Overall asthma control: The relationship between current control and

Overall asthma control: The relationship between current
control and future risk
€ ran Eriksson, MB, PhD,c,d Stefan Peterson, PhD,c
Eric D. Bateman, MD,a Helen K. Reddel, MBBS, PhD, FRACP,b Go
c
e
Ollie Östlund, PhD, Malcolm R. Sears, MB, FRACP, FRCPC, Christine Jenkins, MD, FRACP,b Marc Humbert, MD,g
Roland Buhl, MD,h Tim W. Harrison, MD,i Santiago Quirce, MD, PhD,j and Paul M. O’Byrne, MB, FRCP(C)f Cape Town,
South Africa, Sydney, Australia, Lund, Sweden, Hamilton, Ontario, Canada, Clamart, France, Mainz, Germany, Nottingham, United Kingdom,
and Madrid, Spain
Background: Asthma guidelines emphasize both maintaining
current control and reducing future risk, but the relationship
between these 2 targets is not well understood.
Objective: This retrospective analysis of 5 budesonide/
formoterol maintenance and reliever therapy (Symbicort
From athe Division of Pulmonology, Department of Medicine, University of Cape Town;
b
the Clinical Management Group, Woolcock Institute of Medical Research, Sydney;
c
AstraZeneca Research and Development, Lund; dthe Department of Respiratory
Medicine and Allergology, University Hospital, Lund; ethe Department of Medicine
and fthe Michael G. DeGroote School of Medicine, Faculty of Health Sciences,
McMaster University, Hamilton; gUniversité Paris-Sud 11, Service de Pneumologie
et Réanimation Respiratoire, Hôpital Antoine Béclère, APHP, Clamart; hthe Pulmonary Department, Mainz University Hospital, Mainz; ithe Respiratory Biomedical Research Unit, City Hospital Campus, Nottingham University, Nottingham; and jthe
Department of Allergy, Hospital La Paz, Comunidad Autónoma de Madrid, Madrid.
Supported by AstraZeneca AB, Lund, Sweden.
Disclosure of potential conflict of interest: E. D. Bateman is on advisory boards for and
has received speakers’ honoraria from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; is on advisory boards for Nycomed, Merck, ALK-Abelló, Hoffmann
la Roche (Data Safety Board), and Almirall/Forest Pharmaceuticals; and has received
research support from AstraZeneca, GlaxoSmithKline, Merck, Morris Pharmaceuticals, Pfizer, Replidyne Inc, Almirall, Aeras, and Eumedic Inc. P. M. O’Byrne is on
advisory boards for and has received speakers’ honoraria from AstraZeneca and
GlaxoSmithKline; is on advisory boards for Topigen, Wyeth, and Schering; and has
received research support from AstraZeneca, GlaxoSmithKline, Merck, Wyeth,
Schering, and Alexion. M. R. Sears holds a chair endowed by AstraZeneca; has
received consultation fees from AstraZeneca, Merck Frosst, and Schering-Plough; and
has received research support from GlaxoSmithKline. T. W. Harrison has received
honoraria from AstraZeneca and has received research support from GlaxoSmithKline
and Boehringer Ingelheim. R. Buhl has received speakers’ fees and consultants’ fees,
as well as reimbursement for attending scientific conferences from AstraZeneca, and
his department has received research support from the Deutsche Forschungsgemeinschaft, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and
Novartis. S. Quirce is on advisory boards for and has received speakers’ honoraria from
AstraZeneca and has received research support from Ciber de Enfermedades
Respiratorias (CIBERES), Madrid. G. Eriksson, S. Peterson, and O. Östlund are
employed by AstraZeneca. M. Humbert has consulted for Actelion, AstraZeneca,
Amgen, Chiesi, GlaxoSmithKline, MSD, Novartis, and Pfizer. C. Jenkins has received
speakers’ honoraria from GlaxoSmithKline, Novartis, and AstraZeneca and has
received research support from GlaxoSmithKline and AstraZeneca. H. K. Reddel is on
advisory boards for and has received research support from AstraZeneca and
GlaxoSmithKline and has received speakers’ honoraria from AstraZeneca, Getz
Pharma, and MerckSharp & Dohme.
Received for publication May 6, 2009; revised November 2, 2009; accepted for publication November 5, 2009.
Available online February 12, 2010.
Reprint requests: Eric D. Bateman, MD, Division of Pulmonology, Department of Medicine, University of Cape Town, George Street, Mowbray 7700, Cape Town, South
Africa. E-mail: [email protected].
0091-6749/$36.00
Ó 2010 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2009.11.033
600
SMART Turbuhaler*) studies assessed the relationship between
asthma control questionnaire (ACQ-5) and Global Initiative for
Asthma-defined clinical asthma control and future risk of
instability and exacerbations.
Methods: The percentage of patients with Global Initiative for
Asthma–defined controlled asthma over time was assessed for
budesonide/formoterol maintenance and reliever therapy versus
the 3 maintenance therapies; higher dose inhaled corticosteroid
(ICS), same dose ICS/long-acting b2-agonist (LABA), and
higher dose ICS/LABA plus short-acting b2-agonist. The
relationship between baseline ACQ-5 and exacerbations was
investigated. A Markov analysis examined the transitional
probability of change in control status throughout the studies.
Results: The percentage of patients achieving asthma control
increased with time, irrespective of treatment; the percentage
Controlled/Partly Controlled at study end was at least similar to
budesonide/formoterol maintenance and reliever therapy versus
the 3 maintenance therapies: higher dose ICS (56% vs 45%),
same dose ICS/LABA (56% vs 53%), and higher dose ICS/
LABA (54% vs 54%). Baseline ACQ-5 score correlated
positively with exacerbation rates. A Controlled or Partly
Controlled week predicted at least Partly Controlled asthma the
following week ($80% probability). The better the control, the
lower the risk of an Uncontrolled week. The probability of an
exacerbation was related to current state and was lower with
budesonide/formoterol maintenance and reliever therapy.
Conclusions: Current control predicts future risk of instability
and exacerbations. Budesonide/formoterol maintenance and
reliever therapy reduces exacerbations versus comparators and
achieves at least similar control. (J Allergy Clin Immunol
2010;125:600-8.)
Key words: Asthma control, ACQ, exacerbations, GINA
Recently published asthma guidelines1,2 and a recent Task Force
report by the American Thoracic Society/European Respiratory
Society3,4 recommend changes in the definition of and methods
for measuring asthma control. As in other chronic diseases, it is recognized that control of asthma involves current control and longterm components referred to as ‘‘risk’’1 or ‘‘future risk’’3 (Fig 1).
Current control (termed ‘‘impairment’’ in the National Asthma Education and Prevention Program guidelines [page 36]1) is the patient’s current and recent level of symptoms and functional
status. Longer-term components are the risk of exacerbations,
*Symbicort SMART and Turbuhaler are trademarks owned by AstraZeneca. Neither the
Symbicort SMART posology nor the dry powder formulation Turbuhaler are currently
approved in the United States.
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Abbreviations used
ACQ: Asthma Control Questionnaire
GINA: Global Initiative for Asthma
GOAL: Gaining Optimal Asthma ControL
ICS: Inhaled corticosteroid
LABA: Long-acting b2-agonist
mPEF: Morning peak expiratory flow
SABA: Short-acting b2-agonist
instability (repeated episodes of loss of control), permanent
impairment of lung function, and the adverse effects of treatment.
An important principle in the management of many chronic
diseases, such as diabetes and hypertension, is to ensure that specified
levels of current control are achieved to reduce the risk of future
complications. The possibility of a relationship between current
control and future risk in asthma has received little attention.5 Although exacerbation of asthma with potential hospitalization and
death is the most important future risk, unstable control representing
poorly controlled asthma is associated with significant impairment of
quality of life and psychosocial and economic consequences.6 In addition, some patients with asthma may have impaired lung development or accelerated loss of lung function through the process of what
is loosely termed ‘‘remodeling.’’ These observations suggest the need
to examine more closely the relationship between current control and
future risk in asthma.
The study of this relationship may take several forms. The
simplest approach is to examine the predictive value of single
clinical or demographic features of asthma observed at the beginning of the observation period (baseline) for a favorable treatment
outcome.7-12 For example, a low FEV1 has been shown to predict
risk of exacerbations in the subsequent year, whereas current smoking reduces the probability of patients achieving higher levels of
control.9,10 An approach more consistent with the concept of viewing current control as a composite of endpoints is to consider the relationship between control, assessed over a short period (1–4
weeks) by using recently developed and validated measures of control, and future risk.1,2 Such analyses may be performed using timedependent or time-independent methods. In the former, the relationship between current control, measured during a baseline observation period, with that achieved over a defined period is examined.
An example of this is a recent 1-year study in which current control
measured at the start of the study by using the Asthma Treatment
Assessment Questionnaire predicted the healthcare utilization and
quality of life better than any test of severity.6 With this approach,
the predictive value is influenced by both the dose and duration of
the treatment given during the observation period.13
In time-independent analyses, the probability of change in
control status (transitional probability) for different levels of
control is examined in isolated periods or epochs. The analysis
provides the probability that, based on a patient’s current level of
control, their control status may change (improve or worsen) in a
future epoch.5,13 This method has been used to examine the results of the Gaining Optimal Asthma ControL (GOAL) study.5
The probability of an exacerbation or loss of control (instability)
was shown to relate to the level of current control achieved during
the initial treatment escalation phase of the study and not to the
treatment received before or during the study period. The relationship was between the level of control achieved rather than the
treatment that achieved it, supporting the concept of aiming to
FIG 1. Goals of asthma management.
achieve higher levels of control in order to reduce future risk.
However, this concept needs further testing in different cohorts
of patients using other treatments and treatment approaches.
The use of the combination of budesonide and formoterol in a
single inhaler as maintenance and reliever therapy has been
approved in many countries, having been shown in several largescale randomized controlled trials to achieve similar current control
of asthma and to be superior to comparators in reducing asthma
exacerbations.14-18 The comparators in these studies were either a
higher maintenance dose of budesonide, or the same or higher maintenance doses of inhaled corticosteroid (ICS)/long-acting b2-agonists (LABAs) with a short-acting b2-agonist (SABA) as-needed
for relief, as was used in the GOAL study. The results of the budesonide/formoterol maintenance and reliever therapy studies provide
the opportunity both to confirm the relationships described in the
analysis of GOAL and to investigate whether the relationship between current control and future risk is altered by the different treatment approach (specifically, whether the levels of control achieved
are as high as those of comparators, and whether the probability of
transition to an exacerbation is reduced differentially by the different treatment approaches, and if so, whether this is true in all
subjects or only in those with lesser levels of control). We report
here a retrospective pooled analysis of 5 studies (all 6 or 12 months
in duration) that explores the relationship between current control,
defined by either a Global Initiative for Asthma (GINA) guidelinederived classification or the 5-item Asthma Control Questionnaire
(ACQ-5),19 and future risk of instability and exacerbations, and
whether the relationship between these components of control is
different in patients treated with budesonide/formoterol maintenance and reliever therapy. Both predictive and time-independent
methods are used to explore different aspects of this relationship.
METHODS
Studies and population
All long-term, double-blind, randomized, parallel-group clinical studies
(6–12 months in duration) investigating the efficacy of budesonide/formoterol
maintenance and reliever therapy (Symbicort SMART; AstraZeneca AB,
Lund, Sweden) with comparator therapies (higher maintenance dose budesonide plus a SABA as needed [higher maintenance dose ICS plus SABA],14,15
same maintenance dose budesonide/formoterol [Symbicort; AstraZeneca]
plus SABA as-needed [same maintenance dose ICS/LABA plus SABA]14,18
and higher maintenance dose budesonide/formoterol16 or salmeterol/fluticasone [Seretide; GlaxoSmithKline, Uxbridge, United Kingdom],16,17 plus a
SABA as needed [higher maintenance dose ICS/LABA plus SABA]) with
time to first severe exacerbation as primary endpoint were included in this retrospective analysis. Further details on each of these studies are provided in the
602 BATEMAN ET AL
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TABLE I. Baseline demographics
N
Male, n (%)
Age, y
ICS dose at entry, mg/d
LABA use at entry, %
Median asthma duration, y
FEV1, % predicted normal
As-needed inh/d
Symptom-free days, %
Night-time awakenings, %
Higher maintenance
dose ICS 1 SABA
Same maintenance
dose ICS/LABA 1 SABA
Higher maintenance
dose ICS/LABA 1 SABA
BUD/FORM maintenance
1 reliever therapy
1869
821 (44)
40 (4-80)
685 (100-2000)
35
11 (0-71)
71.6 (37-100)
2.2 (0-9.2)
16.7 (0-100)
22.1 (0-100)
2050
844 (41)
40 (4-83)
683 (200-1600)
45
10 (0-69)
72.3 (39-108)
2.1 (0-13.5)
17.1 (0-100)
25.9 (0-100)
3383
1376 (41)
38 (12-83)
738 (100-3200)
49
11 (0-77)
72.1 (30-222)
2.3 (0-10.8)
9.5 (0-100)
32.2 (0-100)
5246
2173 (41)
39 (4-89)
715 (160-2000)
47
11 (0-70)
71.7 (29-131)
2.1 (0-15.6)
12.8 (0-100)
28.8 (0-100)
BUD/FORM, Budesonide/formoterol; inh, inhalations.
Data are means (ranges) unless otherwise indicated. For the purpose of baseline demographics, all available data for each treatment group are pooled. For individual demographic
data, please see the following references: higher maintenance dose ICS plus SABA,14,15 same maintenance dose ICS/LABA plus SABA,14,18 higher maintenance dose ICS/LABA
plus SABA,16,17 and BUD/FORM maintenance and reliever therapy.14-18 For night-time awakenings, % is percentage of nights with awakenings.
Studies and Population section and Table E1 in this article’s Online Repository
at www.jacionline.org.
All studies were performed in accordance with the Declaration of Helsinki
and Good Clinical Practice guidelines and were approved by independent
ethics committees. Written informed consent was obtained from each adult
patient; for underage patients, informed consent from both the patient and the
patient’s legal guardian was obtained.
Assessments
Severe asthma exacerbations. A severe exacerbation was
defined as deterioration in asthma resulting in hospitalization/emergency
room treatment and/or oral steroid use. Two of the studies originally included a
fall in morning peak expiratory flow (mPEF) to 70% baseline on 2
consecutive days in the definition,14,15 but to harmonize, exacerbations based
only on a fall in mPEF were excluded when pooling the data.
Overall asthma control as defined by GINA criteria.
For each of the 5 studies, GINA-defined asthma control was determined for
each week of the study by evaluation of the exacerbation data and patient diary
card data: (1) night-time symptoms or awakenings/week (none allowed); (2)
daytime symptoms (2 d/wk); (3) reliever use (2 d/wk with up to 2
inhalations each day, or alternatively, up to 4 inhalations on 1 day during the
week); (4) mPEF (80% predicted normal before medication on every
morning of the week) and (5) freedom from activity limitation as determined
from daytime symptoms (daytime symptom score <2 on every day of the
week; see the Assessments section of the Online Repository at www.jacionline.
org for definition of scores). A week for any patient was considered Controlled
if, during that week, all 5 diary card subcriteria were controlled and no severe
exacerbation was recorded. The week was defined as Partly Controlled if any
1 or 2 of the subcriteria were uncontrolled and no exacerbation was recorded. If
the week had 3 uncontrolled subcriteria or an exacerbation, the week was
termed Uncontrolled. Control of subcriteria had to be positively demonstrated
by diary data; if not, subcriteria were considered Uncontrolled.
Asthma control as assessed by ACQ-5. In 3 studies
(budesonide/formoterol maintenance and reliever therapy vs same maintenance
dose ICS/LABA plus SABA18 and vs higher maintenance dose ICS/LABA plus
SABA16,17), the ACQ-5,19-21 a shortened version of 7-item Asthma Control
Questionnaire (ACQ-7),21,22 was self-assessed at clinic visits. The ACQ is a validated method for distinguishing different levels of asthma control19,20 recommended in asthma management guidelines.1,2 Each of the 5 questions on
symptom control were scored on a scale of 0 to 6, where 0 represents good control and 6, poor control. The overall score from the ACQ-5 was the mean of the 5
responses. For further details on the methodologies, please see the Methods section in this article’s Online Repository at www.jacionline.org.
Statistical analysis
Changes in asthma control over time. The proportion of
patients achieving Controlled or Partly Controlled asthma by GINA criteria
each week in the studies was plotted for budesonide/formoterol maintenance
and reliever therapy and the 3 comparators. Time courses for exacerbations
each week were also plotted.
The proportion of patients achieving asthma control over time based on
ACQ-5 cut-points, defined by the limits 0.50, 0.75, 1.00, 1.25, and 1.50, was
plotted for budesonide/formoterol maintenance and reliever therapy and the
comparators same maintenance dose ICS/LABA plus SABA and higher
maintenance dose ICS/LABA plus SABA. All plots were drawn using the Last
Value Extended principle to obtain the same number of patients each week, for
GINA control, or each visit, for ACQ cut-points.
Stability of asthma control: probability of changing
level of GINA-defined weekly control. Stability of asthma
control was assessed in a Markov analysis investigating transitional probability of change in control status (excluding exacerbations), as defined by
GINA. Results from all 5 studies were included in the Markov model5,13 to calculate the weekly transition probability between control states defined as the
probability of a patient, during the next week, moving from one level of control (Controlled, Partly Controlled, or Uncontrolled) to another or remaining at
the same level of control or experiencing an exacerbation. Transition probabilities, estimated by the observed transition frequencies, were tabulated and the
probabilities achieved with budesonide/formoterol maintenance and reliever
therapy compared with comparators. The odds of having an exacerbation
the week following a Controlled, Partly Controlled, or Uncontrolled week
were analyzed in a logistic regression model by using a generalized estimating
equation approach.
ACQ-5 at randomization as a predictor of exacerbations. Exacerbation data from all patients in the two 6-month studies
comparing budesonide/formoterol maintenance and reliever therapy versus
higher maintenance dose ICS/LABA plus SABA16,17 were pooled and the
mean number of exacerbations stratified according to ACQ-5 cut-points at randomization (before first dose of study medication). For a patient to be included
in these calculations, both an assessment of ACQ-5 at randomization and an
assessment of exacerbation status had to be available. The mean number of severe exacerbations over time, stratified by ACQ-5 cut-point at randomization,
was described by using Kaplan–Meier plots and a Poisson regression model.
For further details on the statistical analyses, see the Statistical Analysis
section of this article’s Online Repository at www.jacionline.org.
RESULTS
Studies and population
Baseline characteristics were comparable between the 4 treatment groups within this pooled analysis (Table I). At baseline, patients had a mean FEV1, percentage predicted normal of 71.6% to
72.3%; 35% to 49% of patients were using a LABA at entry.
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BATEMAN ET AL 603
FIG 2. Proportion of patients with Controlled and Controlled/Partly Controlled asthma by week according to
GINA criteria (A) and exacerbations (B), by week. Percentage of patients achieving Controlled (week with all
5 diary card subcriteria controlled and no severe exacerbations) and Controlled/Partly Controlled asthma
(week with no exacerbation and 2 subcriteria uncontrolled) by week (A); with 1 exacerbation requiring
medical intervention during the week (excluding peak expiratory flow) (B). Pooled data from higher maintenance dose ICS plus SABA,14,15 same maintenance dose ICS/LABA plus SABA,14,18 and higher maintenance dose ICS/LABA plus SABA.16,17 *P values refer to analyses at last week of treatment (end of
treatment). BUD/FORM, budesonide/formoterol.
Time course to achieve GINA control targets
The percentage of patients achieving a week of Controlled or
Controlled/Partly Controlled asthma, as defined by GINA criteria,
increased throughout the study periods, irrespective of treatment
used, although most of the increase occurred during the first 3 to 6
months (Fig 2, A). At the last week of study, 17.1% and 55.8% of
patients randomized to budesonide/formoterol maintenance and
reliever therapy achieved Controlled asthma and Controlled/
Partly Controlled asthma versus 12.2% and 45.0% of patients randomized to higher maintenance dose ICS plus SABA, respectively (P < .001; see this article’s Table E2 in the Online
Repository at www.jacionline.org). The percentage of patients
achieving Controlled or Controlled/Partly Controlled asthma
with budesonide/formoterol maintenance and reliever therapy at
study end was at least comparable to same maintenance dose
ICS/LABA plus SABA (Controlled, 17.4% vs 16.8%, P 5 .73;
Controlled/Partly Controlled, 55.7% vs 52.9%, P 5 .076) and
higher maintenance dose ICS/LABA plus SABA (Controlled,
17.8% vs 18.8%, P 5 .56; Controlled/Partly Controlled, 54.3%
vs 54.5%, P 5 .86). Similar trends were seen for the individual
diary card assessments (data not shown).
Exacerbation incidence remained similar over time during the
study for all treatments (Fig 2, B). Consistently for all weeks in
study, fewer patients in the budesonide/formoterol maintenance
and reliever therapy group tended to experience exacerbations requiring medical intervention versus all 3 comparator groups.
Time course of ACQ-5 improvement
In the one 12-month study, analysis of the proportion of
patients at each ACQ-5 cut-point over time indicated that more
patients reached better control over 12 months with no obvious
differences in the proportions of patients achieving various
ACQ-5 cut-points for higher levels of control on budesonide/
formoterol maintenance and reliever therapy versus same maintenance dose ICS/LABA plus SABA (Fig 3). For the two
6-month studies, similar numbers of patients showed improvement over time for budesonide/formoterol maintenance and
reliever therapy versus higher maintenance dose ICS/LABA
plus SABA (see Fig E1 in this article’s Online Repository at
www.jacionline.org). Overall, the data indicated that control
continued to improve over time, irrespective of treatments,
with increasing percentages of patients achieving higher levels
of control.
Probability of moving to or remaining at a given
level of GINA-defined weekly control status
Regardless of treatment group, patients with Controlled or
Partly Controlled asthma in any given week had a similar
(approximately 75%) estimated probability of remaining Controlled or Partly Controlled, respectively, the following week
(Table II). The probability of deteriorating to a lesser level of control (Partly Controlled or Uncontrolled, respectively) was
604 BATEMAN ET AL
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MARCH 2010
FIG 3. Proportion of patients below each ACQ-5 cut-point level over time, randomized to budesonide/
formoterol maintenance and reliever therapy (n 5 963 patients with a baseline ACQ-5 value and at least
1 value on treatment) versus same maintenance dose ICS/LABA plus SABA (n 5 984). Data from Rabe et al.18
BUD/FORM, budesonide/formoterol.
TABLE II. Transitional probability (%) of control status with pairwise comparison of treatments in any week according to GINA-defined
control status in the previous week
Control status in index week
C
Control status in
following week
P
U
C
Higher maintenance dose ICS 1 SABA
U
BUD/FORM maintenance and reliever therapy
C
P
U
75
19
6.0
Ex
0.18
0.33
0.92
Same maintenance dose ICS/LABA 1 SABA
75
8.1
1.8
73
13
19
0.14
0.20
0.59
BUD/FORM maintenance and reliever therapy
74
8.9
1.9
20
73
15
84
5.8
18
0.09
0.35
1.1
Higher maintenance dose ICS/LABA 1 SABA
74
10
2.3
71
15
20
82
5.7
18
0.18
0.31
0.98
5.9
18
83
0.16
0.20
0.49
BUD/FORM maintenance and reliever therapy
73
10
2.1
21
72
15
5.7
18
83
0.08
0.21
0.66
C
P
U
Ex
C
P
U
Ex
6.4
74
19
P
1.2
13
85
74
20
6.1
8.6
73
18
2.0
16
81
BUD/FORM, Budesonide/formoterol; C, Controlled; Ex, exacerbation; P, Partly Controlled; U, Uncontrolled.
Transitional probability of control status in any week (state in the left column) according to control status in the previous week (state in the top row) in patients randomized to higher
maintenance dose ICS plus SABA and BUD/FORM maintenance and reliever therapy,14,15 same maintenance dose ICS/LABA plus SABA and BUD/FORM maintenance and
reliever therapy,14,18 and higher maintenance dose ICS/LABA plus SABA and BUD/FORM maintenance and reliever therapy.16,17 Underlined data indicate the probability of
remaining in the current state in subsequent weeks.
approximately 20%. For Controlled asthma, the probability of being Uncontrolled the next week was approximately 6% for all
treatments. On the other hand, patients who were Partly Controlled or Uncontrolled in any week had a 6% to 16% chance of
improving (13% to 16% for Uncontrolled to Partly Controlled
and 6.4% to 10% from Partly Controlled to Controlled).
The estimated probability of having an exacerbation in any
week was higher the more uncontrolled the asthma was the
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TABLE III. Treatment comparison of probability of exacerbation for each of 3 treatments, in any week according to GINA-defined
control status in the previous week
BUD/FORM maintenance and reliever therapy versus
Higher maintenance dose
ICS 1 SABA*
C
P
U
Same maintenance dose
ICS/LABA 1 SABAy
Higher maintenance dose
ICS/LABA 1 SABAz
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
P value
0.77 (0.37-1.59)
0.61 (0.44-0.86)
0.64 (0.53-0.78)
.473
.004
<.001
1.8 (0.82-3.95)
0.57 (0.40-0.81)
0.46 (0.38-0.56)
.146
.002
<.001
0.48 (0.19-1.22)
0.69 (0.45-1.04)
0.69 (0.56-0.85)
.124
.074
<.001
The OR is the ratio of the probability of an exacerbation the following week in the budesonide/formoterol maintenance and reliever therapy arm and the probability of an exacerbation
the following week in the comparator arm.
Treatment comparison of exacerbation risk by control status in the previous week.
BUD/FORM, Budesonide/formoterol; C, Controlled; OR, odds ratio; P, Partly Controlled; U, Uncontrolled.
*O’Byrne et al,14 Scicchitano et al15: 168,586 weeks, 861 with exacerbation.
O’Byrne et al,14 Rabe et al18: 189,170 weeks, 964 with exacerbation.
àKuna et al,16 Bousquet et al17: 129,123 weeks, 713 with exacerbation.
previous week (Table II). Improved control gave similar risk reductions for all treatments, although the absolute risks differed
between treatments. The odds ratio for experiencing an exacerbation in subsequent weeks, for all treatments pooled, was 1.97
(95% CI, 1.53–2.54) for a Partly Controlled versus Controlled
week (P < .001) and 2.91 (95% CI, 2.59–3.28) for an Uncontrolled versus Partly Controlled week (P < .001), yielding an
odds ratio of 5.74 (95% CI, 4.52–7.29) for an Uncontrolled versus
Controlled week (P < .001).
While the probability of remaining Controlled or Partly Controlled was similar between treatments, the probability of experiencing an exacerbation differed (Table III). In the week following an
Uncontrolled week, the probability of an exacerbation was significantly lower in patients treated with budesonide/formoterol maintenance and reliever therapy versus all 3 comparator groups. A
significant risk reduction was also seen for budesonide/formoterol
maintenance and reliever therapy in patients who had in the previous week experienced a Partly Controlled week, except for the comparison with higher maintenance dose ICS/LABA plus SABA. The
number of exacerbations in the week following a Controlled week
was small (83 in total) and showed no clear treatment pattern.
ACQ-5 at randomization as a predictor of
exacerbation risk
The risk of exacerbations during treatment increased with
increasing ACQ-5 cut-point at randomization (see Fig E2 in this
article’s Online Repository at www.jacionline.org). The exacerbation rate was higher in patients with ACQ-5 0.75 versus patients
with an ACQ-5 <0.50 at randomization (P < .05). A marked increase in future risk of exacerbations was also observed for
ACQ-5 1.50 versus ACQ-5 <0.50 (0.36 events/patient/12 mo
[95% CI, 0.34–0.39] vs 0.13 events/patient/12 mo [95% CI,
0.09–0.20]; P < .001). Analysis of exacerbation rates by treatment
group and ACQ-5 stratum showed that the exacerbation rate
reduction for budesonide/formoterol maintenance and reliever
therapy versus higher maintenance dose ICS/LABA was 12%
for ACQ-5 <1.50 (P 5 .4) and 33% for ACQ-5 1.50 (P < .001).
DISCUSSION
The management of chronic diseases requires an approach to
both the current manifestations and the long-term effects of
disease. The focus of asthma management has shifted from
treatment of an acute disease to that of long-term control and
prevention of future risks. With improvements in controller
therapy, it is now recognized that highly satisfactory levels of
current control can be achieved and maintained for long periods.23 It is thus relevant to consider different strategies for maintaining control and to identify those that are most effective in
reducing future risk. The current study provides several useful
insights on both current control and future risk.
First, in the pooled analysis of 5 studies,14-18 the proportion of
patients achieving GINA-defined levels of Controlled/Partly Controlled asthma each week was approximately 10% higher with all
ICS/LABA combination regimens than with an ICS maintenance
dose alone. These findings are consistent with the results of the
GOAL study.23 However, the current study permitted a comparison of the proportion of patients achieving control with the
LABA-containing regimens involving regular maintenance dosing with ICS and LABA plus SABA for rescue as studied in
GOAL and budesonide/formoterol as both maintenance and reliever therapy. At equivalent maintenance doses of fixed-dose
ICS/LABA, the results were similar. Even doubling the maintenance dose did not improve control further; up to 60% achieved
at least Partly Controlled asthma and fewer than 20% achieved
Controlled asthma at study end. These results are similar in magnitude to those patients in Stratum 3 in the GOAL study who, at
study entry, were Uncontrolled on moderate doses of ICS.23
The analysis also confirms the value of sustained treatment in
the study cohorts, because the proportion of patients achieving
higher levels of both ACQ-5-defined and GINA-defined control
increased over time. Most improvement occurred within the first 3
months, but a further percentage of patients achieved higher levels
of control during sustained treatment.24,25 This benefit of sustained
treatment was reported in the GOAL study,23 but unlike that study,
in which treatment was increased at 3-monthly intervals, the current analysis demonstrated further improvement related to duration of treatment alone. This conclusion is supported by the
observation that patients who received a higher maintenance
dose of ICS/LABA plus SABA did not achieve better results.
Third, our analysis provides insights into the relationship
between current control and future risk. Current control at
randomization (ACQ-5 score) predicted risk of exacerbation
during the study. This finding is consistent with recent reports that
composite measures such as the Asthma Treatment Assessment
Questionnaire predict healthcare use and exacerbations.12,26
However, in our analysis, this relationship differed in patients
606 BATEMAN ET AL
receiving budesonide/formoterol maintenance and reliever therapy; in patients with an ACQ-5 score >1.50 at randomization,
this treatment resulted in a 33% lower exacerbation risk compared
with even those receiving higher maintenance dose ICS/LABA
plus SABA as needed (P < .001).
The analysis of week-by-week exacerbation rates also confirmed differences by treatment and treatment strategy. Although
fewer patients treated with the higher maintenance dose of ICS
alone (plus SABA) achieved control each week, the exacerbation
rate was similar to that in patients receiving the lower maintenance doses of fixed-dose ICS/LABA, confirming the efficacy of
high maintenance doses of ICS in lowering the risk of exacerbations. Increasing the fixed maintenance dose of ICS/LABA
reduced the rate of exacerbations further, but in all comparisons,
the greatest reduction was observed with budesonide/formoterol
maintenance and reliever therapy (a 54% reduction in exacerbations versus same maintenance dose ICS/LABA plus SABA;
P < .001; Table III).
These results, which suggest differences in the relationship
between current control and risk of exacerbations in different
treatment groups, are better understood by considering the results
of the Markov analysis, which provides the time-independent
probability of a patient’s status, or level of control, changing from
one week to another. Although the predictions apply to the week
that follows, the predictions are made on the basis of a very large
database (composed of more than 129,000 weeks of follow-up)
and may be used to estimate the probabilities for any week in the
future, although with increasing uncertainty. This method has
previously been used in a post hoc analysis of the results of the
GOAL study, in which the authors confirmed a negative relationship between the level of asthma control achieved and future risk
of instability, and demonstrated that the probability of becoming
Uncontrolled was inversely related to the level of control
achieved.5 Better stability was associated with reduced probability of unscheduled healthcare resource use and improved patient
quality of life. The authors concluded that these data supported
the guideline recommendation to aim for the highest level of
asthma control achievable as a strategy to reduce future risk of exacerbations. A limitation of their analysis, however, was a smaller
sample size and a relatively small number of exacerbations on
which these conclusions were made.5
The current analysis supports these general conclusions but
provides additional information. First, for all 4 treatment approaches, a high level of asthma control was associated with a
high probability of maintaining this level of control in future
weeks—that is, clinical stability—and the probability of control
status changing was similar between the treatments. Patients with a
Controlled week had a 94% probability of remaining Controlled or
Partly Controlled in other weeks of the study (Table II), regardless of
treatment category. Thus, stability is a feature of the level of control
achieved, regardless of the treatment that achieved it.5 Partly Controlled weeks were associated with a >80% probability of at least
Partly Controlled weeks in the future (Partly Controlled or Controlled) and a smaller probability of an Uncontrolled week—also
a highly satisfactory outcome of treatment. Again, in those achieving this, the probability did not differ with different treatments.
Furthermore, the Markov analysis confirmed that the better the
level of control, the lower the risk of having an exacerbation.
However, although the transitional probability of an exacerbation
was similarly low after a Controlled week, regardless of treatment, the probability differed between treatments in those who
J ALLERGY CLIN IMMUNOL
MARCH 2010
were only Partly Controlled or Uncontrolled. Compared with the
3 other treatment groups, budesonide/formoterol maintenance
and reliever therapy was associated with a reduced probability of
an exacerbation, confirming a selective benefit of the approach of
this component on future risk.
Although it demonstrates a strong relationship between current
control and exacerbation risk, the current analysis does not
provide an estimate of the amount of treatment-related improvement in current control that reduces the risk of an exacerbation in
individual patients. Use of a control measure such as the ACQ-5,
which expresses control as a continuous variable, would be more
responsive and suitable for an assessment of this than the GINA
classification, which is limited to 3 categories of control. In the
studies included in our analysis, the ACQ-5 was recorded on only
a few visits and in only some of the studies (3), whereas the GINA
levels of control were derived from daily diary card data for each
week in every study.
The fact that steady improvements in levels of asthma control
observed throughout the studies in all the treatment arms were not
associated with a further improvement in exacerbation risk
appears to be contradictory to the hypothesis that improved
current control is associated with reduced future risk. This may be
because the increase in control was gradual and slow, and the
reduction in exacerbations that followed might have been too
small for the trend to become apparent during the 6 to 12 months’
duration of the studies. Survival curves for time to first exacerbation in the individual studies indicate a clear trend for a
decreased risk over time. Most likely, patients with repeated
exacerbations (about a third of the exacerbating patients) diminish this signal, and studies of 2 to 3 years’ duration would be
needed to assess such an effect.
The apparent limit or ceiling effect of the treatments used on
the achievement of current control in around 40% of the patients
included in these studies reflects the relatively refractory nature of
their asthma and the limitations of the treatments used. The
inclusion criteria selected patients with Uncontrolled asthma in
spite of regular treatment with ICS 6 LABA. It was thus not
surprising that many would fail to achieve guideline-based goals
of treatment. It was, however, surprising that 40% to 50% were
Uncontrolled at the end of the study. Their refractoriness is further
illustrated in the Markov analysis, which revealed that an
Uncontrolled week is highly likely to be followed by further
Uncontrolled weeks (>80% probability; see Table II), regardless
of treatment. Clearly, such patients represent a cohort of severe
asthma with a high risk of exacerbations and require additional
treatments. However, it is gratifying to note that, even in these patients, the risk of exacerbations was significantly reduced by the
use of budesonide/formoterol maintenance and reliever therapy;
in fact, the largest benefit of this approach was seen in this group.
In this analysis, we have followed the approach recommended
in recent guidelines of defining current asthma control from a
clinical symptom-based perspective supplemented by measures
of lung function and expressed this as a composite.6,12,26,27 Studies evaluating the relative predictive roles of these measures are
limited but agree that although a symptom-based measure of
control may be adequate for the majority of patients, discordance
between current control and future risk is evident in many
patients and may vary according to the treatment given.28-31 In
these circumstances, and particularly in relatively treatmentrefractory patients, measures that reflect other elements of the
condition—bronchial hyperresponsiveness and markers of
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 3
airway inflammation (eg, levels of exhaled nitric oxide32 and
eosinophils in induced sputum33,34)—may be instructive.
These findings have several practical implications. The data
support the recommendation that having a high level of current
control improves stability and reduces the risk of exacerbations
while on a regimen that includes an ICS. In some treatments, for
example, use of regular maintenance doses of LABA or SABA
therapy alone might promote a ‘‘high level of current control’’
without also improving stability and the risk of exacerbations.29,30
Thus, although variability is a hallmark of Uncontrolled asthma,
Controlled asthma may be stable for long periods—an important
message for patients and physicians. The results also confirm the
higher proportion of patients that achieve Controlled asthma with
ICS/LABA maintenance treatment compared with a higher maintenance dose of ICS. Furthermore, the results support the importance of sustained treatment, because additional patients,
particularly those who entered these studies with a poor level of
control and regardless of treatment regimen, continued to improve beyond 6 months. Finally, the data support the additional
benefit of budesonide/formoterol maintenance and reliever therapy on exacerbations. Although exacerbation frequency continues to relate to level of control, a further reduction is
achieved, presumably because of the timely administration of budesonide/formoterol when used for relief. The data also suggest
that increasing the dose of maintenance ICS/LABA therapy to
produce maximal levels of control is not sufficient to provide
optimal outcomes for exacerbations.
This analysis has several limitations. It is a post hoc analysis in
which the GINA control classification variables obtained from diary cards were analyzed retrospectively. In addition, the activity
limitation question was based on a general symptom question
rather than specific enquiry. A further limitation is that the patients recruited in these studies represent the more severe end of
the asthma spectrum. This might explain the relatively large proportion of patients that remained Uncontrolled during the studies.
Prospective studies that also include steroid-naive patients and
controlled patients on lower doses of ICS are required to test these
relationships between current control achieved and future risk.
In the current analysis, we have not attempted to study other
aspects of future risk such as lung function decline (for which the
data are not adequate) or the adverse effects of treatment. In
general, the latter were mild, but a consistent favorable feature
was the significantly lower exposure to systemic corticosteroids,
and in some studies, ICS in the budesonide/formoterol maintenance and reliever therapy group. This, over time, may result in a
diminished risk of adverse outcomes.
In conclusion, this analysis provides new insights on the
relationship between current control and future risk, which
together represent overall asthma control. Treatment with budesonide/formoterol maintenance and reliever therapy further reduces exacerbations and achieves at least similar current control
compared with comparator therapies.
Editorial assistance was provided by Dr Jessica Sample from MediTech
Media Ltd, who provided medical writing assistance on behalf of AstraZeneca.
Clinical implications: The use of budesonide/formoterol as
maintenance and reliever therapy achieves at least similar current control and greater reductions in exacerbations, reflecting
better overall asthma control.
BATEMAN ET AL 607
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ALLERGY ARCHIVES
INNER CITY ASTHMA, ENDEMIC COCKROACH
INFESTATION
Harry Bernton (1885-1979), MD, of Howard University and Washington’s
Provident and Freedman’s Hospitals allergy clinics, noted the prevalence of asthma
in populations within the lowest social and economic strata. His observation led to
his consideration that inhalant route allergenicity of flying insects (May fly, sand
fly, mushroom fly) might have an indigenous indoor insect counterpart. In 1964,
with Halla Brown (1911-1993), MD, of George Washington University, they undertook a controlled study of households that revealed endemic cockroach infestation
and contamination of inadequately protected food. Dead insects, their feces, and
vomitus were demonstrated to be sources of allergens. In Bernton and Brown’s
study, seven and five-tenths percent of 253 normal persons showed positive skin
tests with extracts of cockroaches, compared with 28 percent of an unselected
group of 114 allergic patients. Skin-sensitizing antibodies were present in the blood
sera of skin test positive reactors and cockroach allergen had the capacity to
provoke constitutional reactions in these reactors. Since cockroaches contaminate
food substances, they concluded that derivative allergens, whether ingestant or
inhalant, should be given critical consideration. Accordingly, they recommended
the advisability of adding cockroach extract to the routine tests of allergic patients
as indicated.
Bernton HS, Brown H. Insect allergy—Preliminary studies of the cockroach.
J Allergy 1964;35:506-13.
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 3
BATEMAN ET AL 608.e1
METHODS
Studies and population
Assessments
Overall asthma control as defined by GINA criteria.
All long-term, double-blind, randomized, parallel-group clinical studies
(6–12 months in duration) investigating the efficacy of budesonide/formoterol
maintenance and reliever therapy (Symbicort SMART; AstraZeneca AB, Lund,
Sweden) with comparator therapies (higher maintenance dose budesonide plus
a SABA as needed [higher maintenance dose ICS plus SABA],E1,E2 same
maintenance dose budesonide/formoterol [Symbicort; AstraZeneca] plus
SABA as-needed [same maintenance dose ICS/LABA plus SABA]E1,E3 and
higher maintenance dose budesonide/formoterolE4 or salmeterol/fluticasone
[Seretide; GlaxoSmithKline, Uxbridge, United Kingdom] plus SABA asneeded [higher maintenance dose ICS/LABA plus SABA]E4,E5 were included
in this retrospective analysis. The 1 exception was the study by Rabe et alE6 (budesonide/formoterol maintenance and reliever therapy vs higher maintenance
dose budesonide plus SABA as needed), which had mPEF as the primary variable. Further detail on each of these studies is summarized in Table E1. The
methodologies of the 5 studies have been published in detail previously.E1-E5
Two 12-month studies by O’Byrne et alE1 and Scicchitano et alE2 compared
budesonide/formoterol maintenance and reliever therapy (80/4.5 mg twice
daily [BID]E1 and 160/4.5 mg 2 inhalations once dailyE2) with higher maintenance dose budesonide (Pulmicort; AstraZeneca; 320 mg BID,E1 160 mg 2 inhalations BIDE2) plus terbutaline as needed (Bricanyl; AstraZeneca; 0.4 mg/
inhalation). In a third 12-month study by Rabe et al,E3 and in a further treatment arm in the study by O’Byrne et al,E1 the comparator arm was the same
maintenance dose of ICS/LABA as used in the budesonide/formoterol maintenance and reliever therapy arm (budesonide/formoterol: 160/4.5 mg BIDE3
and 80/4.5 mg BID,E1 respectively) plus formoterol 4.5 mg (Oxis; AstraZeneca)E3 or terbutaline (0.4 mg)E1,3 as needed. Only data from the terbutaline
as-needed arm were included in the current analysis; data from the formoterol
as-needed arm were excluded. Data from two 6-month studies that compared
budesonide/formoterol maintenance and reliever therapy (160/4.5 mg BIDE4
and 160/4.5 mg 2 inhalations BIDE5) with a higher maintenance dose ICS in
combination with LABA (Kuna et alE4: budesonide/formoterol 320/9 mg
BID or salmeterol/fluticasone 25/125 mg 2 inhalations BID; Bousquet et
alE5: salmeterol/fluticasone 50/500 mg BID) plus terbutaline (0.4 mg/inhalation) were also pooled. All aforementioned drugs were administered via Turbuhaler (AstraZeneca) except for salmeterol/fluticasone, which was delivered
via either DiskusE5 or EvohalerE4 (GlaxoSmithKline).
The inclusion and exclusion criteria in each of these studies were similar. In
general, male and female patients aged 12 years with a diagnosis of asthma
were eligible for inclusion if they had a history of 1 asthma exacerbation in 12
months before study entry, use of ICS 3 months before study entry, FEV1
50% of predicted normal (prebronchodilator), and 12% reversibility in increase from baseline FEV1 15 minutes after inhalation of terbutaline 1 mg (Bricanyl Turbuhaler; AstraZeneca). For patients age 18 years, an increase in
basal FEV1 200 mL after inhalation of terbutaline 1 mg was required at study
entry.E2,3 Exclusion criteria included any respiratory infection affecting the
patient’s asthma or use of oral corticosteroids within 1 month of study entry.
The primary endpoint of all 5 studies was time to first severe exacerbation,
defined as deterioration in asthma resulting in hospitalization/emergency room
treatment and/or oral steroid use. In addition, 2 of the studies originally included
a fall in mPEF to 70% baseline on 2 consecutive days in the definition.E1,2 To
harmonize, exacerbations based only on a fall in mPEF were excluded when
pooling the data. Secondary measures included the rate of severe exacerbations
and measures of daily asthma control from daily diaries, which included homemonitored PEF, reliever use, asthma symptoms, and nights with awakenings
caused by asthma symptoms. Daytime and night-time asthma symptom scores,
graded on a scale of 0 to 3 (where 0 5 no symptoms; 1 5 aware of symptoms but
can easily tolerate them; 2 5 asthma causing enough discomfort to cause problems with normal activities/sleep; 3 5 unable to do normal activities/sleep because of asthma), were also recorded in the daily diaries.
All studies were performed in accordance with the Declaration of Helsinki
and Good Clinical Practice guidelines and were approved by independent
ethics committees. Written informed consent was obtained from each adult
patient; for underage patients, informed consent from both the patient and the
patient’s legal guardian was obtained.
For each of the 5 studies, GINA-defined asthma control was determined for
each week of the study by evaluation of the exacerbation data and patient diary
card data: (1) night-time symptoms or awakenings/week (none allowed); (2)
daytime symptoms ( 2 d/wk); (3) reliever use (2 d/wk with up to 2
inhalations each day, or alternatively, up to 4 inhalations on 1 day during the
week); (4) mPEF (80% predicted normal before medication on every
morning of the week); and (5) freedom from activity limitation as determined
from daytime symptoms (daytime symptom score <2 on every day of the week
where 0 5 no asthma symptoms; 1 5 aware of asthma symptoms but can
easily tolerate them; 2 5 asthma causes enough discomfort to cause problems
with normal activities; 3 5 unable to do normal activities because of
symptoms).
A week for any patient was considered Controlled if, during that week, all 5
of the diary card subcriteria were controlled and no severe exacerbation was
recorded. The week was defined as Partly Controlled if any 1 or 2 of the
subcriteria were uncontrolled and no exacerbation was recorded. If the week
had 3 Uncontrolled subcriteria and/or an exacerbation, the week was termed
Uncontrolled. Control of subcriteria had to be positively demonstrated by
diary data; if not, subcriteria were considered Uncontrolled.
Asthma control as assessed by ACQ-5. In 3 studies
(budesonide/formoterol maintenance and reliever therapy vs same maintenance dose ICS/LABA plus SABAE3 and vs higher maintenance dose ICS/
LABA plus SABAE4,E5), the ACQ-5,E7-E9 a shortened version of the
ACQ-7,E8,E10 was self-assessed at clinic visits. The ACQ is a validated method
for distinguishing different levels of asthma controlE7,E9 recommended in
asthma management guidelines.E11,E12 Because ACQ-5 data were collected
in these studies, these data were used in this retrospective pooled analysis
and analyzed for their value in predicting achievement of control and asthma
exacerbations. It is important to note that the ACQ-5 is a widely used clinical
measure of asthma control and provides very similar outcomes to the ACQ-7,
which includes 2 additional questions concerning reliever use and lung
function.E8,E10
Each of the 5 questions on symptom control were scored on a scale of 0 to 6,
where 0 represents good control and 6, poor control. The overall score from the
ACQ-5 was the mean of the 5 responses.
Statistical analysis
Changes in asthma control over time. The proportion of
patients achieving Controlled or Partly Controlled asthma by GINA criteria
each week in the studies was plotted for the budesonide/formoterol maintenance and reliever therapy arm and the 3 comparators. Time courses for
exacerbations each week were also plotted. The proportion of patients
achieving asthma control over time on the basis of ACQ-5 cut-points, defined
by the limits 0.50, 0.75, 1.00, 1.25, and 1.50, was plotted for budesonide/
formoterol maintenance and reliever therapy and the comparators same
maintenance dose ICS/LABA plus SABA and higher maintenance dose ICS/
LABA plus SABA. All plots were drawn by using the Last Value Extended
principle to obtain the same number of patients each week for GINA control,
or each week for ACQ-5 cut-points, thus allowing for withdrawals and missing
data. Incomplete last weeks were removed together with weeks ending with
the last recorded day, because that day generally did not contain evening data.
The baseline week (week 0) was taken to be the 7 days up to the day before
randomization, whereas week 1 started with the day after randomization. Last
Value Extended was also used when assessing the percentage of patients with
ACQ-5 below different cut-points at different visits.
For each of the outcomes, the number of patients who were Controlled, and
the number of patients who were at least Partly Controlled in their last week in
study, was analyzed by using logistic regression with treatment and study as
factors.
Stability of asthma control: probability of changing
level of GINA-defined weekly control. Stability of asthma
control was assessed in a Markov analysis investigating transitional probability of change in control status (excluding exacerbations) as defined by
608.e2 BATEMAN ET AL
GINA. ACQ data that were not measured every week were not included in the
Markov analysis. Results from all 5 studies were included in the Markov
modelE13,E14 to calculate the weekly transition probability between control
states defined as the probability of a patient, during the next week, moving
from one level of control (Controlled, Partly Controlled, or Uncontrolled) to
another or remaining at the same level of control or experiencing an exacerbation. Transition probabilities, estimated by the observed transition frequencies, were tabulated and the probabilities achieved with budesonide/
formoterol maintenance and reliever therapy compared with comparators.
The Markov model is a form of time series model in which the response is discrete and independent of time. The predictions provided relate to the week that
follows. However, the calculations are based on data collected from all weeks
in these 6-month or 12-month studies, and although more complex patterns
may apply, the Markov model may be used to estimate the probability of control for any pattern and for any week in the future.
To assess the impact of control state, treatment, and interaction on the risk of
exacerbation the following week, the outcome ‘‘exacerbation in week/no
exacerbation in week’’ was modeled with a logistic regression model with
factors treatment, previous control state (Controlled, Partly Controlled, or
Uncontrolled), treatment–control interaction, and study. Weeks with ongoing
exacerbation were removed from the analysis, and the model was fitted by using
a generalized estimating equation approach under a working independence
assumption. The results were stable under other choices of working covariance
structures. To obtain treatment comparisons between budesonide/formoterol
maintenance and reliever therapy and comparators, based on concurrent data
while avoiding an excessive number of model parameters, a separate analysis
was performed for each of the 3 comparators on a subset of the data.
To obtain a pooled estimate over all studies and treatments of the impact of
control state on exacerbation risk, the same data (all arms in all studies) were
analyzed by using a similar model with factors previous control state,
treatment, and study.
As an estimate of the transition probability from one weekly control state to
another, the fraction of classified weeks with each previous state that
transitioned to each following state was calculated for each comparator and
each set of concurrent budesonide/formoterol maintenance and reliever
therapy data. Weeks were classified as GINA Controlled, Partly Controlled,
or Uncontrolled, or a week with an exacerbation.
ACQ-5 at randomization as a predictor of
exacerbations. Exacerbation data from all patients in the two 6-month
studies comparing budesonide/formoterol maintenance and reliever therapy
versus higher maintenance dose ICS/LABA plus SABAE4,E5 were pooled and
the mean number of exacerbations stratified according to ACQ-5 cut-points at
randomization (before the first dose of study medication). For a patient to be
included in these calculations, both an assessment of ACQ-5 at randomization
and an assessment of exacerbation status had to be available.
J ALLERGY CLIN IMMUNOL
MARCH 2010
The mean number of severe exacerbations over time, stratified by ACQ-5
cut-point at randomization, was described by using Kaplan–Meier plots and a
Poisson regression model, with adjustments performed for the study factor and
overdispersion.
REFERENCES
E1. O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171:129-36.
E2. Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher
dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004;20:
1403-18.
E3. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-53.
E4. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE, et al.
Effect of budesonide/formoterol maintenance and reliever therapy on asthma
exacerbations. Int J Clin Pract 2007;61:725-36.
E5. Bousquet J, Boulet LP, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar
NE, et al. Budesonide/formoterol for maintenance and relief in uncontrolled
asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007;101:2437-46.
E6. Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T, et al.
Budesonide/formoterol in a single inhaler for maintenance and relief in mildto-moderate asthma: a randomized, double-blind trial. Chest 2006;129:246-56.
E7. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7.
E8. Juniper EF, Svensson K, M€ork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir
Med 2005;99:553-8.
E9. Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘‘well-controlled’’ and
‘‘not well-controlled’’asthma using the Asthma Control Questionnaire. Respir
Med 2006;100:616-21.
E10. Svensson K, Mork AC, Juniper EF. ACQ—is five out of seven items acceptable in
large clinical studies? Qual Life Res 2003;12:771. Abstract 1276.
E11. NAEPP (National Asthma Education and Prevention Program). Expert Panel report 3: guidelines for the diagnosis and management of asthma. 2007. Available
at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed January
11, 2010.
E12. Global Initiative for Asthma (GINA). Global strategy for asthma management
and prevention: NHLBI/WHO Workshop Report. Bethesda: National Institutes
of Health, National Heart, Lung and Blood Institute. Updated 2008. Available
at: http://www.ginasthma.com. Accessed January 11, 2010.
E13. Bateman ED, Bousquet J, Busse WW, Clark TJ, Gul N, Gibbs M, et al. Stability
of asthma control with regular treatment: an analysis of the Gaining Optimal
Asthma controL (GOAL) study. Allergy 2008;63:932-8.
E14. Combescure C, Chanez P, Saint-Pierre P, Daures JP, Proudhon H, Godard P. Assessment of variations in control of asthma over time. Eur Respir J 2003;22:298-304.
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VOLUME 125, NUMBER 3
BATEMAN ET AL 608.e3
FIG E1. Proportion of patients below each ACQ-5 cut-point level over time, randomized to budesonide/
formoterol maintenance and reliever therapy (n 5 2173 patients with a baseline ACQ-5 value and at least
1 value on treatment) versus higher maintenance dose ICS/LABA plus SABA (n 5 3246). Data from Kuna
et alE4 and Bousquet et al.E5 BUD/FORM, budesonide/formoterol.
608.e4 BATEMAN ET AL
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MARCH 2010
FIG E2. Future risk of exacerbations using ACQ-5 at randomization as a predictor. Mean number of
exacerbations over time stratified by ACQ-5 at randomization. Data pooled from all patients randomized to
budesonide/formoterol maintenance and reliever therapy or higher maintenance dose ICS/LABA plus
SABA (n 5 5480).E4,E5 ACQ-5 <0.50, n 5 355; ACQ-5 0.50–<0.75, n 5 250; ACQ-5 0.75–<1.00, n 5 261;
ACQ-5 1.00–<1.25, n 5 686; ACQ-5 1.25–<1.50, n 5 345; ACQ-5 1.50, n 5 3583.
BATEMAN ET AL 608.e5
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VOLUME 125, NUMBER 3
TABLE E1. Summary of the budesonide/formoterol maintenance and reliever therapy clinical trials used in this retrospective analyses
Study duration
Study intervention
Comparison with higher maintenance dose ICS therapy plus SABA
12 mo
BUD/FORM maintenance 1 reliever
O’Byrne et alE1
(80/4.5 mg BID 1 as needed)
BUD (320 mg BID) plus SABA
12 mo
BUD/FORM maintenance 1 reliever
Scicchitano et alE2
(2 3 160/4.5 mg QD 1 as needed)
BUD (2 3 160 mg BID) plus SABA
Comparison with same maintenance dose ICS/LABA therapy plus SABA
12 mo
BUD/FORM maintenance 1 reliever
O’Byrne et alE1
(80/4.5 mg BID 1 as needed)
BUD/FORM (80/4.5 mg BID) plus SABA
12 mo
BUD/FORM maintenance 1 reliever
Rabe et alE3
(160/4.5 mg BID 1 as needed)
BUD/FORM (160/4.5 mg BID) plus
relieverà
Comparison with higher maintenance dose ICS/LABA therapy plus SABA
6 mo
BUD/FORM maintenance 1 reliever
Kuna et alE4
(160/4.5 mg BID 1 as needed)
BUD/FORM (320/9 mg BID) plus SABA
SAL/FLU (2 3 25/125 mg BID) plus SABA
6 mo
BUD/FORM maintenance 1 reliever
Bousquet et alE5
(2 3 160/4.5 mg BID 1 as needed)
SAL/FLU (50/500 mg BID) plus SABA
No. of patients
Mean ICS mg/d (BDP equivalent)*y
925
240 (375)
926
947
640 (1000)
466 (728)
943
640 (1000)
925
240 (375)
909
1113
160 (250)
483 (755)
2281
320 (500)
1107
483 (755)
1105
1123
1154
640 (1000)
500 (1000)
792 (1238)
1155
1000 (2000)
BDP, Beclomethasone dipropionate; BID, twice daily; BUD, budesonide; FLU, fluticasone; FORM, formoterol; QD, once daily; SAL, salmeterol.
In patients on BUD/FORM maintenance and reliever therapy, the additional mean dose of ICS taken as needed as recorded in the patient diary has been added to the regular daily
dose.
*Microgram dose of ICS is stated as prescribed regular daily dose.
Mean ICS doses converted to BDP equivalents based on GINA guidelines.E12
àOnly data from the terbutaline as-needed arm were included in the present analysis (n 5 1141); data from the formoterol as-needed arm (n 5 1140) were excluded.
608.e6 BATEMAN ET AL
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MARCH 2010
TABLE E2. Treatment odds ratios for being Controlled and at least Partly Controlled, according to GINA criteria, last week in study
BUD/FORM maintenance and reliever therapy versus
Higher maintenance dose
ICS 1 SABA*
Control status
C
C/P
Same maintenance dose
ICS/LABA 1 SABAy
Higher maintenance dose
ICS/LABA 1 SABAz
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
P value
1.44 (1.20-1.74)
1.56 (1.37-1.78)
<.001
<.001
1.03 (0.87-1.21)
1.12 (0.99-1.27)
.73
.076
0.96 (0.83-1.10)
0.99 (0.89-1.10)
.56
.86
BUD/FORM, Budesonide/formoterol; C, Controlled; C/P, Partly Controlled; OR, odds ratio.
The OR is the ratio of the probability of being C or at least C/P in the BUD/FORM maintenance and reliever therapy arm and the probability of being C or least C/P in the
comparator arm.
*O’Byrne et al,E1 Scicchitano et alE2: N 5 3681.
O’Byrne et al,E1 Rabe et alE3: N 5 4054.
àKuna et al,E4 Bousquet et alE5: N 5 5586.