Fluticasone Propionate Compared with Zafirlukast in Controlling Persistent Asthma A Randomized Double-Blind, Placebo-Controlled Trial

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Original Research

Fluticasone Propionate Compared with Zafirlukast in Controlling Persistent Asthma A Randomized Double-Blind, Placebo-Controlled Trial

J Fam Pract. 2001 July;50(7):595-602

References

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Discussion

The goals of asthma therapy are to prevent asthma symptoms, maintain normal activity levels, normalize lung function, meet patients’ expectations and satisfaction, and provide optimal therapy with minimal adverse effects.¹ For patients with persistent asthma, daily controller medications are recommended.¹ The results of our study indicate that, compared with zafirlukast or placebo, treatment with FP resulted in greater improvements in patients’ symptoms, quality of life, and overall satisfaction, as well as less albuterol use, fewer nighttime awakenings, and better pulmonary function. Furthermore, fewer FP patients experienced an asthma exacerbation compared with zafirlukast or placebo patients. Improvements in the zafirlukast group were generally similar to improvements reported in previous placebo-controlled trials with zafirlukast.^9,10

In our study, differences between FP and zafirlukast were seen early, and those differences generally persisted throughout the 12-week treatment. Treatment effects that favored FP were seen for all clinical endpoints by week 2, while differences in pulmonary function that favored FP were noted by day 4 of treatment. The rapid improvements noted with FP in our study are consistent with previously published results.¹¹ In the current study, patients treated with FP continued to improve with each subsequent week of treatment, while improvements with zafirlukast generally peaked after 2 weeks of treatment. Although the percentage of symptom-free days in the zafirlukast group appeared to increase in the last 4 weeks of the study, this may be related to the higher withdrawal rate during this period. Patient-rated outcomes support the clinical findings. Significant differences between FP and zafirlukast occurred by week 2 with quality of life, patient satisfaction, and days worked with asthma symptoms. The treatment effects noted in this study may be related to the rapid onset of action of fluticasone¹¹ and may result in improved compliance and better long-term asthma control.

Preventing recurrent exacerbations and minimizing the need for emergency department visits or hospitalizations is an important goal in asthma therapy.¹ The low incidence of exacerbations in the FP group in our study is consistent with data from previous clinical trials.^12-14 With regard to the frequency of asthma exacerbations in patients receiving leukotriene modifiers, available data demonstrate that zileuton, zafirlukast, and montelukast each significantly decrease the risk of asthma exacerbations compared with placebo.^10,15-17 Although leukotriene modifiers are superior to placebo in reducing the risk of asthma exacerbations, the results of our study indicate that patients receiving an inhaled corticosteroid had fewer asthma exacerbations than those receiving a leukotriene receptor antagonist. These data are in agreement with an earlier placebo-controlled, comparative study.¹⁷

A significant placebo effect was seen with FEV₁ in our study and is similar to observations from other FP studies.^18,19 In our study, the placebo effect was larger in patients with a percent predicted FEV¹ of more than 70% at baseline. One possible explanation for this is regression to the mean, since patients typically present for care when their symptoms are worst. Another is that milder patients are affected more by the additional medical attention received in clinical studies or that participation in a clinical study influenced patients to avoid asthma-triggering events. The placebo effect was strongest with the spirometric endpoints, for reasons that are unclear. Regardless of the magnitude of the placebo response, the differences in our study between placebo and each active treatment are consistent with the differences seen in other studies involving FP or zafirlukast.^18,20

Because asthma involves chronic inflammation of the airways, the NIH guidelines recommend long-term controller medications with anti-inflammatory effects. In the present study, an inhaled cortico-steroid and a leukotriene modifier both led to improvements in pulmonary function. However, FP continued to improve pulmonary function throughout the 12-week study, while the benefits of zafirlukast tended to plateau by week 2 of treatment. Although the precise mechanism of action of glucocorticoids in asthma is unknown, the greater degree of effectiveness seen with FP in the present study may be related to the multiple effects of inhaled corticosteroids on airway inflammation.²¹ A post hoc analysis of the patient population stratified by baseline pulmonary function (% predicted FEV₁ of 50% to 70% or 70.1% to 80%) showed that, regardless of baseline lung function, FP was more effective than zafirlukast or placebo with regard to improvement in albuterol use and pulmonary function. These data are consistent with asthma guidelines, which recommend inhaled corticosteroids as first-line treatment for all levels of persistent asthma.¹

Limitations

The design of our study has several potential limitations. First, several studies indicate that dosages of zafirlukast higher than 20 mg twice daily may result in greater pharmacologic results.^22-26 Our study, however, was performed in the United States, where this is the only approved dosage for zafirlukast. Second, outcomes were measured at the end of the dosing interval, before administration of morning dosages of study medication. The timing of these tests may have introduced a potential bias in favor of FP, since there is evidence to support bronchodilatory activity with leukotriene modifiers.²⁷ The lesser effect of zafirlukast could be explained if the drug has a duration of action that is shorter than the recommended 12-hour dosing interval. However, the procedures and timing used in this study are similar to those used in other studies of leukotriene modifiers.^9,10,17 Third, a large number of efficacy measures were collected at multiple time points, which potentially increases the likelihood of finding significant treatment differences. However, many of the differences noted in this study were highly significant, and all of the measures were in agreement. This suggests that treatment differences seen in this study were valid. Finally, zafirlukast tablets were over-encapsulated for the purpose of blinding. The over-encapsulation did not appear to affect the performance of zafirlukast, because over-encapsulated and nonencapsulated tablets exhibited similar dissolution profiles. This conclusion is reinforced by the fact that the efficacy profile of zafirlukast in our study is similar to that seen in previous studies.^9,10