
70
10
30 %
NS
9
Pulmonologist
80
50 %
50 %
100
10
50
40
50 /month
40
10
Pulmonologist
20
50 %
50 %
100
30
40
30
10 %
NS
NS = not stated.
1 Categorised according to NVL criteria.
2 Approximate, physician supplied 3-month data.
Consensus statements on asthma
After discussion consensus was reached on 24 statements given in detail in [Table 3 ], [Table 4 ] and [Table 5 ]. The panellists agreed that they had a high proportion of asthma patients on ICS
monotherapy presenting with symptoms or exacerbations that would met the guideline
recommendations for dose escalation. It was agreed that early initiation of combination
ICS/LABA therapy would reduce the risk of exacerbations and improve control, which
would lead to reduced health care utilisation in terms of additional specialist visits,
emergency room visits and hospitalisations. They also reached a consensus that asthma
patients on ICS/LABA fixed-dose combination (FDC) therapy were more adherent than
patients on free combination ICS + LABA, which could lead to better compliance and
improved outcomes and health care utilisation ([Table 3 ]).
Table 3
Consensus statements on asthma
Consensus statement
Additional comments
Presenting signs and symptoms
A significant share of asthma patients treated with ICS monotherapy experience one
or more symptoms that would, depending on their severity, make you consider escalating
their treatment (such as breathlessness or exacerbations).[1 ]
Exacerbations and their management
Approximately, 30 – 50 % of Patients on ICS monotherapy could experience, on average,
two to three exacerbations per year.
Adherence to therapy
Uncontrolled asthma
A loss of asthma control translates into impairments in daily life, including reduced
productivity and days off work/school. Patients on monotherapy lose, on average, four
to five work days per year due to asthma-related causes, which could be prevented
if they were stepped-up to ICS/LABA therapy earlier
Stepping down medication
1 Considered in more detail in the discussion.
Table 4
Consensus statements on COPD
Consensus statement
Additional comments
Presenting signs and symptoms
How often the long acting bronchodilator treatment needs escalation was considered
to be associated with the severity of the disease, using the GOLD 2010 criteria: 60 – 80 %
annually in Stage 4 patients, 40 – 50 % of Stage 3 patients and 5 – 10 % of Stage
2 patients.
Adverse effects
Exacerbations and worsening of symptoms
A significant proportion of COPD patients treated either with monotherapy or LABA + LAMA
require emergency room visits, additional specialist visits or hospitalisation each
year due to exacerbations, cough, sputum or a worsening of symptoms (e. g. breathlessness).
If medication was escalated or adjusted in a timely manner for symptomatic monotherapy
or LAMA + LABA patients, a significant proportion of these hospital, specialist or
emergency room visits could be prevented.[1 ]
Benefits of early initiation of ICS
1 Considered in more detail in the discussion.
Table 5
General consensus statements on asthma and/or COPD
Consensus statement
Additional comments
Consequences of non-adherence to therapy
It was anticipated that for asthma patients with severe exacerbations use of rescue
medication could be reduced by 50 – 60 %
The improvement might be better in asthma than COPD, since the addition of the bronchodilator,
would increase the patient’s confidence that the agent was providing relief of their
condition.
There are a significant proportion of patients with either obstructive pulmonary disease
who cannot be specifically diagnosed as COPD or asthma, or with concomitant COPD/asthma.
This suggests initiating these patients on ICS/LABA combination treatment from the
outset in order to improve airway hyper-responsiveness, cough, wheezing and dyspnoea
most effectively, and to improve airflow
1 Considered in more detail in the discussion.
Consensus statements on COPD
The panellists agreed that significant proportion of their COPD patients on bronchodilator
therapy presented with exacerbations that would meet the guideline recommendations
for treatment escalation. It was agreed that initiation of combination ICS/LABA therapy
in a timely manner could reduce the risk of exacerbations and improve control, which
would lead to reduced health care utilisation in terms of additional specialist visits,
emergency room visits and hospitalisations ([Table 4 ]).
Consensus statements on adherence
The panellists agreed that poor compliance with ICS/LABA therapy resulted in worse
outcomes for asthma and COPD patients. It was agreed that use of a fixed-dose ICS/LABA
treatment could have a positive effect on adherence which may improve treatment outcomes
and reduce health care resource utilisation ([Table 5 ]).
Rejected statement
A general statement ‘There’s nothing better than a combination therapy if diagnosis is unclear ’ was felt to be correct for a number of cases of ICS/LABA therapy in obstructive
lung disease, but too general to be agreed upon overall.
Discussion
The guidelines of the NVL for asthma and COPD and the international GINA (asthma)
and GOLD (COPD) have been relatively conservative on when combination therapy should
be started, reasons for this include the desire to avoid overtreatment, with a consequent
risk of unwanted side effects. Indeed in both COPD and asthma, specific concerns have
been raised about the safety of combination therapy. Furthermore, unnecessary medications
add to the already considerable costs of treating these conditions. Against this must
be set the benefits of maintaining control of asthma, and reducing exacerbations in
COPD. The Delphi panel examined how ICS/LABA combination therapy is used in real-life
clinical practice in Germany, and how this usage accords with the conservative guideline
recommendations. The panel reached consensus on 24 of the 25 statements on the use
of ICS/LABA combination therapy and the results are presented in [Table 3 ], [Table 4 ], and [Table 5 ]. This discussion considers in more detail some of the key statements.
Use of ICS/LABA combination therapy in asthma
The panel reached a consensus that early initiation of ICS/LABA combination therapy
was appropriate when asthma patients on ICS monotherapy presented with exacerbations
or breathlessness. It was, however, important to take into account the severity of
exacerbations and, for example, a mild cough would not on its own be indicative of
a need for combination therapy. The panel estimated that around 25 % of their asthma
patients presented at the practice with signs or symptoms which suggested that ICS/LABA
combination therapy should have been initiated earlier according to the NVL or GINA
criteria. It was also agreed that such patients represented only a fraction of those
who might benefit from combination therapy and the panel estimated that around 20 – 50 %
of asthma patients with breathing, problems, exacerbations or infections fail to mention
them to their physician ([Table 3 ]). These estimates are in line with figures from the European National Health and
Wellness Survey, which estimated that around two-thirds of asthma patients in Germany
were uncontrolled [10 ]. The panel reached consensus that around 30 – 50 % of asthma patients experience
two to three asthma exacerbations each year and if these were moderate or severe ICS/LABA
combination therapy should be started. Interestingly, this is a very conservative
statement. Asthma guidelines suggest taking even mild exacerbations into account,
since it is hard to predict whether these may develop into potentially life-threatening
problems. They estimated that ICS/LABA therapy would reduce the rate of exacerbations
by up to 50 % and improve asthma control ([Table 3 ]). This is in line with clinical studies that have clearly demonstrated that the
addition of LABAs to a daily regimen of ICS in asthma patients reduces the number
of exacerbations [15 ]
[16 ]
[17 ]. It is worthwhile noting that the panellists favoured escalation by the addition
of LABAs, the option that was the minority recommendation, in the NVL guidelines,
while the option of doubling the ICS dose was not generally used [1 ].
The panel discussed the proposition of whether asthma could be considered as a progressive
disease, since long-term poor control and sustained inflammation, may lead to airway
remodelling and reduced bronchial reversibility. A consensus was reached that uncontrolled
asthma could be a progressive disease, but that well-controlled asthma, with ICS monotherapy
or if necessary with ICS/LABA combination therapy, would be likely to remain stable
for years ([Table 3 ]). Therefore, patients with asthma uncontrolled on ICS monotherapy should be initiated
on ICS/LABA early, that is as soon as it was apparent that control was inadequate.
While it is accepted that early diagnosis and effective control of asthma are likely
to reduce remodelling the mechanism is unclear. There is only limited evidence that
ICS reduces remodelling; a study by Ward et al. indicated that some reduction is seen
on high-dose corticosteroids, but other studies have shown little evidence [18 ]. Another recent suggestion is that sustained bronchoconstriction leads to remodelling,
which if this is the case would support the use of a LABA, in addition to the ICS,
if that is insufficient to maintain control.[19 ]
The guidelines suggest that after asthma patients have been controlled for 3 months,
consideration should be given to stepping down the dose, with the objective of maintaining
control on the lowest dosage levels feasible [4 ]
[8 ]. However, the panel agreed that stepping down to ICS monotherapy by asthma patients
stable on an ICS/LABA combination would lead to an increased risk of exacerbation,
and that around 50 % of patients stepped down to ICS monotherapy would experience
more exacerbations ([Table 3 ]). A study by Bateman et al. which compared the effects of reducing the dose of ICS
with that of stopping LABA in asthma patients maintained on combination therapy concluded
that control was better if the LABA was retained, while the ICS dose was stepped down
[20 ]. Another study by Reddel et al. also showed evidence of better maintenance of control
if LABA was continued while the ICS dose was reduced [21 ]. Part of the rationale for stepping down has been concerns about excess asthma mortality
on salmeterol, and in the USA the FDA has called for further studies on this risk
[22 ]. A meta-analysis of 215 studies has indicated that this risk is mitigated by concurrent
ICS therapy and there is no evidence that combination salmeterol/fluticasone propionate
therapy is associated with an increased risk [23 ]. While the panel was fully aware of the controversy, there was consensus that ICS/LABA
can be continued in the longer term because of the advantages of controlled asthma;
this may lead to reduced health care utilisation, for example, fewer physician visits.
Use of ICS/LABA combination therapy in COPD
For some years there was a degree of controversy over whether ICS were of benefit
to COPD patients in terms of efficacy, although controlled trials have shown reduced
exacerbations in COPD patients receiving ICS/LABA treatment [24 ]
[25 ]
[26 ]
[27 ]. A concern has been whether there is an increased risk of pneumonia associated with
ICS use. The issue of clinically, but not radiologically diagnosed pneumonia first
arose in a paper by Kardos et al. (2007), where the rate of pneumonia over the 44
weeks of the study was around three times higher in the ICS/LABA group than in the
LABA monotherapy group (23 vs. 7 cases) [24 ]. The TORCH investigators also reported, in a much larger study, an increased risk
of pneumonia with ICS in COPD patients [28 ]
[29 ]. Nonetheless, in both the Kardos and TORCH studies, addition of the ICS was associated
with a reduced risk of exacerbations [24 ]
[26 ]
[28 ]. Moreover, mortality in patients with pneumonia was no worse than among those with
exacerbations other than pneumonia. The panel agreed that in their practices cases
of pneumonia associated with the initiation of, or during the course of ICS treatment
were rare and that annually fewer than 1 % of their COPD patients developed overt
pneumonia ([Table 4 ]). This suggests that the increased risk of pneumonia, reported with ICS in COPD
patients, had not been observed in the real-life experience of the panel members.
The panel agreed that exacerbations would lead to a significant proportion of COPD
patients on LABA monotherapy or LABA + LAMA combination therapy requiring visits to
the emergency room, additional specialist visits or hospitalisation and that the risk
increased with disease severity ([Table 4 ]). The panel considered that combination treatment should be initiated in a timely
manner, as soon as practicable after the events, in patients with overt symptoms such
as breathlessness, coughing, or infection. There was consensus that initiating combination
therapy would be likely to produce a meaningful reduction in subsequent event, although
estimates of how many might be prevented ranged from 10 – 40 % ([Table 4 ]). It is interesting to note that the panel considered that decisions to escalate
to ICS/LABA would be made on both the basis of the history of exacerbations and symptoms,
with GOLD stage airflow limitation just as a supporting objective factor, rather than
only considering FEV1 and exacerbations.
Adherence to therapy and fixed-dose combination inhalers
An important issue in combination therapy is using a fixed-dose combination ICS/LABA
inhaler, rather than separate inhalers for each agent. One clear advantage would be
to improve both adherence to therapy and handling with likely consequent improvement
in clinical outcomes. The panel agreed that over a 12-month period, around 30 % of
patients with asthma or COPD on ICS/LABA therapy would visit an emergency room or
make extra visits to a specialist because of problems arising from non-adherence to
treatment, and that fixed-dose combination ICS/LABA therapy could improve adherence,
by 30 – 40 % ([Table 5 ]).
A number of factors may contribute to improved adherence with a single fixed-dose
combination device. The patient will only require one or two devices, including rescue
medication. Another factor agreed on by the panel is that there tends to be better
compliance with combination therapy with a single device; patients do not like taking
too many ‘drugs’. Moreover, asthma patients may tend to favour the inhaler that they
feel is providing directly perceptible relief, usually the bronchodilator – mainly
in the case of asthma, but to a lesser extent in COPD. Furthermore, a combination
device reduces the potential for asthma patients to miss their maintenance dose of
ICS. According to reimbursement restrictions, patients receiving ICS and LABA separately,
may be given different devices when their prescription are filled, without having
been trained on those devices. The co-payment for the fixed combination is lower,
if compared with two separate inhalers, which in the view of the panellists can play
an important role in the acceptance of the treatment.
Conclusion
Among a panel of ten physicians working in primary and secondary care consensus was
achieved on 24 out of 25 statements on the use of ICS/LABA combination therapy in
the management of asthma and COPD. Most of the statements are consistent with the
guidelines. However, early stopping of LABA treatment − as suggested by the FDA −
in asthmatics, recently stepped up to achieve asthma control was opposed. A more liberal,
symptoms- and exacerbations-based prescription of ICS/LABA combinations in COPD fits
well into the new GOLD document, published after this research was done. Moreover,
the agreed benefits of fixed dose ICS/LABA are congruent with both the German Society
of Pneumology asthma guidelines and the FDA recommendations for asthma treatment.
