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* From the University of California School of Medicine (Dr. Kemp), San Diego, CA; and Zeneca Pharmaceuticals (Drs. Minkwitz, Bonuccelli, and Warren), Wilmington, DE.
Correspondence to: Dr. James P. Kemp, Allergy and Asthma Medical Group and Research Center, 9610 Granite Ridge Dr, Suite B, San Diego, CA 92123
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Data were analyzed from a subgroup of 261 steroid-naive patients (zafirlukast, n = 149; placebo, n = 112) from four randomized, double-blind, placebo-controlled, 13-week trials with similar experimental designs, entry criteria, and clinical assessments.
Patients: These patients were mostly men (57%) older than 30 years (56%) with pulmonary obstruction, ie, FEV1/FVC ratio < 0.7 (79%), and reversible airway disease demonstrated by a 15% increase in FEV1 after inhaled bronchodilator use.
Results: At end point, patients who received zafirlukast
monotherapy had significant (p < 0.05) improvements from baseline,
and compared with placebo, in FEV1, morning and evening
peak expiratory flow (PEF), daytime asthma symptoms, nighttime
awakenings, and ß2-agonist use. A stratified analysis
based on the FEV1/FVC ratio showed an interaction between
treatment and the amount of airflow obstruction for nighttime
awakenings and mornings with asthma. Moreover, 37% of patients in both
treatment groups had PEF variability 
20% (an indirect measure of
airway inflammation). Zafirlukast patients with PEF variability
20% had increases from baseline in the morning and evening PEF of
approximately 40 and 11 L/min, respectively. For patients who take
zafirlukast and who have a PEF variability of < 20%, the morning and
evening PEF increased by 25 and 30 L/min, respectively. Regardless of
the degree of PEF variability, zafirlukast significantly (p < 0.05)
increased morning and evening PEF compared with placebo.
Conclusion: Patients with severe persistent asthma who received zafirlukast as monotherapy had clinically significant improvements across all efficacy measures compared with placebo and significant reductions in PEF variability.
Key Words: asthma symptoms • pulmonary function • severe persistent asthma • zafirlukast
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The new National Asthma Education and Prevention Program (NAEPP) guidelines for the diagnosis and management of asthma classify asthma into four categories according to severity, ie, mild intermittent, mild persistent, moderate persistent, and severe persistent.2 Patients diagnosed with severe persistent asthma have one or more of the following characteristics: continual symptoms, symptoms that limit physical activity, or frequent exacerbation of asthma. Other distinguishing features include frequent nighttime symptoms, an FEV1 or peak expiratory flow (PEF) of 60% of predicted or lower, or PEF variability greater than 30%.
For patients with severe persistent asthma, the recommended therapeutic approach for long-term control involves treatment with an anti-inflammatory agent (ie, a high-dose inhaled corticosteroid), a long-acting bronchodilator (either a long-acting ß2-agonist, sustained-release theophylline, or long-acting inhaled ß2-agonist tablets), and long-term treatment with corticosteroid tablets or syrup (2 mg/kg/d, not to exceed 60 mg/d).2 The goals of treatment are to prevent symptoms, restore and maintain normal pulmonary function, help patients regain normal activity levels, prevent recurrent exacerbations, provide optimal pharmacotherapy with minimal side effects, and meet both patient and family expectations of satisfactory care.2
Because clinical manifestations of asthma vary among patients and between seasons, treatment must be selected to suit individual patients. At routine office visits, the severity of asthma can be underestimated. For example, in mild-to-moderate asthma, it is not unusual for patients with symptoms and exacerbations to have normal spirometry results at office visits. In such cases, regular monitoring with peak flowmeters helps evaluate the effectiveness of therapy, avoiding inadequate treatment. Monitoring the frequency of nighttime symptoms and the extent of activity limitation also provides important information for determining the severity of asthma and an appropriate treatment regimen.
The class of compounds known as leukotriene receptor antagonists is currently recommended as an alternative to inhaled corticosteroids or anti-inflammatory medications in patients with mild-to-moderate persistent asthma.2 In reviewing baseline characteristics of patients involved in the zafirlukast (Accolate; Zeneca Pharmaceuticals; Wilmington, DE) clinical trial program, we discovered that a number of patients who were diagnosed as having mild-to-moderate asthma on the basis of their treatment history—therapy with ß2-agonist only—had an FEV1 < 60% of predicted at trial entry. As such, these patients would be classified by the most recent NAEPP guidelines as having severe persistent asthma. This finding prompted our investigation of the efficacy of the recommended dosage of zafirlukast as monotherapy with that of placebo in the subgroup of steroid-naive patients (ie, patients who had not received corticosteroid therapy) classified as having severe persistent asthma. Although data from patients in this subgroup were available from four placebo-controlled trials, the number of such patients in each trial was too small to permit separate analyses. Because the four trials had similar experimental designs, entry criteria, and clinical assessments, we pooled data from patients who had an FEV1 of < 60% of predicted at baseline and frequent nighttime symptoms (ie, two or more awakenings per week).
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patient Population
Entrance criteria varied only slightly among the 13-week trials
and are summarized in Table 1
. For this analysis, we included only patients from the trials who had
an FEV1 < 60% of predicted (a minimum of
6 h after ß2-agonist use). Patients in
this subgroup were nonsmokers 12 years or older who had a documented
history of asthma, reversible airway disease demonstrated by a 15%
increase in FEV1 after inhaled bronchodilator
use, and previous treatment with ß2-agonist
alone at trial entry.
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Screening and Placebo Run-in Periods
During the screening period, patients recorded morning and
evening PEF, daily asthma symptoms, and
ß2-agonist use on diary cards. Other
evaluations included a medical history, interviews about subjective
symptoms, a physical examination, vital signs measurements, a 12-lead
ECG, clinical laboratory tests, and a urine drug screen. All
procedures, except the medical history and urine drug screen, were
repeated at the end of the placebo run-in period.
FEV1 was measured at least 6 h after
ß2-agonist use during screening and run-in
periods. Albuterol was provided for use as rescue medication
throughout the trial.
Double-blind Treatment
In each trial, only symptomatic patients, as determined by their
cumulative daytime asthma symptoms score, were randomized to
double-blind treatment with zafirlukast or placebo (Table 1)
. Each day
throughout the double-blind treatment, patients recorded PEF, asthma
symptoms scores, and ß2-agonist use on diary
cards as previously described by Fish et al.3
FEV1 was measured at least 6 h after
ß2-agonist use at each clinic visit, and the
best of three forced expiratory maneuvers was recorded. Patients were
withdrawn from treatment at their request or because of a significant
adverse event, concurrent illness unrelated to asthma, treatment
failure, or administrative reason.
Efficacy Assessments
The primary efficacy measure for this population was the change
from baseline to end point in the measures of pulmonary function
(FEV1 and morning PEF); secondary end points were
the change from baseline to end point in daytime asthma symptoms score,
nighttime awakenings, mornings with asthma symptoms, and
ß2-agonist use. Response to treatment was
evaluated as the percent change in FEV1 from
baseline to end point. A 10% or greater increase from baseline was
considered a favorable response to treatment. In the individual trials,
the primary efficacy measure was the change from baseline to end point
in the daytime asthma symptoms score.
Safety Assessments
The safety of trial medications was evaluated from the results
of physical examinations, ECGs, clinical laboratory tests (including
clinical chemistry, hematology, and urinalysis), and subjective
symptoms interviews.
Statistical Analysis
The patient population analyzed comprised a subgroup of patients
pooled from intention-to-treat analyses in four 13-week,
placebo-controlled trials. These patients were treated previously with
as-needed ß2-agonist alone, received a 20-mg
dose of zafirlukast or placebo twice daily, and had a baseline
FEV1 of < 60% of predicted.
In individual trial protocols, the primary evaluation point was end point, which included a last value carried forward observation for patients who did not complete 13 weeks of treatment. Consequently, we used end-point data for all formal subgroup analyses.
In an article that identified various statistical problems encountered
when conducting and reporting clinical research, Pocock and
colleagues4
recommended using statistical tests of
interaction to analyze and report treatment differences between
subgroups. Therefore, we used an analysis of covariance with a trial
effect, the assessment baseline as a covariate, strata effect(s),
treatment effect, and strata-by-treatment effect(s). For the purpose of
this analysis, each center was treated as a random component of the
overall variability and not incorporated into the model. Interactions
were considered significant if they were associated with an F-test p
value of < 0.05 and approached significance when associated with an
F-test p value of < 0.10. p Values for comparison between zafirlukast
and placebo were reported using the analysis of covariance model
pairwise comparisons. A Bonferroni adjustment for multiple pairwise
comparisons was used, and a p value of 
0.006 was considered
statistically significant.
Efficacy evaluations were based on the original planned primary analysis as described by Fish et al.3 Briefly, analysis of the primary and secondary efficacy assessments was based on end-point data. End point is defined as the 13-week assessment or the last observed value carried forward for patients withdrawing during the trial treatment period.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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10% in
FEV1 after zafirlukast treatment compared with
50% of patients who received placebo (Fig 1
). Deterioration in pulmonary function was observed for 21% of patients
in the zafirlukast group and 35% of patients in the placebo group (Fig 1)
.
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20%), no interactions were observed between treatments and the
degree of variability. However, for patients with PEF variability
indicative of inadequately controlled asthma, ie, those with
20% variability at baseline, morning and evening PEF variability
was reduced to < 20% for significantly more patients in the
zafirlukast group than in the placebo group (53% vs 34%,
respectively; a 19% difference; p = 0.044; 95% confidence interval,
9% to 29%). Also, these patients had an increase from baseline in
morning and evening PEF of approximately 40 and 11 L/min, respectively,
after zafirlukast treatment (Fig 2 ). For patients with PEF variability of < 20% at baseline,
zafirlukast therapy increased morning and evening PEF by 25 and 30
L/min, respectively (Fig 2)
.
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0.70), significant (p < 0.05) interaction was
observed between treatments and the amount of airflow obstruction for
nighttime awakenings and mornings with asthma. Patients who had an
FEV1/FVC ratio indicative of moderate pulmonary
obstruction (ie, < 0.70) had fewer nighttime awakenings
per week after zafirlukast therapy than did patients who received
placebo (Fig 4
). Patients with less pulmonary obstruction
(FEV1/FVC of 0.70) had a similar reduction in
awakenings regardless of treatment (Fig 4)
. Compared with placebo,
patients in both FEV1/FVC ratio subgroups
reported fewer mornings with asthma after zafirlukast therapy, with the
largest reduction occurring for patients with less pulmonary
obstruction (FEV1/FVC ratio of 0.70) (Fig 4)
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Asthma exacerbation was defined as a worsening of asthma, requiring the withdrawal of the patient from the trial. In one trial, asthma exacerbation was defined a worsening of asthma resulting in patient withdrawal or requiring a burst of oral corticosteroids. Comparison of the effectiveness of treatments on asthma exacerbation rates favored the zafirlukast group over the placebo group, but the difference was not statistically significant (7 vs 11 or 4.7% vs 10.3%, respectively; p = 0.088). No significant treatment differences were observed in the incidence of any adverse event (Table 6 ).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Overall, 18% of patients who were diagnosed as having mild-to-moderate
asthma on the basis of their treatment history (ie, therapy
with ß2-agonist only) had severe persistent
asthma according to their baseline pulmonary function (ie,
an FEV1 of < 60% of predicted). Sixty-one
patients with an FEV1 < 60% of predicted had
two or more awakenings per week at baseline. Of these patients, 66%
had five or more awakenings per week because of asthma. Our analysis
also revealed that within this subgroup of patients with severe
persistent asthma, 79% had moderate airflow obstruction on the basis
of their FEV1/FVC ratio (< 0.7), and 37% had
poorly controlled asthma according to PEF variability ( 20%).
The recommended dosage of zafirlukast (20 mg bid) benefited this group of patients compared with placebo (p < 0.05) by inproving pulmonary function and reducing daytime symptoms, nighttime awakenings, and ß2-agonist use. As might be expected, patients with severe disease responded comparably and, in some cases, better to zafirlukast therapy than did patients with milder disease.3 When reviewing end-point data, we found that patients with severe disease had greater increases in FEV1 (21% vs 6%, respectively) and morning PEF (10% vs 7%, respectively) and greater reductions in nighttime awakenings (27% vs 20%, respectively) and ß2-agonist use (26% vs 22%, respectively) than did patients with mild-to-moderate disease.
The results for FEV1 and morning PEF for patients who received zafirlukast therapy are consistent with those reported for inhaled corticosteroid therapy in patients with moderate or severe asthma, as well as in patients with chronic asthma who had baseline values similar to those in our analysis. For example, the change from baseline in FEV1 of 0.32 L with zafirlukast therapy is comparable to the change of 0.28 L reported by Engel et al5 and 0.27 L observed by Busse et al6 in trials evaluating 1,600 µg budesonide daily, and is approximately 70% of the change of 0.44 L reported by Pearlman et al7 in a trial evaluating 500 µg fluticasone propionate daily. Similarly, the morning FEV1 change of 25 L/min with zafirlukast was within the range of 12 to 51 L/min reported with 1,600 µg budesonide daily5 6 8 9 and 21 to 27 L/min with fluticasone.7 8
The effectiveness of an asthma therapy can also be determined by the reduction in the proportion of patients requiring treatment for asthma exacerbation. In our analysis of patients with severe persistent asthma, the number of patients with exacerbations during zafirlukast therapy was almost half that of the placebo group (4.7% vs 10.3%). Similarly, in a study of patients with milder disease, exacerbation rates during the 13 weeks of the trial were half as high in the zafirlukast group as those in the placebo group (3.1% vs 6.5%).3
The adverse event profile in patients with severe asthma was not different from that observed previously by Fish et al3 in patients with mild-to-moderate disease. No significant differences were observed between zafirlukast and placebo in the occurrence or severity of adverse events. Hence, 13 weeks of treatment with zafirlukast did not place patients with severe persistent asthma at undue risk.
In conclusion, patients with severe persistent asthma who received zafirlukast as monotherapy had clinically significant improvements across all efficacy measures compared with placebo and significant reductions in peak flow variability. Additional studies are required to determine whether zafirlukast may confer additional benefits when combined with an optimized dose of inhaled corticosteroid therapy for the long-term disease management of patients with severe persistent asthma.
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Acknowledgements |
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Footnotes |
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Dr. Kemp is a consultant to Zeneca Pharmaceuticals and
a participating investigator in zafirlukast clinical trials.
Financial support for this study was provided by Zeneca
Pharmaceuticals, Wilmington, DE. 
Abbreviations: NAEPP = National Asthma Education and Prevention Program; PEF = peak expiratory flow
Received for publication March 10, 1998. Accepted for publication August 26, 1998.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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  W. Busse and M. Kraft Cysteinyl Leukotrienes in Allergic Inflammation: Strategic Target for Therapy Chest, April 1, 2005; 127(4): 1312 - 1326. [Abstract] [Full Text] [PDF]
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R. A. Silverman, R. M. Nowak, P. E. Korenblat, E. Skobeloff, Y. Chen, C. M. Bonuccelli, C. J. Miller, and S. G. Simonson Zafirlukast Treatment for Acute Asthma: Evaluation in a Randomized, Double-Blind, Multicenter Trial Chest, November 1, 2004; 126(5): 1480 - 1489. [Abstract] [Full Text] [PDF]
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 O J Dempsey Leukotriene receptor antagonist therapy Postgrad. Med. J., December 1, 2000; 76(902): 767 - 773. [Abstract] [Full Text]
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 Zafirlukast for Severe Persistent Asthma Journal Watch Emergency Medicine, April 1, 1999; 1999(401): 8 - 8. [Full Text]
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= zafirlukast; 
= placebo). A
significant (p = 0.01) interaction was observed between treatments
and the amount of airflow obstruction for both nighttime awakenings and
mornings with asthma.