Why patients with asthma should be given a trial of controller therapy

The burden of asthma--with respect to morbidity, impact on quality of life, and health care costs--continues to be substantial.^1,2 In the United States, asthma causes about 14.5 million missed workdays and 14 million missed school days each year.² In 1999, there were 478,000 hospitalizations, nearly 2 million emergency department (ED) visits, and more than 4000 deaths associated with asthma.²

Anti-inflammatory agents, such as inhaled corticosteroids and leukotriene modifiers, are recommended to reduce the chronic airway inflammation that characterizes asthma. These agents are considered controller therapies and are recommended for patients with persistent asthma.³ However, most patients with asthma should be considered for a trial of controller therapy based on the current evidence, which I will review here.

THE BENEFITS OF CONTROLLER THERAPY

Multiple clinical trials have demonstrated convincingly that the use of controller therapy is associated with significant decreases in asthma-related morbidity and even mortality. Use of controller agents, such as inhaled corticosteroids^4-10 and leukotriene modifiers,^11-17 has been shown to improve asthma control--specifically, decrease exacerbations, reduce symptoms, and improve lung function (Table). These medications provide tremendous benefits to our patients and, when used appropriately, can significantly improve their quality of life.

In addition to the above-mentioned clinical trials, a study by Donahue and associates⁷ provided important information about the effects of controller therapy in a managed care setting. This study documented that the prescription of an inhaled corticosteroid was associated with a significantly reduced risk of hospitalization for asthma.

Malmstrom and colleagues¹⁸ demonstrated that use of the inhaled corticosteroid beclomethasone and the leukotriene receptor antagonist montelukast significantly reduced the risk of asthma exacerbations, compared with placebo, in patients with mild to moderate asthma (Figure 1). Both agents provided a number of benefits, such as improved forced expiratory volume in 1 second (FEV₁), decreased symptoms and nocturnal awakenings, and improved quality of life.

In a randomized, multicenter, double-blind, placebo-controlled study, Israel and colleagues¹⁹ also showed that beclomethasone (200 µg twice daily) and montelukast (10 mg daily) effectively improved asthma control, according to several measures, such as increased number of asthma control days and reduced frequency of asth- ma exacerbations and flare-ups (Figure 2).

The Childhood Asthma Management Program (CAMP) clinical trial,²⁰ which evaluated inhaled corticosteroids and the NSAID nedocromil, did not find a significant effect on lung function (postbronchodilator FEV₁) in children with asthma. However, inhaled corticosteroid therapy led to improvement in many important outcome variables. Specifically, children who received inhaled corticosteroids had fewer hospitalizations, fewer urgent care visits, less use of oral prednisone for exacerbations, reduced symptoms, and decreased airway hyperresponsiveness.

Thus, the above-described data indicate that inhaled corticosteroids and leukotriene modifiers are beneficial for many patients. Would all patients benefit from such therapy? Should you consider a trial of controller therapy even in patients with normal pulmonary function?

We have previously shown that targeting inhaled corticosteroid therapy to certain patient populations, including persons with mild asthma, is more cost-effective than use of as-needed reliever therapy alone.²¹ Over a 10-year period, use of inhaled corticosteroids among patients with mild to moderate asthma did increase total health care costs, but it also improved quality of life, increased symptom-free days, and decreased acute exacerbations, yielding an incremental cost-effectiveness ratio of $13,500 per quality-adjusted life-year gained or $7.50 per symptom-free day gained. Thus, inhaled corticosteroids appear to deliver good comparative value in adults with mild to moderate asthma.

Patients with normal lung function

In a large population-based survey of children with asthma, we found a significant inverse correlation between FEV₁ percent of predicted and the risk of exacerbation in the subsequent year.²² This relationship was observed even in children with an FEV₁ in the higher ranges of the distribution. Similarly, a study that included 2 separate adult cohorts found that higher FEV₁ values were associated with reduced risk of exacerbations, with a trend toward decreasing asthma attacks at higher levels of lung function.²³

The mean FEV₁ of the children entering the CAMP study was about 94% of predicted²⁰; these children clearly benefited from controller therapy. A reanalysis of some of the CAMP data showed that controller therapy resulted in fewer symptoms and more episode-free days even in the children who had higher FEV₁ values.²⁴ FEV₁ at baseline predicted the risk of symptoms over the next 4 months.²⁴

These findings suggest that controller therapy can provide clinical benefits even in patients who have higher levels of lung function. Thus, the presence of normal lung function does not rule out the possibility that the patient will benefit from a trial of controller therapy.

Patients with mild asthma

Evidence from several studies suggests that patients reported to have mild asthma may benefit from controller therapy. The OPTIMA study, which included 698 patients with mild asthma, provided such evidence.²⁵ The participants were not receiving inhaled corticosteroids at entry, their postbronchodilator FEV₁ was at least 80% of predicted, and they had a 12% to 15% variation in peak expiratory flow (PEF). They were randomized to receive either inhaled corticosteroids or inhaled corticosteroids plus a long-acting ß₂-agonist.

Patients in both treatment groups had a longer time to first severe exacerbation, compared with those in the placebo group.²⁵ Similarly, in both treatment groups, there was a significant reduction in the rate of severe exacerbations per year and patients had poorly controlled asthma on fewer days. Thus, controller therapy led to improvement in a number of important clinical outcomes.

However, it is reasonable to ask whether the OPTIMA patients really had mild asthma. As noted, these patients had symptoms at least 2 times a week, and their number of symptom days may have been higher than expected for patients who have mild intermittent disease.

Pauwels and associates⁴ conducted a study--known as START ("inhaled steroid treatment as regular therapy in early asthma study")--that is relevant to this question. This large trial included both children and adults who had had mild asthma for less than 2 years. These patients had not regularly used inhaled corticosteroids, and they all had bronchodilator reversibility. The mean prebronchodilator FEV₁ was 86% of predicted, and the mean postbronchodilator value was 96% of predicted. However, the participants reported symptoms at least once a week, but not daily. As with the OPTIMA trial, it is uncertain whether all the participants had mild intermittent asthma.

The patients were randomly assigned to receive budesonide or placebo, in addition to their regular asthma therapy, for 3 years. The results indicated that use of budesonide was associated with a significant decrease in the risk of severe asthma-related events.⁴ In addition, those who received budesonide had fewer life-threatening exacerbations, required fewer courses of systemic corticosteroids, and had more symptom-free days. Thus, several different outcome measures indicate significant improvement in patients who receive controller therapy.

The IMPACT study by the Asthma Clinical Research Network was designed to include patients who had mild intermittent asthma.²⁶ Their FEV₁ was at least 70% of predicted, they had bronchodilator responsiveness (or methacholine hyperresponsiveness), and they were taking ß₂-agonists only. After 6 weeks of placebo, they were randomly assigned to receive continuous therapy with budesonide (200 µg twice daily), continuous therapy with zafirlukast (20 mg twice daily), or placebo for 12 months. All participants had access to open- label inhaled and oral corticosteroids, which they were instructed to use according to a symptom-based action plan.

The results did not demonstrate a significant difference in the primary outcome, which was morning PEF, over 1 year.²⁶ In addition, controller therapy did not significantly reduce exacerbations; however, this trial was not designed to assess exacerbations. The exacerbation rate was 11.3% in the intermittent-treatment group and 16.1% in the budesonide group, a difference that may have been meaningful to the patients.

It is important to remember that we should not depend on a single outcome in any given trial. Although there was no difference in postbronchodilator lung function, morning PEF, time to first exacerbation, or the asthma quality-of-life questionnaire, there were differences in other important outcomes: greater improvement in prebronchodilator FEV₁, bronchial reactivity, inflammatory markers (percentage of sputum eosinophils, exhaled nitric oxide levels), and symptoms (number of symptom-free days and the asthma control score).²⁶

Thus, the message derived from any given trial depends on which outcome you evaluate. We should consider which outcomes will be most important to patients.

Finally, it is important to note that life-threatening exacerbations of asthma can occur even in patients whose asthma is classified as mild intermittent.²⁷

THE VARIABILITY OF ASTHMA

We may be underestimating the level of asthma control in many patients because of the considerable variability that characterizes asthma. This includes variability in presentation, within-patient variability in asthma status over time, and variability in response to therapy. It is clearly difficult to predict which patients will respond to a specific therapy and which will not.

Variability in presentation

Although some studies indicate that at least two thirds of patients with asthma have mild disease,²⁸ other analyses suggest that the proportion of persons with mild asthma is actually much lower.¹ The data from the Asthma in America survey²⁸ reflected short-term symptoms--those occurring over the past 4 weeks. However, evaluating a longer time frame and considering additional factors, such as activity limitation, reveal more about the impact of disease on daily life. When we performed an analysis of asthma burden, only about 7% of patients actually had mild intermittent asthma; about 77% had moderate to severe persistent disease (Figure 3).¹

We also recently analyzed data on the asthma burden in children.²⁹ Similar to the adult analysis, when we focused on short-term symptoms alone, the proportion of children with milder disease was higher, while an analysis that included longer-term symptoms and activity limitation yielded a marked shift in the distribution of disease. This adds further support to the possibility that we may underestimate the severity of asthma in our patients if we do not ask the correct questions.

Variability in response

Some studies have shown that a substantial proportion of the asthma population may not respond to any given therapy.^18,30 However, it is also true that a number of patients benefit dramatically from a given therapy, as Malmstrom and associates¹⁸ showed with beclomethasone and montelukast. It is very difficult to predict accurately who will respond. Certain variables appear to be associated with response to therapy, but we do not have specific tests that will definitively establish who will and who will not respond to an asthma medication.

There is increasing awareness of the substantial variability of response to asthma therapies.^18,19,31-38 The study of fluticasone and montelukast by Szefler and associates³⁰ demonstrated that some patients respond to one type of therapy, but not another. Some patients respond to both medications, while others do not respond to either. However, these findings were based on the evaluation of a single parameter. If multiple parameters are assessed, the distribution of responses will be different.

Recent work has focused on how genetics can play a role in an individual patient's response to medications. Pharmacogenomics is the study of how genetic variability in individuals influences the variability in the response to pharmacotherapy. This type of information may allow us to target treatment for those who can benefit most from particular asthma medications and to avoid toxicity by not administering certain medications to those who are most likely to experience adverse effects.

Variability over time

There also is variability in asthma severity over time within individual patients. This was alluded to by the enrollment data from the IMPACT trial.²⁶ Patients who were initially thought to be reasonable candidates for the trial were subsequently disqualified because of changes in their level of asthma severity over the run-in period.

Stempel and associates³⁹ recently conducted a retrospective observational study that analyzed administrative claims data from multiple health care plans. This study included more than 63,000 patients who had a diagnosis of asthma and had 3 years of continuous claims coverage. The patients were considered to have controlled asthma in year 1 if they had fewer than 4 claims for a short-acting ß₂-agonist, no claims for an oral corticosteroid, and no asthma-related ED visits or hospitalizations.

The results indicate how common it is for patients to experience episodes of uncontrolled asthma.³⁹ In the first year, 34% of patients met the criteria for uncontrolled asthma. Of those who met the criteria for controlled asthma in the first year, 10% to 14% had a period of uncontrolled asthma during the 2-year follow-up. Overall, 73% of patients met the criteria for uncontrolled asthma at least once during the 3-year study period.

In a subsequent analysis of the same patient population, we categorized patients based on their inhaled corticosteroid use.⁴⁰ Intermittent users were those who used 1 to 3 canisters per year, and consistent users were those who used more than 1 canister per quarter for 4 consecutive quarters.

Patients in a third group used more than 4 canisters per year but did not meet the criteria for consistent users--they did not get a regular dispensing of controller agent every quarter. This group was labeled "adjustable."

Our analysis showed that consistent users in year 1 had a reduced risk of asthma-related ED visits or hospitalizations in the first quarter of year 2, compared with those in the adjustable group--the patients who used more inhaled corticosteroids but did not use them consistently.

This variability suggests that data from one point in time may not provide an accurate assessment of a patient's disease severity over time.

CONCLUSIONS

Based on the information presented above, which includes the variability that characterizes asthma and our inability to predict accurately who will respond to therapy, there is a strong reason to consider a trial of inhaled corticosteroids or leukotriene modifiers for a given patient with asthma. Then, the patient and the physician can decide whether to continue this therapy or, perhaps, try another type of controller therapy. This decision is based on their combined assessment of the change in asthma control, which reflects multiple parameters, and consideration of other factors, such as convenience, toxicity, and cost. Thus, the patient and physician can make their own decision about whether inhaled corticosteroids or another controller therapy is appropriate.

All patients deserve an opportunity to experience asthma control. It is important to consider a trial of controller therapy to see whether a particular patient achieves a significant benefit.

References:

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