Although elucidation of the basic physiologic

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1 Salmeterol Powder Provides Significantly Better Benefit Than Montelukast in Asthmatic Patients Receiving Concomitant Inhaled Corticosteroid Therapy* James E. Fish, MD, FCCP; Elliot Israel, MD, FCCP; John J. Murray, MD, PhD; Amanda Emmett, MS; Rebecca Boone, BS; Steven W. Yancey, MS; and Kathleen A. Rickard, MD Study objectives: Comparison of inhaled salmeterol powder vs oral montelukast treatment in patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids. Design: Randomized, double-blind, double-dummy, parallel-group, multicenter trials of 12-week duration. Setting: Outpatients in private and university-affiliated clinics. Patients: Male and female patients > 15 years of age with a diagnosis of asthma (baseline FEV 1 of 50 to 80% of predicted) and symptomatic despite receiving inhaled corticosteroids. Interventions: Inhaled salmeterol xinafoate powder, 50 g bid, or oral montelukast, 10 mg qd. Measurements and results: Treatment with salmeterol powder resulted in significantly greater improvements from baseline compared with montelukast for most efficacy measurements, including morning peak expiratory flow (35.0 L/min vs 21.7 L/min; p < 0.001), percentage of symptom-free days (24% vs 16%; p < 0.001), and the percentage of rescue-free days (27% vs 20%; p 0.002). Total supplemental albuterol use was decreased significantly more in the salmeterol group compared with the montelukast group ( 1.90 puffs per day vs 1.66 puffs per day; p 0.004) and nighttime awakenings per week decreased significantly more with salmeterol than with montelukast ( 1.42 vs 1.32; p 0.015). Patients treated with inhaled salmeterol were significantly more satisfied with their treatment regimen and how well, how fast, and how long it worked than were patients who were treated with oral montelukast. The safety profiles for the two treatments were similar. Conclusion: In patients with persistent asthma who remain symptomatic while receiving inhaled corticosteroids, adding inhaled salmeterol powder provided significantly greater improvement in lung function and asthma symptoms and was preferred by patients over oral montelukast. (CHEST 2001; 120: ) Key words: asthma; leukotriene receptor antagonist; long-acting 2 -agonist; montelukast; peak expiratory flow; salmeterol; xinafoate Abbreviations: LABA long-acting -agonist; PEF peak expiratory flow Although elucidation of the basic physiologic mechanisms of asthma continues to be one target of biomedical research, it is recognized that asthma *From the Jefferson Medical College (Dr. Fish), Philadelphia, PA; Brigham & Women s Hospital (Dr. Israel), Boston, MA; Vanderbilt Medical Center (Dr. Murray), Nashville, TN; and Glaxo Wellcome Inc (Mss. Emmett and Boone, Mr. Yancey, and Dr. Rickard), Research Triangle Park, NC. This work was funded by Glaxo Wellcome Inc, Research Triangle Park, NC. Manuscript received July 12, 2000; revision accepted February 6, Correspondence to: James E. Fish, MD, FCCP, Jefferson Medical College, 1025 Walnut St, Suite 805, Philadelphia, PA ; james.e.fish@mail.tju.edu is the result of a variety of complex interactions among inflammatory cells, mediators, and other cells and tissues in the airway. 1 The study of these interactions has led to the knowledge that inflammation is an early and persistent component of asthma, 2 and current asthma therapy is focused toward longterm control of the underlying inflammation. Due to their broad actions on the inflammatory process, inhaled corticosteroids are now recognized as providing effective long-term control for persistent asthma. 1 Although the precise mechanism by which inhaled corticosteroids provide clinical benefit in asthma is uncertain, their beneficial clinical effects CHEST / 120 / 2/ AUGUST,

2 may in part be mediated by mechanisms that include reducing inflammation in the airways, 3 reducing cellular infiltrates, decreasing subepithelial fibrosis, and increasing ciliated epithelial cells, some of which appear to be implicated in airway remodeling. 4,5 Inhaled corticosteroids are considered first-line treatment for persistent asthma and have become the cornerstone of asthma care. 6 Although inhaled corticosteroids are effective in controlling symptoms in many patients, some may remain symptomatic despite inhaled corticosteroid therapy. In these patients, the options are to increase the dosage of inhaled corticosteroids or add a second controller medication. There are only limited data to help select a second controller medication from those available, although several studies 7 11 have shown that the combination of an inhaled corticosteroid with a long-acting -agonist (LABA) is more effective than increasing the dosage of inhaled corticosteroids. Adding long-acting bronchodilators to a regimen of inhaled corticosteroids may lead to a decrease in asthma exacerbations with no change in the ability to detect worsening asthma Studies with a combined formulation of the inhaled corticosteroid, fluticasone propionate, and salmeterol have shown that this regimen offers significant clinical advantages over either of the products alone. Compounds that block either the synthesis or receptor activity of cysteinyl leukotrienes have been shown to be efficacious in the treatment of asthma. Although published data comparing leukotriene modifiers with other established long-term control therapies are limited, leukotriene modifiers have been used as monotherapy in patients with mild asthma and as add-on therapy with inhaled corticosteroids or an existing asthma treatment regimen in patients with persistent asthma. 24 The present study compares the long-acting bronchodilator salmeterol with the leukotriene receptor antagonist montelukast as add-on therapy for patients who remain symptomatic while receiving low to intermediate dosages of inhaled corticosteroids. Study Design and Patients Materials and Methods Two multicenter, randomized, double-blind, parallel-group clinical trials were conducted to compare the efficacy and safety of inhaled salmeterol xinafoate (Serevent; Glaxo Wellcome Inc; Research Triangle Park, NC), 50 g bid, via a multidose powder inhaler (Diskus; Glaxo Wellcome, Inc), with oral montelukast (Singulair; Merck & Co, Inc; West Point, PA), 10 mg qd, over a 12-week treatment period in patients with persistent asthma. The studies were conducted at 71 clinical centers in the United States and Puerto Rico. Eligible patients underwent screening assessments including medical history, physical examination, and pulmonary function testing including FEV 1 reversibility. All patients provided written informed consent, and institutional review boards approved the study at each respective center. Male patients and nonpregnant, nonlactating female patients 15 years old were eligible if they had a diagnosis of asthma as defined by the American Thoracic Society 25 for at least 6 months and were symptomatic despite receiving inhaled corticosteroids for at least 6 weeks prior to screening, and at a constant dosage for 30 days prior to screening. Patients had a baseline FEV 1 of 50 to 80% of predicted 26,27 after withholding bronchodilator therapy for 6 h and had at least a 12% increase in FEV 1 30 min following inhalation of 180 g of albuterol. Predicted FEV 1 values were race adjusted for African Americans. 28 After a 7-day to 14-day run-in period to assess symptoms, diary card completion, and patient proficiency with inhaler use, patients whose FEV 1 remained within 50 to 80% of predicted normal values were eligible for enrollment. Patients were also required to meet one or more of the following criteria during the 7 days prior to randomization: use of an average of 4 puffs per day of albuterol, a symptom score of 2 on 3 days, and 3 nights when the patient awakened due to asthma symptoms. At enrollment, patients were supplied with albuterol inhalers (albuterol sulfate; Ventolin; Glaxo Wellcome Inc) for relief of breakthrough symptoms. Use of all other inhaled or oral bronchodilators, systemic corticosteroids, cromolyn, nedocromil, ipratropium, or leukotriene modifiers was prohibited. Concurrent use of theophylline during the study or use of any medication that could potentially interact with sympathomimetic amines or montelukast was not allowed (ie, -blockers, polycyclic antidepressants, monoamine oxidase inhibitors, phenobarbital, and rifampin). Patients used a hand-held peak flowmeter (Astech; Center Laboratories; Port Washington, NY) to measure daily morning and evening peak expiratory flow (PEF), recording the highest of three forced exhalations prior to taking study medications. Patients also recorded nighttime awakenings due to asthma, daytime and nighttime supplemental albuterol use, ratings of asthma symptoms, and use of blinded study drug on daily diary cards. Daytime asthma symptoms of wheezing, chest tightness, and shortness of breath were rated on a 5-point scale: 0 no symptoms, 1 symptoms present but caused no discomfort, 2 symptoms caused discomfort but did not interfere with normal daily activities, 3 symptoms caused discomfort and interfered with at least one normal daily activity, 4 symptoms caused discomfort and interfered with two or more activities, and 5 symptoms that caused discomfort and prevented normal daily activities. Patients returned to the clinic for adverse event assessments after 1, 4, 8, and 12 weeks of treatment. A satisfaction with treatment questionnaire was completed after 12 weeks of treatment. Each item on the questionnaire was scored on a scale of 0 to 6, with higher scores indicating greater satisfaction with therapy. Asthma exacerbations were defined as any worsening of asthma symptoms requiring treatment beyond the use of blinded study drug and/or supplemental albuterol. Patients who experienced an asthma exacerbation were withdrawn from the study. Statistical Analysis The primary efficacy measure was morning PEF at end point. A sample size of 440 patients per treatment arm provided 80% power to detect a significant difference of 15 L/min from baseline in morning PEF measurements between the two treatment groups based on a two-sample, two-sided t test at a significance level of Other efficacy measures included evening PEF, daytime asthma symptom score, supplemental albuterol use, and nighttime awakenings. Asthma exacerbation information and patient-rated satisfaction with study medication were also assessed. 424 Clinical Investigations

3 Descriptive and inferential analyses of the PEF data were performed comparing the two treatment groups at each treatment week, across each 4-week treatment period, across the entire 12-week treatment period, and at end point. End point was defined as the last available treatment week mean. Mean changes in PEF from pretreatment baseline were assessed, and the two treatment groups were compared using analysis of covariance controlling for investigator and baseline. Supplemental albuterol use and nighttime awakenings per week were analyzed in the same manner. Inferential analyses comparing treatment groups based on change from baseline values for daytime asthma symptom scores, percentage of symptom-free days, percentage of rescue-free days, and number of nights per week with awakenings were performed using a van Elteren test 29 controlling for investigator. Asthma exacerbation and adverse event frequencies between the two treatment groups were summarized by frequency of event. Frequencies of treatment satisfaction scores were compared by treatment group using a Cochran-Mantel-Haenszel test 30 controlling for investigator differences. Demographics Results A total of 476 patients received inhaled salmeterol and 472 patients received oral montelukast. The treatment groups had similar demographic and disease characteristics at baseline (Table 1). PEF Mean baseline morning PEF was comparable between the two groups (371.0 L/min vs L/min in the salmeterol and montelukast groups, respectively). During the 12-week treatment period, patients in the salmeterol group had significantly greater increases in mean morning PEF (35.0 L/min) compared with montelukast (21.7 L/min; p 0.001). Significantly greater improvements in morning PEF (Fig 1, top, A) and evening PEF (Fig 1, bottom, B) were noted in the salmeterol group within the first week of treatment, and the superior bronchodilating properties of salmeterol remained significantly greater than montelukast over all treatment weeks. Asthma Symptom Scores, Supplemental -Agonist Use, and Nighttime Awakenings Mean symptom scores at end point and supplemental albuterol use and nighttime awakenings over the 12-week study are shown in Table 2. Patients in the salmeterol group experienced a significantly greater increase in the percentage of symptom-free days than did patients in the montelukast group (24% vs 16%; p 0.001). Although symptom scores were low at baseline, the daytime scores for all symptoms combined decreased by 39% in the salmeterol group compared with a 31% decrease for montelukast (p 0.039). Symptom scores for chest tightness and shortness of breath decreased by 42% and 38%, respectively, in the salmeterol group compared with 31% and 29% in the montelukast group (p and p 0.044, respectively). Wheezing Variables Table 1 Demographics and Disease Characteristics at Baseline Salmeterol (n 476) Treatment Groups Montelukast (n 472) Age, yr Mean (SE) 39.9 (0.6) 39.5 (0.6) Range Gender, No. (%) Female 288 (61) 292 (62) Male 188 (39) 180 (38) Ethnic origin, No. (%) White 413 (87) 393 (83) Black 29 (6) 42 (9) Asian 5 (1) 9 (2) American hispanic 25 (5) 28 (6) Other 4 ( 1) 0 (0) Asthma duration, No. (%) 10 yr 114 (24) 120 (26) 10 yr 362 (76) 352 (74) Mean (SE) FEV 1 before bronchodilation, L 2.33 (0.03) 2.34 (0.03) Mean (SE) percent predicted FEV (0.4) 68.6 (0.4) Mean (range) inhaled corticosteroid use, g Fluticasone 468 (44 1,320) 497 (176 1,760) Triamcinolone 548 (200 1,600) 557 (100 1,600) Beclomethasone 269 (84 672) 261 (84 672) Budesonide 714 (400 1,200) 588 (84 800) Flunisolide 1,117 (250 2,000) 1,036 (800 1,500) CHEST / 120 / 2/ AUGUST,

4 Figure 1. Mean change from baseline in morning (AM; top, A) and evening (PM; bottom, B) PEF values for treatment week 1 through treatment week 12. Overall indicates the comparison of treatment groups at end point. * statistically significant difference between treatment groups (p 0.032). decreased by 39% in the salmeterol group and 31% in the montelukast group (p 0.403). In the salmeterol group, daytime and nighttime supplemental albuterol use decreased by 42% and 51%, respectively, from baseline compared with decreases of 35% and 40%, respectively, in the montelukast group. Both differences between treatment groups were significant (p 0.012). The increase in the percentage of days with no rescue albuterol use in the salmeterol group was also significantly greater than in the montelukast group (27% vs 20%; p 0.002). Over 12 weeks of treatment, patients receiving salmeterol experienced significantly greater reductions in nighttime awakenings per week compared with the montelukast group (1.42 vs 1.32; p 0.015) 426 Clinical Investigations

5 Table 2 Baseline and Mean Change From Baseline in Symptom Scores, Supplemental Albuterol Use, and Nighttime Awakenings Over 12 Weeks of Treatment* Treatment Groups Variables Salmeterol (n 452) Montelukast (n 448) Baseline Change Baseline Change p Value Subject-rated daytime symptoms Wheezing 1.21 (0.04) 0.47 (0.05) 1.19 (0.04) 0.37 (0.04) Shortness of breath 1.55 (0.05) 0.59 (0.05) 1.51 (0.05) 0.44 (0.05) Chest tightness 1.42 (0.04) 0.60 (0.05) 1.34 (0.05) 0.42 (0.05) All symptoms 1.40 (0.04) 0.55 (0.04) 1.34 (0.04) 0.41 (0.04) Percentage of symptom-free days 8 (0.8) 24 (1.5) 10 (1.0) 16 (1.3) Percentage of rescue-free days 10 (1.0) 27 (1.6) 9 (1.0) 20 (1.4) Total supplemental albuterol use, No. of puffs 4.37 (0.12) 1.90 (0.10) 4.66 (0.13) 1.66 (0.11) Daytime supplemental albuterol use, No. of 3.62 (0.10) 1.51 (0.08) 3.79 (0.10) 1.31 (0.09) puffs Nighttime supplemental albuterol use, No. of 0.76 (0.05) 0.39 (0.04) 0.88 (0.05) 0.35 (0.04) puffs Nighttime awakenings per week, No (0.18) 1.42 (0.13) 3.00 (0.19) 1.32 (0.15) Nights per week with awakenings, No (0.11) 1.06 (0.08) 2.25 (0.12) 0.93 (0.09) *Data are presented as mean (SE). Baseline is an average for the 7 days immediately prior to randomization. p values are based on a van Elteren test on change from baseline controlling for investigator. p values are based on an analysis of covariance on change from baseline controlling for investigator and baseline. and a larger decrease in the number of nights per week with awakenings (2.42 vs 2.06, respectively; p 0.078). Patient Satisfaction With Treatment Analysis of surveys of overall satisfaction with treatment favored salmeterol over montelukast (p 0.021; Table 3). Analysis of domains of satisfaction was significantly greater for salmeterol for how well (p 0.006) and how fast (p 0.001) medication worked compared with montelukast. There was no significant difference between groups in satisfaction with how long medication worked (p 0.102). Patients in the salmeterol group were more likely to use study medication again compared with patients in the montelukast group (p 0.004). Asthma Exacerbations Six percent (26 of 476) of patients in the salmeterol group experienced a total of 27 asthma exacerbations compared with 5% (23 of 472) of patients in the montelukast group who experienced 24 asthma exacerbations during the 12-week treatment period. The most common suspected causes of exacerbation in both treatment groups were respiratory infection, allergens, or unknown etiology. Most exacerbations were treated in the clinician s office (54%), while others were treated at home (25%) or in the emergency department (11%). Adverse Events The percentages of patients reporting at least one drug-related adverse event were comparable in the two treatment groups (7% in the salmeterol group compared with 6% in the montelukast group). The most frequently reported drug-related adverse events in the salmeterol and montelukast groups were headache (1% in each group) and insomnia (1% in the salmeterol group). All other drug-related events occurred in 1% of patients in each group. Ten serious adverse events were reported. In the salmeterol group, three patients experienced acute asthma exacerbations related to concurrent illnesses (respiratory tract infection, acute bronchitis, and chicken pox), one patient experienced a syncopal episode, and one patient experienced chest tightness and aches/numbness in the elbows. In the montelukast group, one patient experienced chest pain, one patient had pneumonia, one patient experienced migraine headache, one patient experienced appendicitis, and one patient had a spontaneous abortion. None of these events were considered drug related. Twenty-six patients were withdrawn from the study due to adverse events (13 patients in each treatment group). Discussion The results from these well-controlled, multicenter studies show that the addition of inhaled salmeterol powder to inhaled corticosteroid therapy provides significantly greater improvement in lung function and control of asthma symptoms compared with oral montelukast in patients who remain symptomatic while receiving low or intermediate dosages of inhaled corticosteroids. Our findings are consis- CHEST / 120 / 2/ AUGUST,

6 Table 3 Patient Satisfaction With Treatment and Use* Variables Treatment Groups Salmeterol (n 400) Montelukast (n 386) p Value Overall satisfaction Dissatisfied 23 (6) 43 (11) Neutral 40 (10) 36 (9) Satisfied 337 (84) 306 (79) How well it works Dissatisfied 27 (7) 47 (12) Neutral 35 (9) 42 (11) Satisfied 336 (84) 297 (77) How fast it works Dissatisfied 24 (6) 53 (14) Neutral 91 (23) 90 (23) Satisfied 284 (71) 243 (63) How long it works Dissatisfied 24 (6) 48 (12) Neutral 68 (17) 47 (12) Satisfied 307 (77) 291 (75) Use of study medication again Yes, I would ask my doctor 145 (36) 116 (30) for them Yes, if my doctor thought I 186 (47) 182 (47) should Not sure, I might or might 47 (12) 48 (12) not No, even if my doctor 8 (2) 8 (2) thought I should No, I would ask for something else 14 (4) 31 (8) *Data are presented as No. (%). Treatment comparisons are based on a Cochran-Mantel-Haenszel test controlling for investigator. tent with those of Condemi and colleagues, 11 who found that salmeterol added to a regimen of fluticasone propionate increased morning PEF by 47 L/min, and those reported by Laviolette et al, 31 who found a 10-L/min increase in PEF when montelukast was added to a regimen of beclomethasone, 200 g bid. It is unlikely that our results would have been different had we used different doses of either montelukast or salmeterol. Others 8 have shown salmeterol at 100 g bid had no greater effect than 50 g bid in reducing nocturnal symptoms in symptomatic patients receiving inhaled corticosteroids. Moreover, dose-ranging studies 32,33 with montelukast indicate that optimal improvement in asthma control variables is achieved at the 10-mg/d dosage. It is also important to note that these results are obtained at the nadir of the effect of salmeterol (immediately prior to the morning dose) but near the apex of the effect of montelukast based on once-daily dosing in the evening. 34 These findings are important since there is little published information comparing the effects of these two classes of controller medications. Busse and colleagues 35 found that salmeterol provided significantly greater improvement in asthma control (morning and evening PEF, percentage of symptomfree days, percentage of days with no supplemental albuterol, greater relief in asthma signs and symptoms) than the oral leukotriene receptor antagonist, zafirlukast, in a population in which most, but not all, patients were concurrently receiving inhaled corticosteroids. To our knowledge no other well-controlled studies comparing salmeterol and montelukast have been published to date. The mechanisms by which an inhaled corticosteroid and a long-acting bronchodilator provide clinical benefit in asthma have not been fully elucidated. Clearly, however, asthma is a disease of two components: bronchoconstriction and inflammation. Thus, it is likely that the combination of a long-acting bronchodilator and an inhaled corticosteroid provide benefit via complementary bronchodilatory and antiinflammatory modes of action In vitro studies 39 have suggested that there may be a complementary interaction. Li and colleagues 39 showed a significant fall in the number of eosinophils in the lamina propria of asthmatic patients when salmeterol was added to a regimen of inhaled corticosteroids but not when the inhaled corticosteroid dosage was increased. A concurrent improvement in clinical status also occurred in these patients. Several mechanisms have been proposed for this complementary action. Corticosteroids are believed to inhibit cytokine production and prevent 2 -adrenergic receptor downregulation, allowing 2 -adrenergic agonists to be more effective. 36 Corticosteroids have also been shown to increase 2 -receptor synthesis 40 and to decrease 2 -receptor desensitization. 41 LABAs have been reported to prime the glucocorticoid receptor for steroid-dependent activation. 42 These mechanisms may lead to increased responsiveness to steroids, 43 increased potency or activity of the combination compared with either drug alone, 44,45 or a broader range of pharmacodynamic activity than using either a LABA or corticosteroid alone. 46 These proposed mechanisms are derived from in vitro data and are therefore speculative. Nevertheless, they are of potential clinical significance, insofar as Kraft et al 47 have reported that glucocorticoid binding affinity and pharmacodynamic activity are reduced at night in patients with nocturnal asthma compared to those without nocturnal asthma, and other clinical trials 7 11 have demonstrated improvements in measures of asthma control with combined LABA and corticosteroid therapy. Although it has been suggested that patients prefer oral medications to inhaled medications, 48 Balsbaugh and colleagues 49 found that patients do not 428 Clinical Investigations

7 have strong preferences regarding route of administration and that route of administration is not an important feature of a controller medication. Patients treated with inhaled salmeterol in our study were significantly more satisfied with their treatment regimen and with how well, how fast, and how long it worked than were patients treated with montelukast. These findings suggest that efficacy of the treatment regimen may be a more important determinant of patient compliance than route of administration. In summary, we have demonstrated that the addition of salmeterol to a regimen of inhaled corticosteroids provides significantly greater improvement in lung function and asthma symptoms than the addition of montelukast in patients with mild-to-moderate persistent asthma. 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