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Managing asthma: Options for assessing severity and control

The Journal of Respiratory DiseasesThe Journal of Respiratory Diseases Vol 5 No 10
Volume 5
Issue 10

Abstract: Pulmonary function tests, such as the measurement of forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF), provide an objective, standardized, and quantifiable method of patient assessment and can be essential in the evaluation of asthma. However, FEV1 and PEF are relatively insensitive for detecting changes in persons with good baseline pulmonary function, and they do not directly measure worsening airway inflammation. One way to deal with the shortcomings of these tests is to include multiple outcomes assessment. Evaluating patient-oriented variables, such as symptoms, need for rescue medication, nocturnal awakenings, and unscheduled medical care visits, can detect clinically relevant changes that pulmonary function tests do not identify. Composite outcomes provide a more comprehensive approach to patient follow-up. For example, a patient who is considered to be a "nonresponder" to a given therapy on the basis of pulmonary function criteria might, in fact, be responding favorably according to assessment of composite outcomes. Two patient-centric tools for measuring outcome are the asthma control questionnaire and the asthma control test.

Health care providers who manage asthma today rely on standard measures of pulmonary function, such as forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF), to assess the severity of disease and the patient's response to treatment. These traditional pulmonary function tests are particularly helpful in that they serve as a universal and quantifiable standard for patient care. Measurement of FEV1 and PEF is also valuable in clinical trials and evaluation of new drug therapies: no matter what the study design, clinicians can get a quick grasp of the outcomes because they are expressed in terms of standardized, objective, quantifiable criteria.

Despite these advantages, pulmonary function tests have many limitations. These shortcomings exist for patients with all degrees of asthma severity, and they are confounded by variability in therapeutic response. Within a group of patients given the same dose of a certain asthma medication, some will be deemed "responders" while others will be considered "nonresponders." If pulmonary function tests were the only method of handling responder analysis, patients who are subresponders or nonresponders might be assessed inaccurately.

Given these challenges, it makes sense that clinical trials use multiple end points and outcomes assessment when testing the effects of different interventions. These end points could include not only pulmonary function but also such clinical parameters as ß2-agonist use, lost workdays, and quality of life. This would give physicians objective and subjective perspectives with which to evaluate study findings and could capture patients who might be missed using only one method. Two "patient-centric" evaluation tools--the asthma control questionnaire (ACQ) and the asthma control test (ACT)--are gaining acceptance both in clinical trials and in daily practice.

In this article, I will discuss the advantages of incorporating multiple-outcomes assessment into asthma management strategies. I will also address the question of whether "perfect" asthma control is possible.


Limitations of pulmonary function tests

A recent study by the National Heart, Lung, and Blood Institute (NHLBI)-supported Asthma Clinical Research Network (ACRN) illustrates the limitations inherent in relying only on pulmonary function tests to measure outcome.1 The Improving Asthma Control Trial (IMPACT) involved 225 adults with mild persistent asthma. The investigators wanted to know whether twice-daily treatment with budesonide, zafirlukast, or placebo (with as-needed corticosteroid treatment, based on symptoms), given for 1 year, had different effects on the following outcomes: morning PEF; FEV1--alone, after albuterol, and after 2 weeks of albuterol plus anti-inflammatory treatment; asthma control; frequency of exacerbations; asthma-specific quality of life; and symptom-free days.

Fortunately, other outcome criteria were used in addition to FEV1, because the participants had an FEV1 that averaged 90% of predicted. When pulmonary function is this good, it is difficult to detect any changes in FEV1.

This trial highlighted another important aspect of asthma management: asthma is dynamic, and patients change classification frequently. A patient might be classified as having severe asthma at study onset but be changed to mild asthma during the run-in phase. This is something to consider when designing trials and determining how the data will be interpreted.

The Childhood Asthma Management Program (CAMP) trial, like the IMPACT study, randomly assigned a group of children to receive budesonide, nedocromil, or placebo, plus albuterol to control symptoms, for 4 to 6 years.2 The investigators examined patient outcomes according to FEV1 as well as such criteria as symptoms, need for a rescue ß2-agonist or prednisone, episode-free days, nocturnal awakenings, and urgent care visits. The primary outcome was FEV1 after ß2-agonist use. The investigators were looking for longer-term changes over several years and regarded FEV1 as a measurement of decrements or changes in lung growth or absolute lung function. That seemed more reasonable than relying on FEV1 to measure short-term outcome.

The children in this study had an FEV1 that averaged 94% of predicted before ß2-agonist use.2 After ß2-agonist use, FEV1 increased to 103% of predicted. FEV1 did not differ significantly among the placebo and treatment groups, perhaps because the children in this study, like many children with asthma, had good lung function to begin with.

In looking at the other end point assessments, however, treatment groups fared significantly better than placebo groups. Children given budesonide had fewer asthma-related hospitalizations and urgent care visits, used prednisone and albuterol less often, and had more episode-free days compared with those who received placebo. Nedocromil reduced urgent care visits and prednisone use. When budesonide and nedocromil were discontinued, the children's bronchial hyperreactivity returned to baseline.

The CAMP study illustrates how FEV1 can be deceiving. If patients have mild asthma, with normal or relatively normal lung function to begin with, it can be difficult to detect differences among treatment groups.

Need for multiple end points

These shortcomings of FEV1 underscore the importance of incorporating multiple end points into a trial design. This is especially true when addressing issues pertaining to patients with mild asthma.

My colleagues and I in the NHLBI-supported ACRN conducted a randomized, placebo-controlled study of the effectiveness of salmeterol, a long-acting ß2-agonist, as replacement therapy in patients whose asthma was well controlled by low doses of inhaled triamcinolone.3 The salmeterol and triamcinolone groups had very similar outcomes, as assessed by PEF, symptoms, rescue ß2-agonist use, and quality of life. However, in persons who received salmeterol, there was an increased incidence of other adverse outcomes, including asthma exacerbations and treatment failures, as well as increased airway inflammation, as shown by the presence of inflammatory markers in sputum. There were significantly fewer treatment failures in the triamcinolone group (3) than in the salmeterol (13) and placebo (20) groups.

During the run-in period--when all patients in the study were receiving triamcinolone--the sputum eosinophil count decreased to its lowest point.3 During the double-blind treatment period, sputum eosinophilia increased markedly in both the placebo and salmeterol groups, but not in the triamcinolone group; this difference was statistically significant.

These results highlight the discrepancies that can occur among some measures of outcome, such as pulmonary function and symptoms, and others, such as treatment failure, asthma exacerbations, and airway inflammation. Assessing patient outcome according to several criteria provides more comprehensive information and can help reduce errors when evaluating therapeutic response.

Other outcomes/considerations

Some outcomes assessments--notably, those used to gauge the patient's satisfaction with treatment or quality of life--are subtle and are dissociated from the major outcomes assessments (pulmonary function tests) traditionally used in respiratory studies. The following study is a case in point.

A 12-month, open-label trial examined the long-term efficacy and safety of switching asthmatic patients maintained on a stable dose of chlorofluorocarbon-beclomethasone dipropionate (CFC-BDP) to treatment with hydrofluoroalkane-134a (HFA)-BDP, given at about half the previous daily dose of CFC-BDP.4 The medications were delivered by a pressurized metered-dose inhaler.

The 2 preparations of beclomethasone did not differ with respect to morning PEF, FEV1, asthma symptoms, or rescue ß2-agonist use.4 However, there was an overall increase from baseline in the percentage of symptom-free days that averaged 11.5% in the HFA-BDP group and 4.6% in the CFC-BDP group. Patients in the HFA group also experienced a significantly higher percentage of nights without sleep disturbance than patients in the CFC group. If the investigators had examined outcome according to pulmonary function tests only, they would have missed the greater benefit of HFA-BDP versus CFC-BDP.

Juniper and colleagues5 also assessed the effect of switching from CFC-BDP to HFA-BDP, at half the dosage, in patients with stable asthma. To determine how this change in treatment affected health-related quality of life, the investigators evaluated outcomes according to pulmonary function tests and the Asthma Quality of Life Questionnaire (AQLQ).

After 12 months, persons receiving HFA-BDP had an improved AQLQ score of approximately 0.3 to 0.4 units (more than the improvement in the CFC group).5 Although the improvement in the HFA group overall was just shy of the minimum--0.5 units--needed to achieve significance on the AQLQ, several persons within the group did meet that benchmark. Identifying the number of persons needed to treat to produce a clinically important benefit in 1 person is a common technique for determining the cost/benefit ratio of various asthma interventions. The number needed to treat in this case was 7.3 for the overall AQLQ score.

Juniper and colleagues6 also examined 22 different kinds of questions and parameters that can be used to evaluate asthma and asthma control (Table 1). These questions can be divided into 4 differ-ent domains: daytime symptoms, such as wheezing, chest tightness, and activity limitations; nighttime symptoms, including wakening and ß2-agonist use; pulmonary function parameters, such as PEF and FEV1; and quality-of-life indices, such as symptoms, emotions, and activities. The parameters in these domains encompass the most important issues in asthma control. The answers to these questions explain about 80% of the important findings that patients try to communicate to their doctors when they say they are not doing very well.

There are a number of different costs associated with uncontrolled asthma, including those related to unscheduled medical care visits, the morbidity associated with time lost from school or work, and the costs of medication use. In the IMPACT study, patients regularly receiving budesonide or zafirlukast took medication for an average of 47 weeks per year, while patients receiving placebo (who were guided by the symptom-based action plan) took inhaled corticosteroids for an average of 1.25 weeks per year.1

One of the major implications could be summarized by the following estimate: If 20% of the 15 million Americans with asthma have "mild persistent asthma" and 1 canister of an inhaled corticosteroid is needed per patient-year when taken as needed, versus 12 when taken regularly, full compliance with the current recommendation for daily treatment would increase medication expenditures by more than $1.5 billion per year.


Variable treatment response

Not every patient with asthma responds in the same way to a given intervention: some are known as responders, others as nonresponders. This observation needs to be considered when designing studies, determining end points, and interpreting results.

One of the first trials to show the responder/nonresponder difference among persons with asthma was a study comparing low-dose inhaled beclomethasone, oral montelukast, and placebo in 895 persons with chronic asthma.7 Primary end points were daytime asthma symptom score and FEV1.

Of the patients who received montelukast, 42% experienced a change in FEV1 from baseline of at least 11%. The proportions of patients who did not have at least an 11% improvement were 22% with beclomethasone and 34% with montelukast. The initial response to montelukast was faster and more pronounced than the response to beclomethasone. By 7 to 10 days, however, the effect of beclomethasone exceeded that of montelukast. With each drug, some patients (nonresponders) had little improvement and some (responders) had marked improvement (Figure 1).7

Another study by Israel and colleagues8 showed a similar distribution of FEV1 responses in patients treated with montelukast or beclomethasone. Overall, the 2 drugs were similarly effective.

One of the clinical end points in this trial was the number of days on which asthma control was good.8 Over 6 weeks, the number of good control days improved more in the beclomethasone and montelukast groups than in the placebo group. Nonetheless, only 40% to 45% of days were good control days in the actively treated patients (Figure 2). Further analysis revealed that only 20% to 30% of patients had 90% to 100% of good asthma control days.

One possible explanation for these results is that the baseline FEV1 of the participants averaged 66% to 67% of predicted. This kind of moderately severe asthma is generally not controllable with a low-dose inhaled corticosteroid or a single agent such as montelukast. The severity of asthma and the trial interventions were mismatched.

Matching outcomes and patient

The study by Israel and colleagues8 shows the importance of matching treatments and outcomes assessment to the patient. Certainly, treatment that is not aggressive enough could contribute to the patient's being considered a nonresponder, when in fact, he or she might be a responder if the treatment-- and the evaluation of therapeu- tic response--were appropriately matched to symptoms.

The INNOVATE trial examined the benefits of omalizumab, a monoclonal anti-IgE antibody, in a population of patients with difficult-to-treat asthma.9 The participants had clinical features that were consistent with Global Initiative for Asthma (GINA) steps 3 and 4 asthma, which is very severe. Each year, these patients averaged at least 2 clinically significant exacerbations of asthma, 5 unscheduled office visits, 30 days missed from work or school, and poor quality of life. Their mean FEV1 was 62% of predicted.

This study used different end points than did trials in persons with mild or moderate asthma.9 Rather than trying to evaluate pulmonary function in patients taking maximum medications (including inhaled corticosteroids and bronchodilators), the study investigators chose number of asthma exacerbations as the primary end point. Secondary end points were reduction in inhaled corticosteroid use, daytime and nighttime symptoms, pulmonary function test outcomes, bronchodilator use, and asthma- related quality-of-life scores.

The investigators tried to match the outcomes assessment to the severity of asthma and the characteristics of the patients enrolled in the trial.9 This is important for drawing a proper clinical conclusion about the data generated from a clinical trial.

Reasons for response versus nonresponse

The question of why some persons respond well to one asthma medication but not another has attracted considerable attention. Investigators are especially interested in finding out whether there is a biologic explanation.

The CARE investigators designed a multicenter, double-blind, cross-over trial of 144 children, aged 6 to 17 years, to test whether they responded equally well to an inhaled corticosteroid (low-dose fluticasone) and to a leukotriene receptor antagonist (montelukast).10 The primary outcome was the percentage change in prebronchodilator FEV1: a 7.5% increase in FEV1 defined a therapeutic response.

Of 144 enrollees, 127 completed both arms of the trial. The response rates were 22% for montelukast and 40% for fluticasone. Some children responded to one agent only: 5% to montelukast and 23% to fluticasone. More troubling was that 69 of the children--55%--did not respond to either medication.10

It is logical to ask whether there are any variables that allow us to predict which patients might respond to one asthma medication or another. In the CARE study, the patients who responded better to fluticasone therapy had the following characteristics:

• Prebronchodilator FEV1 less than 90% of predicted.

• FEV1:FVC ratio less than 80% of predicted.

• Hyperresponsiveness to methacholine challenge.

• Increased markers of inflammation (exhaled nitric oxide greater than 25 ppb, blood eosinophil count of more than 350/µL).

• Serum IgE level of more than 200 kU/L.

Persons who tended to respond better to montelukast had these characteristics:

• Low FEV1:FVC ratio (less than 80% of predicted).

• Urinary leukotriene E4 level of more than 100 pg/mg creatine.

• Age less than 10 years.

The children who responded to fluticasone and montelukast or fluticasone alone had a lower FEV1 that averaged 88% to 90% of predicted. Children who did not respond to either medication had an average FEV1 of 99% of predicted, which is essentially normal.

As mentioned above, it is very difficult to detect any change in values when pulmonary function is normal or near normal. When selecting an outcome to follow, it is obviously important to choose one that allows you to detect and document a change. I believe that symptom-based outcomes will eventually be as important for our patients as pulmonary function- based outcomes are now--especially for persons who have very good FEV1 at baseline.

Some differences in patient responses to different medications can be explained by genetic factors. For example, the ACRN recently reported that patients who were homozygous for arginine at position 16 of the ß2-adrenergic receptor did not respond as well to regular use of albuterol as did patients who were homozygous for glycine at this same position.11


Composite outcomes are a combination of several different outcomes assessments, such as symptoms, changes in pulmonary function, excessive use of rescue medication, or asthma exacerbations. When any one criterion is reached, treatment failure is considered to have occurred. As a result, treatment can fail by different means in different patients.

My colleagues and I12 used a composite outcome in a trial that explored whether colchicine could be substituted for an inhaled corticosteroid in persons with moderate asthma. The primary end point was treatment failure, defined by any of these criteria:

• A decline in FEV1 to less than 80% of baseline.

• An FEV1 of 40% of predicted or lower.

• A slow decrease in PEF to 65% of baseline or lower on 2 of 3 consecutive scheduled morning or evening measurements.

• An increase from baseline in as-needed ß2-agonist use (at least 8 puffs/h or at least 16 puffs/24 h for 48 hours).

• Refusal to continue with study drugs because of dissatisfaction with the treatment regimen.

Treatment failure rates were similar for patients in the place- bo (56%) and colchicine (60%) groups.12 Thus, colchicine could not be satisfactorily substituted for the inhaled corticosteroid. Most of the 41 patients who met the criteria for treatment failure did so because of changes in FEV1. Others had treatment failure because of excessive ß2-agonist use, intolerable symptoms, or dissatisfaction with treatment. Twelve patients failed by more than 1 criterion; one person met 3 failure criteria. Allowing different patients to fail by different criteria both increased our clinical "signal" and accounted for interindividual variability in the response to these treatments.

The primary measure of efficacy was the time to treatment failure after withdrawal of inhaled corticosteroids. We therefore asked the patients and study coordinators to specify whether they thought treatment failure had occurred at the right time. In 25 of 41 cases, patients and coordinators thought that treatment failure had occurred at the correct time. In 10 cases, either the patient or coordinator indicated that withdrawal from the study had happened prematurely (the patient could have continued in the trial longer), and in 12 cases, either the patient or the coordinator indicated that withdrawal from the study had occurred too late.12

This study was one of our first attempts to use a major therapeutic end point that had multiple components by which treatment failure could occur. Our analysis indicated that the criteria selected for treatment failure reflected a clinically meaningful, but safe, level of deterioration. Other ACRN trials have used composite end points, with similarly good results.


There are 2 outcomes assessments that are oriented toward the patient rather than toward pulmonary function: the ACQ and the ACT.

Asthma control questionnaire

Juniper and colleagues6 generated a list of 10 symptoms used to assess asthma control and asked 91 specialists to rate the importance of each. Five of the highest-scoring symptoms were selected for the ACQ (Table 2).

There are 2 forms of the ACQ. The short form only uses questions that are based on symptoms. The long form, in addition, asks about ß2-agonist use and FEV1. Both forms are validated and equivalent, although they are not numerically equivalent because scoring differs for each (Table 3).

The ACQ questions are scored on a scale from 0 (good control) to 6 (very poor control), and the average is taken. The higher the score, the worse the asthma control. For example, a score of 1.5 indicates bad or insufficient asthma control, whereas a score of 0.75 or less means reasonable control.

The ACQ is sensitive to small changes in control. A 0.5 change is the minimum to be considered clinically significant. Thus, a person whose score increased by 0.7, for example, would be experiencing a significant loss of asthma con-trol. A score that declined by that amount would indicate significant improvement. The ACQ has proved useful in clinical trials, although it has not yet been validated for individual patients.

Asthma control test

The ACT is another instrument that is being used more frequently and is being validated over time. Nathan and colleagues13 prepared a 22-item survey that they gave to 170 patients, asking them to estimate their asthma control over the past month. They also asked specialists to rate these patients' asthma after the specialists saw the patients' answers to the questions and measured their FEV1. The 5 items that were identified as being most closely related to specialists' ratings of asthma control were chosen as the basis of the ACT (Table 4). (Note: there were only low to moderate correlations [correlation coefficient, 0.19 to 0.45] among ACT, FEV1, and specialist rating.)

The ACT is scored on a scale of 1 to 5 for each question (Table 5). A total score of 25 reflects completely controlled asthma, a score of less than 19 indicates a need for better asthma control, and a score of 5 represents completely uncontrolled asthma. The ACT differs from the ACQ in using the specialists' rating of asthma control for validation. Also, unlike the long form of the ACQ, the ACT does not require that FEV1 be measured. However, the originators of the ACT concede that the best measure of asthma control is a combination of ACT score and FEV1. They also do not recommend one particular score level as a cutoff point that should be used in all cases.13


For most patients, asthma is not controlled according to precise guidelines. This leads us to wonder whether it is possible to achieve complete asthma control. One study attempted to achieve 2 composite, guideline-based measures of asthma control--total and well-controlled asthma--in persons with uncontrolled asthma.

The Gaining Optimal Asthma Control (GOAL) trial was a 12-month, stratified, double-blind study that randomly assigned 3421 patients to receive fluticasone, either alone or in combination with salmeterol.14 The dosage of fluticasone was increased until the patient was taking a maximum of 1000 µg/d or had achieved ideal asthma control. The average FEV1 of the study participants was 78% of predicted.

Total asthma control was defined as the absence of exacerbations, emergency department (ED) visits, treatment-related adverse effects, daytime symptoms, nocturnal awakenings, and rescue ß2-agonist use, and a PEF of at least 80% of predicted. Well-controlled asthma was defined by all of the following: absence of asthma exacerbations, ED visits, treatment-related adverse events, and nocturnal awakenings, and 2 of 3 of the following: minimal symptoms present on 2 days per week or less; use of a rescue ß2-agonist on fewer than 2 days and 4 uses per week or less; or a PEF of at least 80% of predicted. These were very high standards. Results were stratified according to the patient's use of beclomethasone (500 µg/d or less, or more than 500 to 1000 µg/d) during the past 6 months.14

The combination of fluticasone and salmeterol was the most effective at achieving total asthma control (Figure 3). However, even with this combination regimen, only 29% and 44% of persons who had been taking higher and lower dosages of beclomethasone within the past 6 months, respectively, satisfied the criteria for complete control. A higher percentage of persons receiving combination therapy--75% of those taking a lower dosage and 62% of those taking a higher dosage of beclomethasone--attained the goal of well-controlled asthma.

This trial showed that it is possible to achieve ideal or near-ideal asthma control, but at a cost of pushing the medication to a high dosage. Whether physicians should be doing this is unclear.

Contrary to published treatment guidelines, this trial did not continually adjust the medication dos- age to the lowest amount needed to maintain control. Thus, the patients could have been overtreated. The investigators did not step down therapy to see whether the participants' asthma could be controlled at a lower dosage of inhaled corticosteroids.


Broadening our perspective to look beyond FEV1 as an outcome measure offers many advantages. Incorporating more clinically oriented criteria, such as number of hospital visits and need for rescue medications, and more patient-centric criteria, such as perceived quality of life, days missed from work or school, and nocturnal awakenings, can provide a more "real-world" perspective of patients' therapeutic responses.

The use of combination end points encompassing objective pulmonary function tests and subjective patient-centric measurements, such as the ACT and ACQ, provides a more complete perspective on clinical outcome. Combination end points appear to be especially worthwhile in persons with mild to moderate asthma who have good pulmonary function to begin with. In such persons, it can be difficult to detect changes in pulmonary function parameters.

In considering the results of asthma trials, ask whether the intervention and outcomes assessment were suitable for the level of illness of the participants. A treatment that is too mild for the patient's severity of asthma can make the patient appear to be a nonresponder. Also, question whether the trial may have involved overtreatment of patients to achieve the level of control attained.



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