Potential Role for Leukotriene Inhibitors in Asthma Management

Abstract & Commentary

Source: Silverman RA, et al. Zafirlukast treatment for acute asthma: Evaluation in a randomized, double-blind, multicenter trial. Chest 2004;126:1480-1489.

The objective of this study was to determine the effect of zafirlukast, an oral leukotriene receptor antagonist, in ED patients presenting with acute exacerbations of asthma. Adult patients presenting with asthma exacerbations were enrolled provided that they had an FEV1 less than 70% of predicted after an initial dose of nebulized albuterol 2.5 mg. Patients who had serious comorbidities or had received oral corticosteroids or leukotriene-modifying drugs within two weeks of presentation were excluded. All study subjects received repeated doses of nebulized albuterol and prednisone 60 mg orally. Patients were randomized, in a double-blinded fashion, to experimental and control groups. Those in the experimental group received either zafirlukast 160 mg (Z160) or zafirlukast 20 mg (Z20) orally; those in the control group received a matching placebo.

All patients remained in the ED for 4 hours, and then a disposition decision was made. Patients not ready for discharge, per the treating physicians’ assessment, were discontinued from the study protocol. Those patients in the zafirlukast group who were suitable for discharge at 4 hours received zafirlukast 20 mg BID for 28 days, while those in the control group received a matching placebo. Discharged patients also were provided with prednisone 20 mg BID, an albuterol inhaler to use as needed, and instructions to resume their usual asthma regimen. The primary study endpoint was time to relapse, defined as the need to return to the ED or make an unscheduled office visit due to exacerbation of asthma before the end of the 28-day study period. A secondary endpoint was the need for extended ED care after the initial four-hour treatment period.

The authors enrolled 641 patients with approximately equal numbers in the control and zafirlukast groups. Within the zafirlukast group, approximately equal numbers were assigned to the Z20 and Z160 arms. Baseline demographics, spirometry values, and dyspnea scores were similar between the groups.

Treatment beyond 4 hours was required in 17% of patients in the group receiving Z20, 10% of those receiving Z160, and 15% of control patients (odds ratio of 0.54 for Z160 vs. placebo, difference not significant for Z20 vs. placebo). Compared with the placebo group, dyspnea scores at 4 hours were significantly better in the Z160 group, but not in the Z20 group. Relapse within 28 days of ED evaluation was noted in 24% of patients discharged with zafirlukast, vs. 29% of control patients (5% risk reduction, p < 0.05). The relapse rate did not differ according to the dose of zafirlukast initially administered in the ED.

Adverse events were uncommon, mild, and did not differ significantly between the treatment groups. The authors concluded that treatment with zafirlukast 160 mg in the ED and zafirlukast 20 mg BID after discharge reduces the need for prolonged ED care and the rate of relapse after ED discharge. Four of the study authors are employees of the manufacturer of zafirlukast.

Commentary by David J. Karras, MD, FAAEM, FACEP

This study represents the growing interest in adding disease-controlling agents to the medical regimen of asthma patients treated for acute disease exacerbations.

Agents such as inhaled corticosteroids and oral leukotriene receptor antagonists clearly help many patients avoid acute asthma exacerbations; but it is less clear whether they have a role in preventing short-term asthma relapses following an exacerbation. Studies of inhaled corticosteroids started upon ED discharge have yielded conflicting results.1,2 It is likely that the potency of oral corticosteroids, now administered routinely after ED discharge, obviates the local disease-modifying effects of inhaled medication.

Studies of the leukotriene receptor antagonists in acute asthma exacerbations have had similarly mixed results. One study found a benefit to intravenous montelukast in patients with acute disease.3 Given that placement of an IV is no longer necessary for the majority of patients treated for asthma exacerbation, an effective oral supplement to standard asthma therapy would have obvious advantages.

The benefit to zafirlukast noted in this study is somewhat limited. Treatment with high-dose zafirlukast reduced by 34% the relative rate of treatment beyond 4 hours, but the absolute risk reduction was only 5%. We are not provided with information regarding how many patients actually required hospitalization, only the number requiring therapy beyond 4 hours. The benefit of zafirlukast after ED discharge was similar, reducing the relative relapse rate by 18% but the absolute rate by only 5%. These reductions in relative risk are not small, but they do not translate into dramatic ifferences in outcome; relatively few patients have poor outcomes

It is important to remember that the study was funded by the manufacturer of the study product, and four representatives of the company—including, apparently, the biostatistician—are listed as authors. This does not negate the importance of the study, and indeed the study design does not appear biased toward the product. However, the conclusions would be far more convincing if the authors did not have an overwhelming interest in presenting the data in the most favorable light.

Dr. Karras, Associate Professor of Emergency Medicine, Associate Chair for Academic Affairs, and Research Director, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.

References

1. Rowe BH, et al. Inhaled budesonide in addition to oral corticosteroids to prevent asthma relapse following discharge from the emergency department: A randomized controlled trial. JAMA 1999; 281:2119–2126.

2. Brenner BE, et al. Randomized trial of inhaled flunisolide versus placebo among asthmatic patients discharged from the emergency department. Ann Emerg Med 2000; 36:417–426.

3. Camargo CA Jr., et al. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167:528–533.