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Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation
Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation Eli O. Meltzer, MD,a William W. Busse, MD,b Sally E. Wenzel, MD,c Vasily Belozeroff, PhD,d Haoling H. Weng, MD, MHS,d JingYuan Feng, MS,d Yun Chon, PhD,d Chiun-Fang Chiou, PhD,d Denise Globe, PhD,d and Shao-Lee Lin, MD, PhDd San Diego and Thousand Oaks, Calif, Madison, Wis, and Pittsburgh, Pa Background: Direct correlation of assessments of a validated composite measure such as the Asthma Control Questionnaire (ACQ) and risk of exacerbation has not been previously demonstrated in a randomized controlled trial. Objective: To evaluate the ability of the ACQ score over time to predict risk of a future asthma exacerbation. Methods: This analysis included data from a 12-week placebocontrolled trial (N 5 292) of AMG 317, an IL-4 receptor a antagonist, in patients with moderate to severe atopic asthma. _1.5. Exacerbations At baseline, patients had an ACQ score > were defined as requirement for systemic corticosteroids. A Cox proportional hazards model was used, with ACQ score as the time-dependent covariate. The analysis was repeated for individual components of the ACQ. Results: Each 1-point increase in ACQ was associated with a 50% increased risk of exacerbation (hazard ratio, 1.50; 95% CI, 1.03-2.20) for the following 2-week period. Evaluation of individual ACQ components also demonstrated a similar
From athe Allergy and Asthma Medical Group and Research Center, San Diego; bthe University of Wisconsin; cthe University of Pittsburgh Medical Center; and dAmgen Inc, Thousand Oaks. Supported by Amgen Inc. Trial registration: This study is registered with ClinicalTrials.gov with the identifier NCT 00436670. Disclosure of potential conflict of interest: E. O. Meltzer has received research support from UCB, Alcon, Alexza, Amgen, Antigen Labs, Apotex, Astellas, AstraZeneca, Boehringer Ingelheim, Capnia, Critical Therapeutics, GlaxoSmithKline, MAP, MEDA, Merck, Novartis, Proctor & Gamble, Schering-Plough, and Teva; has served as a consultant or on an advisory board for Schering Plough, Alcon, Alexza Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Capnia, Dainippon Sumitomo Pharma, Dey, ISTA, Johnson & Johnson, Kalypsys, MAP, Meda, Merck, National Jewish Health, Rady Children’s Hospital San Diego, Sandoz, Sepracor, SRxA, Teva, VentiRx, Wockhardt, and Wyeth; is a speaker for GlaxoSmithKline, MEDA, Merck, Sanofi-Aventis, Schering-Plough, Sepracor, and SRxA; has served as an expert in legal matters on the topics of desloratadine, fexofenadine, montelukast, and levocetirizine; and is a fellow for the AAAAI and the American College of Allergy, Asthma and Immunology. W. W. Busse is on the advisory board for Altair, GlaxoSmithKline, Merck, Wyeth, Pfizer Centocor, Amgen, and Johnson & Johnson; is a speaker for Merck; is a consultant for Novartis, Astra Zeneca, TEVA, Boehringer Ingelhim, and GlaxoSmithKline; and has received research support from NIH-NIAID, NIH-NHLBI, Novartis, AstraZeneca, GlazoSmithKline, MedImmune, and Ception. S. E. Wenzel is a consultant for GlaxoSmithKline, Merck, Amgen, and Pearl Therapeutics; is on the advisory board for Amira, Altair, and Epigenesis; and has received research support from GlaxoSmithKline, Amgen, and MedImmune. V. Belozeroff, H. H. Weng, D. Globe, and S.-L. Lin are employed by Amgen. Y. Chon holds stock in Amgen. The rest of the authors have declared that they have no conflict of interest. Received for publication June 21, 2010; revised August 20, 2010; accepted for publication August 23, 2010. Available online November 18, 2010. Reprint requests: Eli O. Meltzer, MD, Allergy and Asthma Medical Group and Research Center, 9610 Granite Ridge Drive, Suite B, San Diego, CA 92123. E-mail: eomeltzer@ aol.com. 0091-6749/$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2010.08.042
trend, though each to a lesser degree than the full composite ACQ. Conclusion: Although based on a retrospective analysis, with small number of exacerbations, these findings support the utility of the composite ACQ score measurement to predict risk of future exacerbation in clinical trials and clinical practice. The composite ACQ score measurement was found to be a better predictor of future risk than individual ACQ components. (J Allergy Clin Immunol 2011;127:167-72.) Key words: Asthma exacerbation, ACQ score, asthma control, prediction, IL-4 receptor a, antagonist
Asthma is a chronic inflammatory disorder of the airways that affects over 300 million people worldwide.1 Many patients with asthma experience ongoing symptoms that interrupt daily activities, cause overall poor quality of life, and may subsequently lead to lower productivity and greater health care costs.2 In a recently published cross-section survey of 2500 patients with asthma, the percentage who needed acute care for asthma in the past 12 months has not changed significantly in 2009 versus 1998 (34% vs 36%).3,4 Several large community-based asthma surveys have also shown that the majority of patients have a high rate of symptoms and impairment from their disease.4-6 Recent community-based surveys have shown that 51% to 59% of patients have uncontrolled asthma even with the use of standard asthma medications.7-9 The Gaining Optimal Asthma Control (GOAL) clinical trial found that <45% of patients achieved total asthma control (ie, no daytime symptoms, use of bronchodilators, _80% in 7 of or exacerbations, and morning peak expiratory flow > 8 weeks) despite intensive therapy and dose escalation based on existing treatment guidelines.10 The importance of asthma control has been emphasized by the recent disease management guidelines, including the Global Initiative for Asthma guidelines and the National Asthma Education and Prevention Program.11,12 Control of asthma is monitored by level of current control (impairment) and risk for long-term effects on exacerbations, progressive impairment of lung function, and medication side effects.11,12 Achieving adequate asthma control and minimizing future risk of exacerbations are the primary goals in the management of the disease. Level of asthma control may be examined by a single clinical feature of asthma such as FEV1. However, the American Thoracic Society/European Respiratory Society statement on endpoints for asthma clinical trials recommends considering use of a validated composite measure, such as the Asthma Control Questionnaire (ACQ), in clinical trials to assess asthma control.13 The utility of composite measures to predict long-term risk, particularly exacerbations, remains poorly studied. Although measurements such as variation in peak expiratory flow rate (PEFR) and low 167
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discriminator between patients with asthma who are well controlled and those who are not well controlled.19 Shorter versions of the ACQ have been validated, including the ACQ-6, which excludes lung function, and ACQ-5, which excludes lung function and rescue medication use.17,18
Abbreviations used ACQ: Asthma Control Questionnaire HR: Hazard ratio MID: Minimal important difference PEFR: Peak expiratory flow rate
Asthma exacerbation 14
FEV1 have been associated with risk of exacerbations, it is conceivable that a composite measure such as the ACQ,15 which assesses the adequacy of asthma control by using symptoms, activity limitation, use of rescue medications, and lung function, may better capture different aspects of asthma control and prediction of risk. Direct correlation of sequential measurements of asthma control over time and risk of exacerbation has not been previously reported in a randomized clinical trial. The purpose of this study was to examine the association between the ACQ score and the risk of future exacerbation within a randomized controlled trial of patients with moderate to severe asthma. Individual components of the ACQ as well as the ACQ 6-item (ACQ-6) and 5-item (ACQ5) versions were also examined for their association with the risk of exacerbation.
METHODS Patients A post hoc analysis of data from a 12-week multicenter, double-blind, randomized, placebo-controlled clinical trial16 was conducted to assess the association between the ACQ and asthma exacerbation. Patients with moderate to severe atopic asthma were enrolled in a dose-ranging phase 2 study to assess the safety and efficacy of AMG 317, an IL-4 receptor a antagonist. Patients were randomly assigned in a 1:1:1:1 ratio to receive 1 of 3 doses of the IL-4 receptor a antagonist or placebo administered once weekly for 12 weeks. To be eligible for the study, patients had to meet the following inclusion _50% to < _80%, (3) at criteria: (1) age 18 to 65 years, (2) FEV1% predicted > least 12% reversibility over baseline FEV1 with b-agonist inhalation, (4) in_200 and < _1000 mg/d fluticasone propionate or equivahaled corticosteroid > lent, (5) positive to skin prick test or RAST to at least 2 allergens, and (6) _1.5. ongoing asthma symptoms with ACQ score at screening and baseline > Subjects who received oral or parenteral corticosteroids within 6 weeks before the first run-in visit were excluded from the study. Details for this clinical trial have been previously published.16 Before enrollment into the study, the institutional review board for each site provided written approval of the protocol, and patients provided informed consent to participate in the study.
ACQ Eligible patients completed the ACQ weekly for 2 weeks before treatment initiation and every 2 weeks for 16 weeks after treatment initiation. The ACQ is a validated 7-item questionnaire that measures asthma control and is increasingly being used in clinical practice and research.15,17,18 Patients are asked to recall their symptoms during the previous week and to respond to the first 6 questions (nighttime waking, symptoms on waking, activity limitation, shortness of breath, wheeze, and rescue short-acting medication use) on a 7-point scale from 0 (no impairment) to 6 (maximum impairment). Clinicians score the percent predicted prebronchodilator FEV1 (the seventh question) on a similar 7-point scale as the other ACQ questions. The items are equally weighted, and the ACQ score is the mean of the 7 items, with scores between 0 (totally controlled) and 6 (severely uncontrolled). The minimal important difference (MID) is 0.5, representing the smallest change that is considered clinically meaningful.17 An ACQ score of 1.5 has been identified as the best
Asthma exacerbation was defined as ‘‘requirement for systemic corticosteroids.’’ An alternative definition, ‘‘requirement for systemic corticosteroids or doubling of inhaled corticosteroid dose,’’ was also separately evaluated. Both definitions were prespecified in the study protocol and analysis plan. Time to event for asthma exacerbation was defined as the time to the first exacerbation after treatment initiation for patients with at least 1 exacerbation. For patients with no exacerbations through 12 weeks of study, the time to event was considered censored and was thus observed from randomization to either week 12 or their last follow-up date, whichever date occurred first.
Other assessments Spirometry assessments were performed at screening and every 2 weeks for 16 weeks. Rescue medication use was defined as the number of puffs per day of short-acting b-agonist use and was recorded daily in an electronic diary (eDiary). Patients recorded daily peak flows and asthma symptoms in the morning and evening using the eDiary. The nighttime symptom score was rated on a 0 to 3 scale with 0 meaning ‘‘no symptoms,’’ 1 meaning ‘‘mild, awoke wheezing at least once but returned to sleep,’’ 2 meaning ‘‘moderate, awakened more than once and remained awake for >1 hour,’’ and 3 meaning ‘‘severe, awake most of the night.’’
Statistical analysis The association between baseline ACQ score and exacerbation was assessed by using a Cox proportional hazards model adjusting for treatment assignment. A second Cox proportional hazards model used all ACQ scores before exacerbation as time-dependent covariates.20 The time-dependent model was selected to enable the use of all the ACQ scores over time before the exacerbation occurred, rather than the single baseline or the last ACQ score. The association between the last ACQ score before exacerbation and the risk of exacerbation was also assessed by using a logistic regression model. The linearity assumption between ACQ and odds of asthma exacerbation was assessed by plotting the log of the odds and mean ACQ in 5 ACQ categories _2, >2 and < _3, >3 and < _4, >4). (&1, >1 and < To identify a threshold ACQ score that would predict future asthma exacerbation, the sensitivity and specificity for the prediction at a given ACQ score were calculated for all ACQ scores measured immediately before exacerbation. Individual components of ACQ, ACQ-6, and ACQ-5 were also evaluated for their association with risk of exacerbation. The eDiary measures were recorded daily and summarized weekly as an independent measure from the ACQ. Effects of asthma measures, such as night-time symptom score from eDiary and lung function on the risk of exacerbation, were assessed to evaluate whether the effects of these asthma measures were similar to the effects of those components in ACQ.
RESULTS Patients A total of 292 patients with moderate to severe asthma were included in the analysis. The study population was 71% white, 18% black, 58% women, and had a mean age of 41 years (Table I). At baseline, patients had a mean FEV1 of 68.3% and mean ACQ score of 2.54. Baseline characteristics were similar between patients with and without an exacerbation. All baseline
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TABLE I. Characteristics of the study population at baseline Characteristics
Age (y), mean (SD) Women, n (%) Race, n (%) White Black Hispanic/Latino Body mass index (kg/m2), mean (SD) Asthma duration (y), mean (SD) %FEV1, mean (SD) Rescue medication use (puffs/d),* mean (SD) Inhaled corticosteroid dose (mg),à mean (SD) ACQ score, mean (SD)
All patients (N 5 292)
Patients without asthma exacerbation (N 5 261)
Patients with asthma exacerbationy (N 5 31)
41.3 (11.0) 168 (57.5)
41.4 (11.3) 150 (57.5)
40.8 (8.1) 18 (58.1)
208 52 27 31.0 26.0 68.3 3.68 440 2.54
184 50 22 31.0 26.3 68.3 3.63 436 2.53
24 2 5 30.5 23.2 68.1 4.06 472 2.58
(71.2) (17.8) (9.2) (8.0) (13.7) (12.0) (3.64) (223) (0.70)
(70.5) (19.2) (8.4) (8.1) (13.8) (12.0) (3.68) (224) (0.70)
(77.4) (6.5) (16.1) (7.3) (12.5) (11.5) (3.30) (219) (0.70)
For FEV1, comparisons of patients with and without exacerbation had P values >.10. *No. of puffs per day of short-acting b-agonist use. Exacerbation defined as requirement for systemic corticosteroids. àFluticasone equivalent.
characteristics were considered for the final model; none were determined as potential confounders relative to exacerbations.
ACQ and exacerbations Asthma Control Questionnaire scores observed in this study ranged from 0 to 5.71. Thirty-one patients each experienced 1 exacerbation in the study. The mean (SD) time between the ACQ assessment immediately before an exacerbation and the actual onset of the exacerbation was 9.9 (4.5) days. A time-dependent covariate model demonstrated that the ACQ score was significantly associated with risk of asthma exacerbation. For each 1-point increase in ACQ score, the risk of exacerbation increased by 1.5-fold or 50% (hazard ratio [HR], 1.50; 95% CI, 1.03-2.2; P 5 .035). Using the MID for the ACQ (0.5), an increase of 0.5 in ACQ score was associated with a 23% increased risk of exacerbation. Because ACQ scores were measured every 2 weeks, statements of relative risk of asthma exacerbation correspond to the 2-week period after a given ACQ measurement. The current analysis did not demonstrate a significant association between the baseline ACQ score and asthma exacerbation (HR, 1.13; 95% CI, 0.69-1.87). A logistic regression model was also used to determine whether the closest ACQ score before the exacerbation was a predictor of exacerbation. Results demonstrated that a higher ACQ score increased the odds of asthma exacerbation, and the association revealed a linear relationship. This relationship was examined within the range (0-4.85) of the last ACQ score measured before exacerbation for those patients having exacerbation events, or the last ACQ score measured before week 12 or last follow-up, whichever came first, for patients who did not have an exacerbation. In addition, assessment of cutpoints in ACQ score to determine whether a threshold existed above which most individuals would be at risk of an exacerbation within the following 2 weeks did not yield any specific threshold of ACQ score with meaningful sensitivity or specificity to allow for definitive association. Components of ACQ Analysis of individual components of the ACQ revealed similar trends for association with the risk of asthma exacerbation. The HRs for exacerbation with every ACQ component
ranged from 1.1 to 1.3 (Fig 1). Use of rescue medication (HR, 1.34) demonstrated a significant association with risk of exacerbation (P < .05).
ACQ-6 and ACQ-5 Using the time-dependent covariate model, the association of ACQ-6 with risk of exacerbation demonstrated a trend toward significance (HR, 1.41; 95% CI, 0.99-2.02; P 5 .056). Although not significant, the point estimate for the HR also suggested an association of higher ACQ-5 with increased risk of exacerbation (HR, 1.35; 95% CI, 0.95-1.92; P 5 .10). Baseline ACQ-6 (HR, 1.14; 95% CI, 0.73-1.78; P 5 .56) and ACQ-5 (HR, 1.04; 95% CI, 0.67-1.62; P 5 .86) scores were not significantly associated with exacerbation risk. The full composite ACQ demonstrated a stronger association with the risk of exacerbation than ACQ-6, with ACQ-5 having the least strong association. Asthma measures from eDiary and spirometry The analysis of independent measures from the eDiary showed that nighttime symptoms and use of rescue medications were significantly associated with risk of exacerbations. The HR using the time-dependent model was 3.10 (95% CI, 1.70-5.64; P <.001) for nighttime symptoms and 1.08 (95% CI, 1.01-1.15; P 5.02) for use of rescue medication. FEV1 and PEFR were also evaluated. Using the timedependent model where all values up to the exacerbation are included, percent predicted FEV1 and FEV1 were not significantly associated with risk of exacerbation (HR, 0.98; 95% CI, 0.95-1.01; P 5 .10; and HR, 0.52; 95% CI, 0.23-1.19; P 5 .12, respectively). Although not significant, the point estimates for HR demonstrated a trend suggesting that higher FEV1 values are associated with decreased risk of exacerbation. The AM peak flow and diurnal variation of peak flow (reported as 10 L/min unit change) were significantly associated with the risk of asthma exacerbation (HR, 0.96; 95% CI, 0.92-1.00; P 5 .049; and HR, 1.14; 95% CI, 1.02-1.29; P 5 .026, respectively; Table II). Higher AM peak flow and decreased diurnal variation were each associated with a lower risk of asthma exacerbation.
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FIG 1. Association of individual ACQ components with asthma exacerbations. The HR estimates were obtained from Cox proportional hazard models on asthma exacerbation by using total ACQ score or each component of ACQ as time-dependent covariates.
TABLE II. Association of independent measures of eDiary and FEV1 with risk of asthma exacerbation HR (95% CI)
Night-time symptom score Rescue medication (puffs/d) Peak flow AM (10 L/min)* Peak flow PM (10 L/min)* Diurnal variation (10 L/min)* FEV1% predicted FEV1 (L)*
3.10 1.08 0.96 0.96 1.14 0.98 0.52
(1.70-5.64) (1.01-1.15) (0.92-1.00) (0.91-1.00) (1.02-1.29) (0.95-1.01) (0.23-1.19)
P value*
<.001 .017 .049 .068 .026 .103 .121
Asthma exacerbation defined as requirement for systemic corticosteroids. *The model included age, race, sex, and height in addition to treatment assignment.
Other analyses Similar results were observed for association of ACQ and its individual components with risk of exacerbation by using the exacerbation definition of ‘‘requirement of systemic corticosteroids or doubling of ICS dose’’ (data not shown). DISCUSSION In this retrospective analysis of data from a randomized clinical trial, asthma control as measured by the ACQ composite score was found to be significantly associated with the risk of future exacerbation. This finding was confirmed with the analysis demonstrating consistently higher odds of having an exacerbation with an increase in the proximate ACQ score. A direct correlation between sequential measurements of ACQ, an indicator of asthma impairment, and the risk of future exacerbation, as observed in this study, has not been previously demonstrated in a randomized clinical trial. Thirty-one exacerbations were observed among 292 patients over a 12-week period (exposure-adjusted rate, 0.61; 95% CI, 0.43-0.85). The rate of exacerbation was comparable to the rate seen in other studies with similar patient populations.21
The time-dependent model used all ACQ scores before an exacerbation. At any given point in time, each 1-point increase in ACQ score increased the risk of asthma exacerbation within the following 2-week period by 50%. Expressed in terms of the validated MID for the ACQ measure, each 0.5-point increase in ACQ score increased the risk of exacerbation within the following 2-week period by 23%. Among the individual ACQ components, use of rescue medication showed a significant association with risk of exacerbation. However, the point estimates for the HRs for exacerbation with each individual ACQ component were less than that found for the overall ACQ score. Similarly, the associations of ACQ-6 and ACQ-5 with risk of exacerbation demonstrated trends toward significance but to a lesser degree than the full ACQ composite score. Overall, these findings suggest that composite ACQ is a better predictor of exacerbation than individual ACQ components. Among other parameters from this study including the eDiary and spirometry measurements, a statistically significant association was observed between rescue medication use, AM peak flow, diurnal variation, and nighttime symptoms, and the risk of exacerbation (Table II). Significance levels found within the analyses of rescue medication use and variation in PEFR were similar to that of ACQ. Overall, the night-time symptom score was best correlated with exacerbation. The implications for clinical practice from these analyses are that some individual signs and symptoms or the variation in PEFR are comparable to ACQ in their ability to predict risk of asthma exacerbation. However, from a practical perspective, adherence to daily diary records as was required by this study is generally untenable long-term. The ACQ can be measured at clinic visits, thereby providing an accurate and reliable method of measurement. Shorter versions of the ACQ such as the ACQ-6 and ACQ-5 could be potentially assessed by the patient outside the clinic setting to assess asthma control and risk for asthma exacerbation.
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Other studies have shown that low FEV1 at baseline is associated with asthma exacerbation.14,22-25 The current study found a similar trend between FEV1 and exacerbation using all the FEV1 measurements up to the time of exacerbation, but the association was not significant. The time-dependent model performed in this analysis used ACQ scores collected frequently across the study period, whereas other published studies have been limited in their analyses by datasets with only baseline asthma control scores or scores collected at intervals farther apart than every other week.26,27 A recently published retrospective pooled analysis26 of 5 studies examined the relationship between current control (defined per the Global Initiative for Asthma guideline-derived classification or the ACQ-5) and future risk of exacerbation. Patients were classified into 2 groups by their baseline ACQ-5 score. The study _1.5 verdemonstrated that patients with a baseline ACQ-5 score > sus an ACQ score <0.5 had a significantly higher exacerbation rate over a 12-month period (0.36 events/patient/12 mo vs 0.13 events/patient/12 mo). The current study evaluated the ACQ 7item version and included a comparison to understand the predictive value of ACQ-6 and ACQ-5. Frequent evaluation of the ACQ in the current study revealed a linear association between ACQ and asthma exacerbation. In addition, this study allowed the quantification of risk of asthma exacerbation for a given individual within the near-term period of 2 weeks, suggesting that measurement of the ACQ at clinic visits may have clinical utility in asthma management and may not only assess current control but also predict future loss of control. Limitations of this study include the post hoc nature of analysis with a small number of exacerbation events. The small number of exacerbation events in this study may have limited the ability to detect ACQ patterns in terms of characterizing the progression to exacerbation and to identify any specific threshold ACQ score with meaningful sensitivity or specificity to predict future exacerbation. Additional datasets may provide further insight into potential relationships with future evaluations. A second limitation was that the patient population may differ from other asthma patient populations, especially with regard to asthma con_1.5). Although basetrol (inclusion criterion baseline ACQ score > _1.5, they ranged from 0 to line ACQ scores in this study were > 5.71 during the study, demonstrating a range of asthma control within this dataset. In conclusion, the ability to predict an exacerbation could have a significant impact on asthma management and control, including increased vigilance at patient visits and an action plan review to facilitate proactive adjustments in treatment regimen. In this study, a significant correlation was found between the measurements of the ACQ composite score over time and the risk of future asthma exacerbation. The results with the ACQ composite measure were superior to those with the individual ACQ components, thereby supporting the utility of composite ACQ score measurement in clinical trials and clinical practice. We acknowledge Meera Kodukulla, PhD, of Amgen Inc and Kathy Fox, PhD, on behalf of Amgen Inc, for writing and editorial support.
Clinical implications: A quantitative evaluation of the risk of future exacerbations using the ACQ may allow for better treatment of patients in clinical practice and supports using ACQ as an endpoint in asthma clinical trials.
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27. Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, Chipps BE, et al. Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2009;124:895-902, e1-e4.
From athe Allergy and Asthma Medical Group and Research Center, San Diego; bthe University of Wisconsin; cthe University of Pittsburgh Medical Center; and dAmgen Inc, Thousand Oaks. Supported by Amgen Inc. Trial registration: This study is registered with ClinicalTrials.gov with the identifier NCT 00436670. Disclosure of potential conflict of interest: E. O. Meltzer has received research support from UCB, Alcon, Alexza, Amgen, Antigen Labs, Apotex, Astellas, AstraZeneca, Boehringer Ingelheim, Capnia, Critical Therapeutics, GlaxoSmithKline, MAP, MEDA, Merck, Novartis, Proctor & Gamble, Schering-Plough, and Teva; has served as a consultant or on an advisory board for Schering Plough, Alcon, Alexza Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Capnia, Dainippon Sumitomo Pharma, Dey, ISTA, Johnson & Johnson, Kalypsys, MAP, Meda, Merck, National Jewish Health, Rady Children’s Hospital San Diego, Sandoz, Sepracor, SRxA, Teva, VentiRx, Wockhardt, and Wyeth; is a speaker for GlaxoSmithKline, MEDA, Merck, Sanofi-Aventis, Schering-Plough, Sepracor, and SRxA; has served as an expert in legal matters on the topics of desloratadine, fexofenadine, montelukast, and levocetirizine; and is a fellow for the AAAAI and the American College of Allergy, Asthma and Immunology. W. W. Busse is on the advisory board for Altair, GlaxoSmithKline, Merck, Wyeth, Pfizer Centocor, Amgen, and Johnson & Johnson; is a speaker for Merck; is a consultant for Novartis, Astra Zeneca, TEVA, Boehringer Ingelhim, and GlaxoSmithKline; and has received research support from NIH-NIAID, NIH-NHLBI, Novartis, AstraZeneca, GlazoSmithKline, MedImmune, and Ception. S. E. Wenzel is a consultant for GlaxoSmithKline, Merck, Amgen, and Pearl Therapeutics; is on the advisory board for Amira, Altair, and Epigenesis; and has received research support from GlaxoSmithKline, Amgen, and MedImmune. V. Belozeroff, H. H. Weng, D. Globe, and S.-L. Lin are employed by Amgen. Y. Chon holds stock in Amgen. The rest of the authors have declared that they have no conflict of interest. Received for publication June 21, 2010; revised August 20, 2010; accepted for publication August 23, 2010. Available online November 18, 2010. Reprint requests: Eli O. Meltzer, MD, Allergy and Asthma Medical Group and Research Center, 9610 Granite Ridge Drive, Suite B, San Diego, CA 92123. E-mail: eomeltzer@ aol.com. 0091-6749/$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2010.08.042
trend, though each to a lesser degree than the full composite ACQ. Conclusion: Although based on a retrospective analysis, with small number of exacerbations, these findings support the utility of the composite ACQ score measurement to predict risk of future exacerbation in clinical trials and clinical practice. The composite ACQ score measurement was found to be a better predictor of future risk than individual ACQ components. (J Allergy Clin Immunol 2011;127:167-72.) Key words: Asthma exacerbation, ACQ score, asthma control, prediction, IL-4 receptor a, antagonist
Asthma is a chronic inflammatory disorder of the airways that affects over 300 million people worldwide.1 Many patients with asthma experience ongoing symptoms that interrupt daily activities, cause overall poor quality of life, and may subsequently lead to lower productivity and greater health care costs.2 In a recently published cross-section survey of 2500 patients with asthma, the percentage who needed acute care for asthma in the past 12 months has not changed significantly in 2009 versus 1998 (34% vs 36%).3,4 Several large community-based asthma surveys have also shown that the majority of patients have a high rate of symptoms and impairment from their disease.4-6 Recent community-based surveys have shown that 51% to 59% of patients have uncontrolled asthma even with the use of standard asthma medications.7-9 The Gaining Optimal Asthma Control (GOAL) clinical trial found that <45% of patients achieved total asthma control (ie, no daytime symptoms, use of bronchodilators, _80% in 7 of or exacerbations, and morning peak expiratory flow > 8 weeks) despite intensive therapy and dose escalation based on existing treatment guidelines.10 The importance of asthma control has been emphasized by the recent disease management guidelines, including the Global Initiative for Asthma guidelines and the National Asthma Education and Prevention Program.11,12 Control of asthma is monitored by level of current control (impairment) and risk for long-term effects on exacerbations, progressive impairment of lung function, and medication side effects.11,12 Achieving adequate asthma control and minimizing future risk of exacerbations are the primary goals in the management of the disease. Level of asthma control may be examined by a single clinical feature of asthma such as FEV1. However, the American Thoracic Society/European Respiratory Society statement on endpoints for asthma clinical trials recommends considering use of a validated composite measure, such as the Asthma Control Questionnaire (ACQ), in clinical trials to assess asthma control.13 The utility of composite measures to predict long-term risk, particularly exacerbations, remains poorly studied. Although measurements such as variation in peak expiratory flow rate (PEFR) and low 167
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discriminator between patients with asthma who are well controlled and those who are not well controlled.19 Shorter versions of the ACQ have been validated, including the ACQ-6, which excludes lung function, and ACQ-5, which excludes lung function and rescue medication use.17,18
Abbreviations used ACQ: Asthma Control Questionnaire HR: Hazard ratio MID: Minimal important difference PEFR: Peak expiratory flow rate
Asthma exacerbation 14
FEV1 have been associated with risk of exacerbations, it is conceivable that a composite measure such as the ACQ,15 which assesses the adequacy of asthma control by using symptoms, activity limitation, use of rescue medications, and lung function, may better capture different aspects of asthma control and prediction of risk. Direct correlation of sequential measurements of asthma control over time and risk of exacerbation has not been previously reported in a randomized clinical trial. The purpose of this study was to examine the association between the ACQ score and the risk of future exacerbation within a randomized controlled trial of patients with moderate to severe asthma. Individual components of the ACQ as well as the ACQ 6-item (ACQ-6) and 5-item (ACQ5) versions were also examined for their association with the risk of exacerbation.
METHODS Patients A post hoc analysis of data from a 12-week multicenter, double-blind, randomized, placebo-controlled clinical trial16 was conducted to assess the association between the ACQ and asthma exacerbation. Patients with moderate to severe atopic asthma were enrolled in a dose-ranging phase 2 study to assess the safety and efficacy of AMG 317, an IL-4 receptor a antagonist. Patients were randomly assigned in a 1:1:1:1 ratio to receive 1 of 3 doses of the IL-4 receptor a antagonist or placebo administered once weekly for 12 weeks. To be eligible for the study, patients had to meet the following inclusion _50% to < _80%, (3) at criteria: (1) age 18 to 65 years, (2) FEV1% predicted > least 12% reversibility over baseline FEV1 with b-agonist inhalation, (4) in_200 and < _1000 mg/d fluticasone propionate or equivahaled corticosteroid > lent, (5) positive to skin prick test or RAST to at least 2 allergens, and (6) _1.5. ongoing asthma symptoms with ACQ score at screening and baseline > Subjects who received oral or parenteral corticosteroids within 6 weeks before the first run-in visit were excluded from the study. Details for this clinical trial have been previously published.16 Before enrollment into the study, the institutional review board for each site provided written approval of the protocol, and patients provided informed consent to participate in the study.
ACQ Eligible patients completed the ACQ weekly for 2 weeks before treatment initiation and every 2 weeks for 16 weeks after treatment initiation. The ACQ is a validated 7-item questionnaire that measures asthma control and is increasingly being used in clinical practice and research.15,17,18 Patients are asked to recall their symptoms during the previous week and to respond to the first 6 questions (nighttime waking, symptoms on waking, activity limitation, shortness of breath, wheeze, and rescue short-acting medication use) on a 7-point scale from 0 (no impairment) to 6 (maximum impairment). Clinicians score the percent predicted prebronchodilator FEV1 (the seventh question) on a similar 7-point scale as the other ACQ questions. The items are equally weighted, and the ACQ score is the mean of the 7 items, with scores between 0 (totally controlled) and 6 (severely uncontrolled). The minimal important difference (MID) is 0.5, representing the smallest change that is considered clinically meaningful.17 An ACQ score of 1.5 has been identified as the best
Asthma exacerbation was defined as ‘‘requirement for systemic corticosteroids.’’ An alternative definition, ‘‘requirement for systemic corticosteroids or doubling of inhaled corticosteroid dose,’’ was also separately evaluated. Both definitions were prespecified in the study protocol and analysis plan. Time to event for asthma exacerbation was defined as the time to the first exacerbation after treatment initiation for patients with at least 1 exacerbation. For patients with no exacerbations through 12 weeks of study, the time to event was considered censored and was thus observed from randomization to either week 12 or their last follow-up date, whichever date occurred first.
Other assessments Spirometry assessments were performed at screening and every 2 weeks for 16 weeks. Rescue medication use was defined as the number of puffs per day of short-acting b-agonist use and was recorded daily in an electronic diary (eDiary). Patients recorded daily peak flows and asthma symptoms in the morning and evening using the eDiary. The nighttime symptom score was rated on a 0 to 3 scale with 0 meaning ‘‘no symptoms,’’ 1 meaning ‘‘mild, awoke wheezing at least once but returned to sleep,’’ 2 meaning ‘‘moderate, awakened more than once and remained awake for >1 hour,’’ and 3 meaning ‘‘severe, awake most of the night.’’
Statistical analysis The association between baseline ACQ score and exacerbation was assessed by using a Cox proportional hazards model adjusting for treatment assignment. A second Cox proportional hazards model used all ACQ scores before exacerbation as time-dependent covariates.20 The time-dependent model was selected to enable the use of all the ACQ scores over time before the exacerbation occurred, rather than the single baseline or the last ACQ score. The association between the last ACQ score before exacerbation and the risk of exacerbation was also assessed by using a logistic regression model. The linearity assumption between ACQ and odds of asthma exacerbation was assessed by plotting the log of the odds and mean ACQ in 5 ACQ categories _2, >2 and < _3, >3 and < _4, >4). (&1, >1 and < To identify a threshold ACQ score that would predict future asthma exacerbation, the sensitivity and specificity for the prediction at a given ACQ score were calculated for all ACQ scores measured immediately before exacerbation. Individual components of ACQ, ACQ-6, and ACQ-5 were also evaluated for their association with risk of exacerbation. The eDiary measures were recorded daily and summarized weekly as an independent measure from the ACQ. Effects of asthma measures, such as night-time symptom score from eDiary and lung function on the risk of exacerbation, were assessed to evaluate whether the effects of these asthma measures were similar to the effects of those components in ACQ.
RESULTS Patients A total of 292 patients with moderate to severe asthma were included in the analysis. The study population was 71% white, 18% black, 58% women, and had a mean age of 41 years (Table I). At baseline, patients had a mean FEV1 of 68.3% and mean ACQ score of 2.54. Baseline characteristics were similar between patients with and without an exacerbation. All baseline
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TABLE I. Characteristics of the study population at baseline Characteristics
Age (y), mean (SD) Women, n (%) Race, n (%) White Black Hispanic/Latino Body mass index (kg/m2), mean (SD) Asthma duration (y), mean (SD) %FEV1, mean (SD) Rescue medication use (puffs/d),* mean (SD) Inhaled corticosteroid dose (mg),à mean (SD) ACQ score, mean (SD)
All patients (N 5 292)
Patients without asthma exacerbation (N 5 261)
Patients with asthma exacerbationy (N 5 31)
41.3 (11.0) 168 (57.5)
41.4 (11.3) 150 (57.5)
40.8 (8.1) 18 (58.1)
208 52 27 31.0 26.0 68.3 3.68 440 2.54
184 50 22 31.0 26.3 68.3 3.63 436 2.53
24 2 5 30.5 23.2 68.1 4.06 472 2.58
(71.2) (17.8) (9.2) (8.0) (13.7) (12.0) (3.64) (223) (0.70)
(70.5) (19.2) (8.4) (8.1) (13.8) (12.0) (3.68) (224) (0.70)
(77.4) (6.5) (16.1) (7.3) (12.5) (11.5) (3.30) (219) (0.70)
For FEV1, comparisons of patients with and without exacerbation had P values >.10. *No. of puffs per day of short-acting b-agonist use. Exacerbation defined as requirement for systemic corticosteroids. àFluticasone equivalent.
characteristics were considered for the final model; none were determined as potential confounders relative to exacerbations.
ACQ and exacerbations Asthma Control Questionnaire scores observed in this study ranged from 0 to 5.71. Thirty-one patients each experienced 1 exacerbation in the study. The mean (SD) time between the ACQ assessment immediately before an exacerbation and the actual onset of the exacerbation was 9.9 (4.5) days. A time-dependent covariate model demonstrated that the ACQ score was significantly associated with risk of asthma exacerbation. For each 1-point increase in ACQ score, the risk of exacerbation increased by 1.5-fold or 50% (hazard ratio [HR], 1.50; 95% CI, 1.03-2.2; P 5 .035). Using the MID for the ACQ (0.5), an increase of 0.5 in ACQ score was associated with a 23% increased risk of exacerbation. Because ACQ scores were measured every 2 weeks, statements of relative risk of asthma exacerbation correspond to the 2-week period after a given ACQ measurement. The current analysis did not demonstrate a significant association between the baseline ACQ score and asthma exacerbation (HR, 1.13; 95% CI, 0.69-1.87). A logistic regression model was also used to determine whether the closest ACQ score before the exacerbation was a predictor of exacerbation. Results demonstrated that a higher ACQ score increased the odds of asthma exacerbation, and the association revealed a linear relationship. This relationship was examined within the range (0-4.85) of the last ACQ score measured before exacerbation for those patients having exacerbation events, or the last ACQ score measured before week 12 or last follow-up, whichever came first, for patients who did not have an exacerbation. In addition, assessment of cutpoints in ACQ score to determine whether a threshold existed above which most individuals would be at risk of an exacerbation within the following 2 weeks did not yield any specific threshold of ACQ score with meaningful sensitivity or specificity to allow for definitive association. Components of ACQ Analysis of individual components of the ACQ revealed similar trends for association with the risk of asthma exacerbation. The HRs for exacerbation with every ACQ component
ranged from 1.1 to 1.3 (Fig 1). Use of rescue medication (HR, 1.34) demonstrated a significant association with risk of exacerbation (P < .05).
ACQ-6 and ACQ-5 Using the time-dependent covariate model, the association of ACQ-6 with risk of exacerbation demonstrated a trend toward significance (HR, 1.41; 95% CI, 0.99-2.02; P 5 .056). Although not significant, the point estimate for the HR also suggested an association of higher ACQ-5 with increased risk of exacerbation (HR, 1.35; 95% CI, 0.95-1.92; P 5 .10). Baseline ACQ-6 (HR, 1.14; 95% CI, 0.73-1.78; P 5 .56) and ACQ-5 (HR, 1.04; 95% CI, 0.67-1.62; P 5 .86) scores were not significantly associated with exacerbation risk. The full composite ACQ demonstrated a stronger association with the risk of exacerbation than ACQ-6, with ACQ-5 having the least strong association. Asthma measures from eDiary and spirometry The analysis of independent measures from the eDiary showed that nighttime symptoms and use of rescue medications were significantly associated with risk of exacerbations. The HR using the time-dependent model was 3.10 (95% CI, 1.70-5.64; P <.001) for nighttime symptoms and 1.08 (95% CI, 1.01-1.15; P 5.02) for use of rescue medication. FEV1 and PEFR were also evaluated. Using the timedependent model where all values up to the exacerbation are included, percent predicted FEV1 and FEV1 were not significantly associated with risk of exacerbation (HR, 0.98; 95% CI, 0.95-1.01; P 5 .10; and HR, 0.52; 95% CI, 0.23-1.19; P 5 .12, respectively). Although not significant, the point estimates for HR demonstrated a trend suggesting that higher FEV1 values are associated with decreased risk of exacerbation. The AM peak flow and diurnal variation of peak flow (reported as 10 L/min unit change) were significantly associated with the risk of asthma exacerbation (HR, 0.96; 95% CI, 0.92-1.00; P 5 .049; and HR, 1.14; 95% CI, 1.02-1.29; P 5 .026, respectively; Table II). Higher AM peak flow and decreased diurnal variation were each associated with a lower risk of asthma exacerbation.
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FIG 1. Association of individual ACQ components with asthma exacerbations. The HR estimates were obtained from Cox proportional hazard models on asthma exacerbation by using total ACQ score or each component of ACQ as time-dependent covariates.
TABLE II. Association of independent measures of eDiary and FEV1 with risk of asthma exacerbation HR (95% CI)
Night-time symptom score Rescue medication (puffs/d) Peak flow AM (10 L/min)* Peak flow PM (10 L/min)* Diurnal variation (10 L/min)* FEV1% predicted FEV1 (L)*
3.10 1.08 0.96 0.96 1.14 0.98 0.52
(1.70-5.64) (1.01-1.15) (0.92-1.00) (0.91-1.00) (1.02-1.29) (0.95-1.01) (0.23-1.19)
P value*
<.001 .017 .049 .068 .026 .103 .121
Asthma exacerbation defined as requirement for systemic corticosteroids. *The model included age, race, sex, and height in addition to treatment assignment.
Other analyses Similar results were observed for association of ACQ and its individual components with risk of exacerbation by using the exacerbation definition of ‘‘requirement of systemic corticosteroids or doubling of ICS dose’’ (data not shown). DISCUSSION In this retrospective analysis of data from a randomized clinical trial, asthma control as measured by the ACQ composite score was found to be significantly associated with the risk of future exacerbation. This finding was confirmed with the analysis demonstrating consistently higher odds of having an exacerbation with an increase in the proximate ACQ score. A direct correlation between sequential measurements of ACQ, an indicator of asthma impairment, and the risk of future exacerbation, as observed in this study, has not been previously demonstrated in a randomized clinical trial. Thirty-one exacerbations were observed among 292 patients over a 12-week period (exposure-adjusted rate, 0.61; 95% CI, 0.43-0.85). The rate of exacerbation was comparable to the rate seen in other studies with similar patient populations.21
The time-dependent model used all ACQ scores before an exacerbation. At any given point in time, each 1-point increase in ACQ score increased the risk of asthma exacerbation within the following 2-week period by 50%. Expressed in terms of the validated MID for the ACQ measure, each 0.5-point increase in ACQ score increased the risk of exacerbation within the following 2-week period by 23%. Among the individual ACQ components, use of rescue medication showed a significant association with risk of exacerbation. However, the point estimates for the HRs for exacerbation with each individual ACQ component were less than that found for the overall ACQ score. Similarly, the associations of ACQ-6 and ACQ-5 with risk of exacerbation demonstrated trends toward significance but to a lesser degree than the full ACQ composite score. Overall, these findings suggest that composite ACQ is a better predictor of exacerbation than individual ACQ components. Among other parameters from this study including the eDiary and spirometry measurements, a statistically significant association was observed between rescue medication use, AM peak flow, diurnal variation, and nighttime symptoms, and the risk of exacerbation (Table II). Significance levels found within the analyses of rescue medication use and variation in PEFR were similar to that of ACQ. Overall, the night-time symptom score was best correlated with exacerbation. The implications for clinical practice from these analyses are that some individual signs and symptoms or the variation in PEFR are comparable to ACQ in their ability to predict risk of asthma exacerbation. However, from a practical perspective, adherence to daily diary records as was required by this study is generally untenable long-term. The ACQ can be measured at clinic visits, thereby providing an accurate and reliable method of measurement. Shorter versions of the ACQ such as the ACQ-6 and ACQ-5 could be potentially assessed by the patient outside the clinic setting to assess asthma control and risk for asthma exacerbation.
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Other studies have shown that low FEV1 at baseline is associated with asthma exacerbation.14,22-25 The current study found a similar trend between FEV1 and exacerbation using all the FEV1 measurements up to the time of exacerbation, but the association was not significant. The time-dependent model performed in this analysis used ACQ scores collected frequently across the study period, whereas other published studies have been limited in their analyses by datasets with only baseline asthma control scores or scores collected at intervals farther apart than every other week.26,27 A recently published retrospective pooled analysis26 of 5 studies examined the relationship between current control (defined per the Global Initiative for Asthma guideline-derived classification or the ACQ-5) and future risk of exacerbation. Patients were classified into 2 groups by their baseline ACQ-5 score. The study _1.5 verdemonstrated that patients with a baseline ACQ-5 score > sus an ACQ score <0.5 had a significantly higher exacerbation rate over a 12-month period (0.36 events/patient/12 mo vs 0.13 events/patient/12 mo). The current study evaluated the ACQ 7item version and included a comparison to understand the predictive value of ACQ-6 and ACQ-5. Frequent evaluation of the ACQ in the current study revealed a linear association between ACQ and asthma exacerbation. In addition, this study allowed the quantification of risk of asthma exacerbation for a given individual within the near-term period of 2 weeks, suggesting that measurement of the ACQ at clinic visits may have clinical utility in asthma management and may not only assess current control but also predict future loss of control. Limitations of this study include the post hoc nature of analysis with a small number of exacerbation events. The small number of exacerbation events in this study may have limited the ability to detect ACQ patterns in terms of characterizing the progression to exacerbation and to identify any specific threshold ACQ score with meaningful sensitivity or specificity to predict future exacerbation. Additional datasets may provide further insight into potential relationships with future evaluations. A second limitation was that the patient population may differ from other asthma patient populations, especially with regard to asthma con_1.5). Although basetrol (inclusion criterion baseline ACQ score > _1.5, they ranged from 0 to line ACQ scores in this study were > 5.71 during the study, demonstrating a range of asthma control within this dataset. In conclusion, the ability to predict an exacerbation could have a significant impact on asthma management and control, including increased vigilance at patient visits and an action plan review to facilitate proactive adjustments in treatment regimen. In this study, a significant correlation was found between the measurements of the ACQ composite score over time and the risk of future asthma exacerbation. The results with the ACQ composite measure were superior to those with the individual ACQ components, thereby supporting the utility of composite ACQ score measurement in clinical trials and clinical practice. We acknowledge Meera Kodukulla, PhD, of Amgen Inc and Kathy Fox, PhD, on behalf of Amgen Inc, for writing and editorial support.
Clinical implications: A quantitative evaluation of the risk of future exacerbations using the ACQ may allow for better treatment of patients in clinical practice and supports using ACQ as an endpoint in asthma clinical trials.
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27. Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, Chipps BE, et al. Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2009;124:895-902, e1-e4.