Overall asthma control: The relationship between current control and future risk

Overall asthma control: The relationship between currentcontrol and future risk

Eric D. Bateman, MD,a Helen K. Reddel, MBBS, PhD, FRACP,b G€oran Eriksson, MB, PhD,c,d Stefan Peterson, PhD,c

Ollie Ostlund, PhD,c Malcolm R. Sears, MB, FRACP, FRCPC,e 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 maintainingcurrent control and reducing future risk, but the relationshipbetween 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;bthe Clinical Management Group, Woolcock Institute of Medical Research, Sydney;cAstraZeneca 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; gUniversite Paris-Sud 11, Service de Pneumologie

et Reanimation Respiratoire, Hopital Antoine Beclere, APHP, Clamart; hthe Pulmo-

nary Department, Mainz University Hospital, Mainz; ithe Respiratory Biomedical Re-

search Unit, City Hospital Campus, Nottingham University, Nottingham; and jthe

Department of Allergy, Hospital La Paz, Comunidad Autonoma 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 Boeh-

ringer Ingelheim; is on advisory boards for Nycomed, Merck, ALK-Abello, Hoffmann

la Roche (Data Safety Board), and Almirall/Forest Pharmaceuticals; and has received

research support from AstraZeneca, GlaxoSmithKline, Merck, Morris Pharmaceuti-

cals, 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 Forschungsgemein-

schaft, 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. Ostlund 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 publica-

tion November 5, 2009.

Available online February 12, 2010.

Reprint requests: Eric D. Bateman, MD, Division of Pulmonology, Department of Med-

icine, University of Cape Town, George Street, Mowbray 7700, Cape Town, South

Africa. E-mail: [email protected].

0091-6749/$36.00

� 2010 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2009.11.033

600

SMART Turbuhaler*) studies assessed the relationship betweenasthma control questionnaire (ACQ-5) and Global Initiative forAsthma-defined clinical asthma control and future risk ofinstability and exacerbations.Methods: The percentage of patients with Global Initiative forAsthma–defined controlled asthma over time was assessed forbudesonide/formoterol maintenance and reliever therapy versusthe 3 maintenance therapies; higher dose inhaled corticosteroid(ICS), same dose ICS/long-acting b2-agonist (LABA), andhigher dose ICS/LABA plus short-acting b2-agonist. Therelationship between baseline ACQ-5 and exacerbations wasinvestigated. A Markov analysis examined the transitionalprobability of change in control status throughout the studies.Results: The percentage of patients achieving asthma controlincreased with time, irrespective of treatment; the percentageControlled/Partly Controlled at study end was at least similar tobudesonide/formoterol maintenance and reliever therapy versusthe 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 correlatedpositively with exacerbation rates. A Controlled or PartlyControlled week predicted at least Partly Controlled asthma thefollowing week ($80% probability). The better the control, thelower the risk of an Uncontrolled week. The probability of anexacerbation was related to current state and was lower withbudesonide/formoterol maintenance and reliever therapy.Conclusions: Current control predicts future risk of instabilityand exacerbations. Budesonide/formoterol maintenance andreliever therapy reduces exacerbations versus comparators andachieves at least similar control. (J Allergy Clin Immunol2010;125:600-8.)

Key words: Asthma control, ACQ, exacerbations, GINA

Recently published asthma guidelines1,2 and a recent Task Forcereport by the American Thoracic Society/European RespiratorySociety3,4 recommend changes in the definition of and methodsfor measuring asthma control. As in other chronic diseases, it is rec-ognized that control of asthma involves current control and long-term components referred to as ‘‘risk’’1 or ‘‘future risk’’3 (Fig 1).Current control (termed ‘‘impairment’’ in the National Asthma Ed-ucation and Prevention Program guidelines [page 36]1) is the pa-tient’s current and recent level of symptoms and functionalstatus. 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.

mailto:[email protected]

J ALLERGY CLIN IMMUNOL

VOLUME 125, NUMBER 3

BATEMAN ET AL 601

Abbreviations used

ACQ: A
sthma Control Questionnaire
GINA: G
lobal Initiative for Asthma
GOAL: G
aining Optimal Asthma ControL
ICS: In
haled corticosteroid
LABA: L
ong-acting b2-agonist
mPEF: M
orning peak expiratory flow
SABA: S
hort-acting b2-agonist
FIG 1. Goals of asthma management.

instability (repeated episodes of loss of control), permanentimpairment of lung function, and the adverse effects of treatment.

An important principle in the management of many chronicdiseases, such as diabetes and hypertension, is to ensure that specifiedlevels of current control are achieved to reduce the risk of futurecomplications. The possibility of a relationship between currentcontrol and future risk in asthma has received little attention.5 Al-though exacerbation of asthma with potential hospitalization anddeath is the most important future risk, unstable control representingpoorly controlled asthma is associated with significant impairment ofquality of life and psychosocial and economic consequences.6 In ad-dition, some patients with asthma may have impaired lung develop-ment or accelerated loss of lung function through the process of whatis loosely termed ‘‘remodeling.’’ These observations suggest the needto examine more closely the relationship between current control andfuture risk in asthma.

The study of this relationship may take several forms. Thesimplest approach is to examine the predictive value of singleclinical or demographic features of asthma observed at the begin-ning of the observation period (baseline) for a favorable treatmentoutcome.7-12 For example, a low FEV1 has been shown to predictrisk of exacerbations in the subsequent year, whereas current smok-ing reduces the probability of patients achieving higher levels ofcontrol.9,10 An approach more consistent with the concept of view-ing current control as a composite of endpoints is to consider the re-lationship between control, assessed over a short period (1–4weeks) by using recently developed and validated measures of con-trol, and future risk.1,2 Such analyses may be performed using time-dependent or time-independent methods. In the former, the relation-ship between current control, measured during a baseline observa-tion period, with that achieved over a defined period is examined.An example of this is a recent 1-year study in which current controlmeasured at the start of the study by using the Asthma TreatmentAssessment Questionnaire predicted the healthcare utilization andquality of life better than any test of severity.6 With this approach,the predictive value is influenced by both the dose and duration ofthe treatment given during the observation period.13

In time-independent analyses, the probability of change incontrol status (transitional probability) for different levels ofcontrol is examined in isolated periods or epochs. The analysisprovides the probability that, based on a patient’s current level ofcontrol, their control status may change (improve or worsen) in afuture epoch.5,13 This method has been used to examine the re-sults 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 duringthe initial treatment escalation phase of the study and not to thetreatment received before or during the study period. The relation-ship was between the level of control achieved rather than thetreatment that achieved it, supporting the concept of aiming to

achieve higher levels of control in order to reduce future risk.However, this concept needs further testing in different cohortsof patients using other treatments and treatment approaches.

The use of the combination of budesonide and formoterol in asingle inhaler as maintenance and reliever therapy has beenapproved in many countries, having been shown in several large-scale randomized controlled trials to achieve similar current controlof asthma and to be superior to comparators in reducing asthmaexacerbations.14-18 The comparators in these studies were either ahigher maintenance dose of budesonide, or the same or higher main-tenance doses of inhaled corticosteroid (ICS)/long-acting b2-ago-nists (LABAs) with a short-acting b2-agonist (SABA) as-neededfor relief, as was used in the GOAL study. The results of the bude-sonide/formoterol maintenance and reliever therapy studies providethe opportunity both to confirm the relationships described in theanalysis of GOAL and to investigate whether the relationship be-tween current control and future risk is altered by the different treat-ment approach (specifically, whether the levels of control achievedare as high as those of comparators, and whether the probability oftransition to an exacerbation is reduced differentially by the differ-ent treatment approaches, and if so, whether this is true in allsubjects or only in those with lesser levels of control). We reporthere a retrospective pooled analysis of 5 studies (all 6 or 12 monthsin duration) that explores the relationship between current control,defined by either a Global Initiative for Asthma (GINA) guideline-derived classification or the 5-item Asthma Control Questionnaire(ACQ-5),19 and future risk of instability and exacerbations, andwhether the relationship between these components of control isdifferent in patients treated with budesonide/formoterol mainte-nance and reliever therapy. Both predictive and time-independentmethods are used to explore different aspects of this relationship.

METHODS

Studies and populationAll 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 budeso-

nide 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/flutica-

sone [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 ret-

rospective analysis. Further details on each of these studies are provided in the

TABLE I. Baseline demographics

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

N 1869 2050 3383 5246

Male, n (%) 821 (44) 844 (41) 1376 (41) 2173 (41)

Age, y 40 (4-80) 40 (4-83) 38 (12-83) 39 (4-89)

ICS dose at entry, mg/d 685 (100-2000) 683 (200-1600) 738 (100-3200) 715 (160-2000)

LABA use at entry, % 35 45 49 47

Median asthma duration, y 11 (0-71) 10 (0-69) 11 (0-77) 11 (0-70)

FEV1, % predicted normal 71.6 (37-100) 72.3 (39-108) 72.1 (30-222) 71.7 (29-131)

As-needed inh/d 2.2 (0-9.2) 2.1 (0-13.5) 2.3 (0-10.8) 2.1 (0-15.6)

Symptom-free days, % 16.7 (0-100) 17.1 (0-100) 9.5 (0-100) 12.8 (0-100)

Night-time awakenings, % 22.1 (0-100) 25.9 (0-100) 32.2 (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.


MARCH 2010

602 BATEMAN ET AL

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.

AssessmentsSevere 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 val-

idated method for distinguishing different levels of asthma control19,20 recom-

mended 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 con-

trol 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 sec-

tion in this article’s Online Repository at www.jacionline.org.

Statistical analysisChanges 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 proba-

bility of change in control status (excluding exacerbations), as defined by

GINA. Results from all 5 studies were included in the Markov model5,13 to cal-

culate the weekly transition probability between control states defined as the

probability of a patient, during the next week, moving from one level of con-

trol (Controlled, Partly Controlled, or Uncontrolled) to another or remaining at

the same level of control or experiencing an exacerbation. Transition probabil-

ities, 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 exacerba-

tions. 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 ran-

domization (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 se-

vere 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 populationBaseline characteristics were comparable between the 4 treat-

ment groups within this pooled analysis (Table I). At baseline, pa-tients had a mean FEV1, percentage predicted normal of 71.6% to72.3%; 35% to 49% of patients were using a LABA at entry.

http://www.jacionline.org





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 main-

tenance dose ICS plus SABA,14,15 same maintenance dose ICS/LABA plus SABA,14,18 and higher mainte-

nance dose ICS/LABA plus SABA.16,17 *P values refer to analyses at last week of treatment (end of

treatment). BUD/FORM, budesonide/formoterol.



BATEMAN ET AL 603

Time course to achieve GINA control targetsThe 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 treatmentused, although most of the increase occurred during the first 3 to 6months (Fig 2, A). At the last week of study, 17.1% and 55.8% ofpatients randomized to budesonide/formoterol maintenance andreliever therapy achieved Controlled asthma and Controlled/Partly Controlled asthma versus 12.2% and 45.0% of patients ran-domized to higher maintenance dose ICS plus SABA, respec-tively (P < .001; see this article’s Table E2 in the OnlineRepository at www.jacionline.org). The percentage of patientsachieving Controlled or Controlled/Partly Controlled asthmawith budesonide/formoterol maintenance and reliever therapy atstudy end was at least comparable to same maintenance doseICS/LABA plus SABA (Controlled, 17.4% vs 16.8%, P 5 .73;Controlled/Partly Controlled, 55.7% vs 52.9%, P 5 .076) andhigher 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 individualdiary card assessments (data not shown).

Exacerbation incidence remained similar over time during thestudy for all treatments (Fig 2, B). Consistently for all weeks instudy, fewer patients in the budesonide/formoterol maintenanceand reliever therapy group tended to experience exacerbations re-quiring medical intervention versus all 3 comparator groups.

Time course of ACQ-5 improvementIn the one 12-month study, analysis of the proportion of

patients at each ACQ-5 cut-point over time indicated that morepatients reached better control over 12 months with no obviousdifferences in the proportions of patients achieving variousACQ-5 cut-points for higher levels of control on budesonide/formoterol maintenance and reliever therapy versus same main-tenance dose ICS/LABA plus SABA (Fig 3). For the two6-month studies, similar numbers of patients showed improve-ment over time for budesonide/formoterol maintenance andreliever therapy versus higher maintenance dose ICS/LABAplus SABA (see Fig E1 in this article’s Online Repository atwww.jacionline.org). Overall, the data indicated that controlcontinued to improve over time, irrespective of treatments,with increasing percentages of patients achieving higher levelsof control.

Probability of moving to or remaining at a given

level of GINA-defined weekly control statusRegardless of treatment group, patients with Controlled or

Partly Controlled asthma in any given week had a similar(approximately 75%) estimated probability of remaining Con-trolled or Partly Controlled, respectively, the following week(Table II). The probability of deteriorating to a lesser level of con-trol (Partly Controlled or Uncontrolled, respectively) was



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 P U C P U

Control status in

following week Higher maintenance dose ICS 1 SABA BUD/FORM maintenance and reliever therapy

C 75 6.4 1.2 74 8.6 2.0

P 19 74 13 20 73 16

U 6.0 19 85 6.1 18 81

Ex 0.18 0.33 0.92 0.14 0.20 0.59

Same maintenance dose ICS/LABA 1 SABA BUD/FORM maintenance and reliever therapy

C 75 8.1 1.8 74 8.9 1.9

P 19 73 13 20 73 15

U 5.8 18 84 5.9 18 83

Ex 0.09 0.35 1.1 0.16 0.20 0.49

Higher maintenance dose ICS/LABA 1 SABA BUD/FORM maintenance and reliever therapy

C 74 10 2.3 73 10 2.1

P 20 71 15 21 72 15

U 5.7 18 82 5.7 18 83

Ex 0.18 0.31 0.98 0.08 0.21 0.66

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.


MARCH 2010

604 BATEMAN ET AL

approximately 20%. For Controlled asthma, the probability of be-ing Uncontrolled the next week was approximately 6% for alltreatments. On the other hand, patients who were Partly Con-trolled or Uncontrolled in any week had a 6% to 16% chance of

improving (13% to 16% for Uncontrolled to Partly Controlledand 6.4% to 10% from Partly Controlled to Controlled).

The estimated probability of having an exacerbation in anyweek was higher the more uncontrolled the asthma was the

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*

Same maintenance dose

ICS/LABA 1 SABAy


ICS/LABA 1 SABAzOR (95% CI) P value OR (95% CI) P value OR (95% CI) P value

C 0.77 (0.37-1.59) .473 1.8 (0.82-3.95) .146 0.48 (0.19-1.22) .124

P 0.61 (0.44-0.86) .004 0.57 (0.40-0.81) .002 0.69 (0.45-1.04) .074

U 0.64 (0.53-0.78) <.001 0.46 (0.38-0.56) <.001 0.69 (0.56-0.85) <.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.

�Kuna et al,16 Bousquet et al17: 129,123 weeks, 713 with exacerbation.



BATEMAN ET AL 605

previous week (Table II). Improved control gave similar risk re-ductions for all treatments, although the absolute risks differedbetween treatments. The odds ratio for experiencing an exacerba-tion in subsequent weeks, for all treatments pooled, was 1.97(95% CI, 1.53–2.54) for a Partly Controlled versus Controlledweek (P < .001) and 2.91 (95% CI, 2.59–3.28) for an Uncon-trolled versus Partly Controlled week (P < .001), yielding anodds ratio of 5.74 (95% CI, 4.52–7.29) for an Uncontrolled versusControlled week (P < .001).

While the probability of remaining Controlled or Partly Con-trolled was similar between treatments, the probability of experi-encing an exacerbation differed (Table III). In theweek following anUncontrolled week, the probability of an exacerbation was signifi-cantly lower in patients treated with budesonide/formoterol mainte-nance and reliever therapy versus all 3 comparator groups. Asignificant risk reduction was also seen for budesonide/formoterolmaintenance and reliever therapy in patients who had in the previ-ous week experienced a Partly Controlled week, except for the com-parison with higher maintenance dose ICS/LABA plus SABA. Thenumber of exacerbations in the week following a Controlled weekwas small (83 in total) and showed no clear treatment pattern.

ACQ-5 at randomization as a predictor of

exacerbation riskThe risk of exacerbations during treatment increased with

increasing ACQ-5 cut-point at randomization (see Fig E2 in thisarticle’s Online Repository at www.jacionline.org). The exacerba-tion rate was higher in patients with ACQ-5� 0.75 versus patientswith an ACQ-5 <0.50 at randomization (P < .05). A marked in-crease in future risk of exacerbations was also observed forACQ-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 treatmentgroup and ACQ-5 stratum showed that the exacerbation ratereduction for budesonide/formoterol maintenance and relievertherapy 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).

DISCUSSIONThe management of chronic diseases requires an approach to

both the current manifestations and the long-term effects ofdisease. The focus of asthma management has shifted from

treatment of an acute disease to that of long-term control andprevention of future risks. With improvements in controllertherapy, it is now recognized that highly satisfactory levels ofcurrent control can be achieved and maintained for long pe-riods.23 It is thus relevant to consider different strategies for main-taining control and to identify those that are most effective inreducing future risk. The current study provides several usefulinsights on both current control and future risk.

First, in the pooled analysis of 5 studies,14-18 the proportion ofpatients achieving GINA-defined levels of Controlled/Partly Con-trolled asthma each week was approximately 10% higher with allICS/LABA combination regimens than with an ICS maintenancedose alone. These findings are consistent with the results of theGOAL study.23 However, the current study permitted a compari-son of the proportion of patients achieving control with theLABA-containing regimens involving regular maintenance dos-ing with ICS and LABA plus SABA for rescue as studied inGOAL and budesonide/formoterol as both maintenance and re-liever therapy. At equivalent maintenance doses of fixed-doseICS/LABA, the results were similar. Even doubling the mainte-nance dose did not improve control further; up to 60% achievedat least Partly Controlled asthma and fewer than 20% achievedControlled asthma at study end. These results are similar in mag-nitude to those patients in Stratum 3 in the GOAL study who, atstudy entry, were Uncontrolled on moderate doses of ICS.23

The analysis also confirms the value of sustained treatment inthe study cohorts, because the proportion of patients achievinghigher levels of both ACQ-5-defined and GINA-defined controlincreased over time. Most improvement occurred within the first 3months, but a further percentage of patients achieved higher levelsof control during sustained treatment.24,25 This benefit of sustainedtreatment was reported in the GOAL study,23 but unlike that study,in which treatment was increased at 3-monthly intervals, the cur-rent analysis demonstrated further improvement related to dura-tion of treatment alone. This conclusion is supported by theobservation that patients who received a higher maintenancedose of ICS/LABA plus SABA did not achieve better results.

Third, our analysis provides insights into the relationshipbetween current control and future risk. Current control atrandomization (ACQ-5 score) predicted risk of exacerbationduring the study. This finding is consistent with recent reports thatcomposite measures such as the Asthma Treatment AssessmentQuestionnaire predict healthcare use and exacerbations.12,26

However, in our analysis, this relationship differed in patients



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606 BATEMAN ET AL

receiving budesonide/formoterol maintenance and reliever ther-apy; in patients with an ACQ-5 score >1.50 at randomization,this treatment resulted in a 33% lower exacerbation risk comparedwith even those receiving higher maintenance dose ICS/LABAplus SABA as needed (P < .001).

The analysis of week-by-week exacerbation rates also con-firmed differences by treatment and treatment strategy. Althoughfewer patients treated with the higher maintenance dose of ICSalone (plus SABA) achieved control each week, the exacerbationrate was similar to that in patients receiving the lower mainte-nance doses of fixed-dose ICS/LABA, confirming the efficacy ofhigh maintenance doses of ICS in lowering the risk of exacerba-tions. Increasing the fixed maintenance dose of ICS/LABAreduced the rate of exacerbations further, but in all comparisons,the greatest reduction was observed with budesonide/formoterolmaintenance and reliever therapy (a 54% reduction in exacerba-tions versus same maintenance dose ICS/LABA plus SABA;P < .001; Table III).

These results, which suggest differences in the relationshipbetween current control and risk of exacerbations in differenttreatment groups, are better understood by considering the resultsof the Markov analysis, which provides the time-independentprobability of a patient’s status, or level of control, changing fromone week to another. Although the predictions apply to the weekthat follows, the predictions are made on the basis of a very largedatabase (composed of more than 129,000 weeks of follow-up)and may be used to estimate the probabilities for any week in thefuture, although with increasing uncertainty. This method haspreviously been used in a post hoc analysis of the results of theGOAL study, in which the authors confirmed a negative relation-ship between the level of asthma control achieved and future riskof instability, and demonstrated that the probability of becomingUncontrolled was inversely related to the level of controlachieved.5 Better stability was associated with reduced probabil-ity of unscheduled healthcare resource use and improved patientquality of life. The authors concluded that these data supportedthe guideline recommendation to aim for the highest level ofasthma control achievable as a strategy to reduce future risk of ex-acerbations. A limitation of their analysis, however, was a smallersample size and a relatively small number of exacerbations onwhich these conclusions were made.5

The current analysis supports these general conclusions butprovides additional information. First, for all 4 treatment ap-proaches, a high level of asthma control was associated with ahigh probability of maintaining this level of control in futureweeks—that is, clinical stability—and the probability of controlstatus changing was similar between the treatments. Patients with aControlled week had a 94% probability of remaining Controlled orPartly Controlled inother weeks of the study (Table II), regardless oftreatment category. Thus, stability is a feature of the level of controlachieved, regardless of the treatment that achieved it.5 Partly Con-trolled weeks were associated with a >80% probability of at leastPartly Controlled weeks in the future (Partly Controlled or Con-trolled) and a smaller probability of an Uncontrolled week—alsoa highly satisfactory outcome of treatment. Again, in those achiev-ing this, the probability did not differ with different treatments.

Furthermore, the Markov analysis confirmed that the better thelevel of control, the lower the risk of having an exacerbation.However, although the transitional probability of an exacerbationwas similarly low after a Controlled week, regardless of treat-ment, the probability differed between treatments in those who

were only Partly Controlled or Uncontrolled. Compared with the3 other treatment groups, budesonide/formoterol maintenanceand reliever therapy was associated with a reduced probability ofan exacerbation, confirming a selective benefit of the approach ofthis component on future risk.

Although it demonstrates a strong relationship between currentcontrol and exacerbation risk, the current analysis does notprovide an estimate of the amount of treatment-related improve-ment in current control that reduces the risk of an exacerbation inindividual patients. Use of a control measure such as the ACQ-5,which expresses control as a continuous variable, would be moreresponsive and suitable for an assessment of this than the GINAclassification, which is limited to 3 categories of control. In thestudies included in our analysis, the ACQ-5 was recorded on onlya few visits and in only some of the studies (3), whereas the GINAlevels of control were derived from daily diary card data for eachweek in every study.

The fact that steady improvements in levels of asthma controlobserved throughout the studies in all the treatment arms were notassociated with a further improvement in exacerbation riskappears to be contradictory to the hypothesis that improvedcurrent control is associated with reduced future risk. This may bebecause the increase in control was gradual and slow, and thereduction in exacerbations that followed might have been toosmall for the trend to become apparent during the 6 to 12 months’duration of the studies. Survival curves for time to first exacer-bation in the individual studies indicate a clear trend for adecreased risk over time. Most likely, patients with repeatedexacerbations (about a third of the exacerbating patients) dimin-ish this signal, and studies of 2 to 3 years’ duration would beneeded to assess such an effect.

The apparent limit or ceiling effect of the treatments used onthe achievement of current control in around 40% of the patientsincluded in these studies reflects the relatively refractory nature oftheir asthma and the limitations of the treatments used. Theinclusion criteria selected patients with Uncontrolled asthma inspite of regular treatment with ICS 6 LABA. It was thus notsurprising that many would fail to achieve guideline-based goalsof treatment. It was, however, surprising that 40% to 50% wereUncontrolled at the end of the study. Their refractoriness is furtherillustrated in the Markov analysis, which revealed that anUncontrolled week is highly likely to be followed by furtherUncontrolled weeks (>80% probability; see Table II), regardlessof treatment. Clearly, such patients represent a cohort of severeasthma with a high risk of exacerbations and require additionaltreatments. However, it is gratifying to note that, even in these pa-tients, the risk of exacerbations was significantly reduced by theuse 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 recommendedin recent guidelines of defining current asthma control from aclinical symptom-based perspective supplemented by measuresof lung function and expressed this as a composite.6,12,26,27 Stud-ies evaluating the relative predictive roles of these measures arelimited but agree that although a symptom-based measure ofcontrol may be adequate for the majority of patients, discordancebetween current control and future risk is evident in manypatients and may vary according to the treatment given.28-31 Inthese circumstances, and particularly in relatively treatment-refractory patients, measures that reflect other elements of thecondition—bronchial hyperresponsiveness and markers of



BATEMAN ET AL 607

airway inflammation (eg, levels of exhaled nitric oxide32 andeosinophils in induced sputum33,34)—may be instructive.

These findings have several practical implications. The datasupport the recommendation that having a high level of currentcontrol improves stability and reduces the risk of exacerbationswhile on a regimen that includes an ICS. In some treatments, forexample, use of regular maintenance doses of LABA or SABAtherapy 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 importantmessage for patients and physicians. The results also confirm thehigher proportion of patients that achieve Controlled asthma withICS/LABA maintenance treatment compared with a higher main-tenance dose of ICS. Furthermore, the results support the impor-tance of sustained treatment, because additional patients,particularly those who entered these studies with a poor level ofcontrol and regardless of treatment regimen, continued to im-prove beyond 6 months. Finally, the data support the additionalbenefit of budesonide/formoterol maintenance and reliever ther-apy on exacerbations. Although exacerbation frequency con-tinues to relate to level of control, a further reduction isachieved, presumably because of the timely administration of bu-desonide/formoterol when used for relief. The data also suggestthat increasing the dose of maintenance ICS/LABA therapy toproduce maximal levels of control is not sufficient to provideoptimal outcomes for exacerbations.

This analysis has several limitations. It is a post hoc analysis inwhich the GINA control classification variables obtained from di-ary cards were analyzed retrospectively. In addition, the activitylimitation question was based on a general symptom questionrather than specific enquiry. A further limitation is that the pa-tients recruited in these studies represent the more severe end ofthe asthma spectrum. This might explain the relatively large pro-portion of patients that remained Uncontrolled during the studies.Prospective studies that also include steroid-naive patients andcontrolled patients on lower doses of ICS are required to test theserelationships between current control achieved and future risk.

In the current analysis, we have not attempted to study otheraspects of future risk such as lung function decline (for which thedata are not adequate) or the adverse effects of treatment. Ingeneral, the latter were mild, but a consistent favorable featurewas the significantly lower exposure to systemic corticosteroids,and in some studies, ICS in the budesonide/formoterol mainte-nance and reliever therapy group. This, over time, may result in adiminished risk of adverse outcomes.

In conclusion, this analysis provides new insights on therelationship between current control and future risk, whichtogether represent overall asthma control. Treatment with bude-sonide/formoterol maintenance and reliever therapy further re-duces exacerbations and achieves at least similar current controlcompared 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 asmaintenance and reliever therapy achieves at least similar cur-rent control and greater reductions in exacerbations, reflectingbetter overall asthma control.

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), MD, of Howard University and Washington’s spitals allergy clinics, noted the prevalence of asthma est social and economic strata. His observation led to

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useholds that revealed endemic cockroach infestation uately protected food. Dead insects, their feces, and to be sources of allergens. In Bernton and Brown’s percent of 253 normal persons showed positive skin aches, compared with 28 percent of an unselected

. Skin-sensitizing antibodies were present in the blood actors and cockroach allergen had the capacity to

ons in these reactors. Since cockroaches contaminate uded that derivative allergens, whether ingestant or itical consideration. Accordingly, they recommended ckroach extract to the routine tests of allergic patients

t allergy—Preliminary studies of the cockroach.

LERGY ARCHIVES

THMA, ENDEMIC COCKROACH INFESTATION



BATEMAN ET AL 608.e1

METHODS

Studies and populationAll 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 as-

needed [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 (bu-

desonide/formoterol maintenance and reliever therapy vs higher maintenance

dose budesonide plus SABA as needed), which had mPEF as the primary vari-

able. 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 mainte-

nance dose budesonide (Pulmicort; AstraZeneca; 320 mg BID,E1 160 mg 2 in-

halations 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 treat-

ment 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 main-

tenance 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; Astra-

Zeneca)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/inhala-

tion) were also pooled. All aforementioned drugs were administered via Tur-

buhaler (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 in-

crease from baseline FEV1 15 minutes after inhalation of terbutaline 1 mg (Bri-

canyl 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 home-

monitored 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 prob-

lems with normal activities/sleep; 3 5 unable to do normal activities/sleep be-

cause 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.

AssessmentsOverall 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

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).

Aweek 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 mainte-

nance 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 analysisChanges 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 mainte-

nance 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 proba-

bility of change in control status (excluding exacerbations) as defined by

REFERENCES

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desonide/formoterol combination therapy as both maintenance and reliever med-

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ficacy and safety of budesonide/formoterol single inhaler therapy versus a higher

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exacerbations. Int J Clin Pract 2007;61:725-36.

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NE, et al. Budesonide/formoterol for maintenance and relief in uncontrolled

asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007;101:2437-46.

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MARCH 2010

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 exacerba-

tion. Transition probabilities, estimated by the observed transition frequen-

cies, 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 dis-

crete 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 con-

trol 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.

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.

http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

http://www.ginasthma.com

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.




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.


MARCH 2010


TABLE E1. Summary of the budesonide/formoterol maintenance and reliever therapy clinical trials used in this retrospective analyses

Study duration Study intervention No. of patients Mean ICS mg/d (BDP equivalent)*y

Comparison with higher maintenance dose ICS therapy plus SABA

O’Byrne et alE1 12 mo BUD/FORM maintenance 1 reliever

(80/4.5 mg BID 1 as needed)

925 240 (375)

BUD (320 mg BID) plus SABA 926 640 (1000)

Scicchitano et alE2 12 mo BUD/FORM maintenance 1 reliever

(2 3 160/4.5 mg QD 1 as needed)

947 466 (728)

BUD (2 3 160 mg BID) plus SABA 943 640 (1000)

Comparison with same maintenance dose ICS/LABA therapy plus SABA

O’Byrne et alE1 12 mo BUD/FORM maintenance 1 reliever


925 240 (375)

BUD/FORM (80/4.5 mg BID) plus SABA 909 160 (250)

Rabe et alE3 12 mo BUD/FORM maintenance 1 reliever


1113 483 (755)

BUD/FORM (160/4.5 mg BID) plus

reliever�2281 320 (500)

Comparison with higher maintenance dose ICS/LABA therapy plus SABA

Kuna et alE4 6 mo BUD/FORM maintenance 1 reliever


1107 483 (755)

BUD/FORM (320/9 mg BID) plus SABA 1105 640 (1000)

SAL/FLU (2 3 25/125 mg BID) plus SABA 1123 500 (1000)

Bousquet et alE5 6 mo BUD/FORM maintenance 1 reliever

(2 3 160/4.5 mg BID 1 as needed)

1154 792 (1238)

SAL/FLU (50/500 mg BID) plus SABA 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

�Only 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.




TABLE E2. Treatment odds ratios for being Controlled and at least Partly Controlled, according to GINA criteria, last week in study

Control status

BUD/FORM maintenance and reliever therapy versus


ICS 1 SABA*

Same maintenance dose

ICS/LABA 1 SABAy


ICS/LABA 1 SABAzOR (95% CI) P value OR (95% CI) P value OR (95% CI) P value

C 1.44 (1.20-1.74) <.001 1.03 (0.87-1.21) .73 0.96 (0.83-1.10) .56

C/P 1.56 (1.37-1.78) <.001 1.12 (0.99-1.27) .076 0.99 (0.89-1.10) .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.

�Kuna et al,E4 Bousquet et alE5: N 5 5586.


MARCH 2010


Overall asthma control: The relationship between current control and future risk

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