- Email: [email protected]
Use of Montelukast in tapering inhaled corticosteroid therapy: an open-label, 48-week trial
VOL. 62, No. 11, NOVEMBER 2001
Use of Montelukast in Tapering Inhaled Corticosteroid Therapy: An Open-Label, 48-Week Trial David B. Price, MB, BCh, 1 Michel Y. Rouleau, MD, 2 Christopher P. Fletcher, MB, 3 Piyush Patel, MD, 4 Ronald Olivenstein, MD, s Leiv Myhr, MD, 6 J. Christian Virchow, Jr, MD, 7 W.R. Cameron Aitchison, MB, 8 Ernst R. Omenaas, MD, PhD, 9 Pam S. Dellea, BS,1° Martino Laurenzi, MD, 1° Jonathan A. Left, MD, 1° and the Montelukast/Inhaled Steroid Taper Study Group*
1Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom, 2H6pital du St.-Sacrement, Quebec, Canada, 3Woolwell Medical Centre, Woolwell, Plymouth, United Kingdom, 4Clinical Immunology, Allergy & Asthma, Mississauga, Ontario, Canada, 5Montreal Chest Institute, Montreal, Quebec, Canada, 6LovisenbergHospital, Oslo, Norway, 7Department of Pneumology, Medical University Clinics, Freiburg, Germany, 8The Surgery, Renfrewshire, United Kingdom, 9Universityof Bergen, Bergen, Norway, and Z°Merck and Co, Inc, Whitehouse Station, New Jersey
ABSTRACT
Background: International asthma treatment guidelines recommend tapering inhaled corticosteroid (ICS) therapy to the lowest dose that provides the maximum effect. Montelukast, a leukotriene receptor antagonist with complementary anti-inflammatory actions, has been shown in a tightly controlled trial to allow effective tapering of ICS therapy. Objectives: The purpose of this naturalistic study was to assess whether administration of montelukast could assist in the tapering of ICS therapy in patients with established asthma and whether the reduced dose achieved at 12 weeks could be maintained at 48 weeks without loss of asthma control. Methods: Patients with proven chronic asthma who were being treated with moderate to high doses of ICS (beclomethasone equivalent of 600 to 3200 pg/d) and required, according to their physician, the prescribed dose to maintain asthma control, were given open-label oral montelukast (10 mg/d at bedtime) for 48 weeks. Patients who were clinically stable, based on a composite clinical performance score, had their ICS dose reduced by -25% at 2-week intervals for 12 weeks and at 6-week intervals for the remaining 36 weeks. The percentage *Members of the Montelukast/Inhaled SteroidTaper StudyGroup are listed in the Acknowledgments.
AcceptedforpublicationSeptember18, 2001.
Printed in the USA.Reproduction in whole or part is not permitted.
0011-393X/01/$19.00
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reduction in final ICS dose associated with clinical stability was the primary end point of the study. Results: Five hundred eighty-one patients were enrolled (57% female; mean age, 41 years). At 12 weeks, the mean ICS dose had been tapered by 82.3% (from 959 IJg/d to 172 IJg/d) and a total of 345 patients (59.5%) had completely stopped ICS. At 48 weeks, mean ICS dose had been tapered by 81.3% (from 959 IJg/d to 178 pg/d; P < 0.001), and 356 patients (61.3%) had completely stopped ICS. During tapering, patients remained clinically stable despite a significant -30% reduction in beta-agonist use (P < 0.001). There was a small but significant 2.7% decrease in forced expiratory volume in 1 second (P < 0.001). The extent of tapering was similar regardless of the ICS used (fluticasone, budesonide, beclomethasone, or flunisolide) and independent of baseline betaagonist use. Montelukast was generally well tolerated. Fifty-one patients (9%) discontinued due to clinical adverse events. Conclusion: In patients with chronic asthma treated with ICS, the addition of montelukast to assist in ICS tapering can be applied in clinical practice without loss of asthma control. Key words: inhaled steroids, leukotriene receptor antagonists, montelukast, asthma, steroid sparing, steroid tapering. (Curr Ther Res Clin Exp. 2001;62:743-
755)
INTRODUCTION Although inhaled corticosteroids (ICS) are effective in the treatment of bronchial asthma, chronic administration of moderate to high doses of ICS may cause side effects such as cataract formation, oral thrush, dysphonia, and skin bruising. ~-6 International guidelines, therefore, recommend that the ICS dose be minimized whenever possible. 7 It may be useful to develop new strategies that will help reduce ICS dose requirements to the lowest dose while providing the maximum benefit. Montelukast sodium* is a specific and potent leukotriene (CysLT1) receptor antagonist with demonstrated efficacy in the treatment of chronic asthma in adults and children. 8-x5 The benefits of montelukast therapy have been demonstrated in patients who have not been treated with ICS and also have been found to be additive in patients receiving ICS.1° In a randomized, placebo-controlled trial, H montelukast enabled a 47% reduction of ICS doses over a 12-week treatment period compared with 30% for placebo. Although this study was well designed, it was a classic efficacy study in which patients had to meet inclusion criteria not representative of the "real-life" target population, had to make numerous study visits, and tended to be highly compliant with administered therapy. Thus, while this study may provide data on absolute efficacy of the drug in an *Trademark: Singuiair® (Merck & Co, Inc, Whitehouse Station, New Jersey).
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ideal scenario and in a relatively homogeneous patient population, it yields limited information about the actual effectiveness of the drug in clinical practice. The present study was therefore designed to assess whether the method of tapering used in the previous clinical trial ]~ could be safely and effectively extended to an actual clinical practice setting and whether short-term reductions in ICS dose could be maintained over a longer period of time. We conducted a multicenter, open-label study in patients with proven asthma who required moderate to high ICS doses to assess whether tapering of ICS therapy could be undertaken according to a protocol of beta-agonist use and lung function monitoring in conjunction with montelukast therapy. We also determined whether the tapering achieved at 12 weeks could be maintained at 48 weeks and assessed its impact on asthma control. The inclusion of a placebo arm was considered unethical, considering the duration of the study and results from a previous study H that showed greater loss of asthma control and a 30% discontinuation rate in the placebo arm. PATIENTS AND METHODS Patients Patients 15 to 70 years of age with clinically stable asthma were enrolled from 10 countries--Australia, Austria, Belgium, Canada, Germany, Ireland, the Netherlands, Norway, Switzerland, and the United Kingdom. Eligible patients had a history of persistent and currently stable asthma. Asthma was demonstrated by either (1) a >12% increase in forced expiratory volume in 1 second (FEV1) or 15% increase in peak expiratory flow after beta-agonist administration or (2) airway hyperresponsiveness as defined by a ->20% reduction in FEV] in response to methacholine or histamine <4 mg/mL (determined either during the run-in period or within 1 year of study entry). In addition, patients had to be nonsmokers for at least 1 year, with a smoking history of -<20 pack-years. Stability of asthma was demonstrated by an FEV] ->70% of the predicted value before beta-agonist use. Excluded were patients who had had emergency treatment for asthma within 1 month of the first visit, hospitalization for asthma within 3 months, an unresolved upper respiratory tract infection within 3 weeks of study entry, or sinus infection within 1 week of study entry. Patients required, according to their physician, treatment with an ICS for at least 3 months at any dose, and at the following stable daily doses for at least 1 month before the study: fluticasone 300 to 1600 pg/d, beclomethasone or budesonide 800 to 3000 pg/d, flunisolide 1000 to 3000 pg/d, or triamcinolone 1200 to 3200 pg/d. Patients used a daily average of -<6 puffs of inhaled betaagonist as needed (measured on a diary card) during the baseline period (ie, between visits 1 and 2). Thus, although clinically stable, many patients could still show clinical improvement in terms of reduced beta-agonist use. Patients were in good health except for their asthma. The following asthma medications were excluded: oral, intravenous, or intramuscular corticosteroids
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within 1 month; cromolyn sodium or nedocromil within 1 month; leukotriene receptor antagonists or theophylline within 2 weeks; and long-acting inhaled or oral beta-agonists or inhaled anticholinergic agents within 1 week of the first visit. Nasal corticosteroids and nasal cromolyn sodium were allowed as needed. Inhaled albuterol and short-acting antihistamines were allowed as needed, but were withheld for at least 6 and 48 hours, respectively, before s t u d y visits. The ethical review committees of all participating centers approved the protocol, and written informed consent was obtained from all participants.
Study Design The study consisted of 3 periods over 50 weeks. Period 1 was a 2-week screening period that included the administration of a questionnaire regarding the stability of asthma over the preceding year. Period 2 was a 12-week treatment phase in which ICS dosage could be adjusted at clinic visits every 2 weeks. Period 3 was a 36-week treatment phase in which ICS dosage could be adjusted at 6-week intervals. During period 1 (visits 1 and 2), patients maintained their usual dose and formulation of ICS. During periods 2 and 3, patients took montelukast sodium (one 10-mg film-coated tablet daily at bedtime). At visit 2 (ie, week 0), the dose of ICS was tapered by 1 step (Table I) for all patients. Beginning at visit 3, ICS doses were tapered, increased, or maintained based on a clinical performance score (CPS).
Clinical Performance Score and Taper Method The CPS was calculated based on the FEV~ recorded at the clinic visit and beta-agonist use recorded during the 7 days immediately preceding the visit (determined from patient diary cards). This was based on the scoring methodology of the previous steroid taper study using montelukast. H One point was given if FEV~ was ---90% of the pre-beta-agonist baseline (average of values at visits 1 and 2), and 1 point was given if beta-agonist use did not exceed 135% of the baseline value (average daily use on days between visits 1 and 2). The CPS therefore ranged between 0 (worst outcome) and 2 (best outcome). The ICS
Table I. Study protocol for tapering inhaled corticosteroid (ICS) dose based on current ICS use. Current ICS Dose (puffs/d)
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2-10
2 (1 in AM, 1 in PM)
12--18
4 (2 in AM, 2 in PM)
20-26 28-32 34-40
6 (3 in AM, 3 in PM) 8 (4 in AM, 4 in PM) 10 (5 in AM, 5 in PM)
D.B. Price et eL
dose was tapered for patients with a score of 2, maintained for those with a score of 1, and increased (Table II) for those with a score of 0. Therapy was not tapered for patients whose dose had been increased at the previous visit, even if they had a CPS of 2. Patients receiving increased ICS doses who subsequently did not restabilize (ie, CPS = 0 at 2 consecutive clinic visits) were withdrawn from the study at the discretion of the investigator.
End Points The primary end point was the percentage reduction in ICS dose from baseline to the last tolerated dose at week 12. The last tolerated dose was defined as the last dose at which the CPS was 1 or 2. Other end points included the percentage of patients who did not require any ICS therapy by weeks 12 and 48, the percentage reduction in ICS dose at week 48, and the change in daily beta-agonist use.
Statistical Analysis The efficacy analysis was performed on the intent-to-treat population, that is, all patients with a baseline measurement and at least 1 postbaseline measurement. At each visit, the number of patients whose therapy was tapered and the number (percentage) of successful tapers (CPS score at next visit of 1 or 2) were summarized. The percentage reduction in ICS dose was analyzed with a 1-sample t test, and 95% CIs were constructed around the mean dose reduction. Statistical significance was set at P -< 0.05.
RESULTS A total of 581 patients were enrolled. Baseline characteristics of the patients are listed in Table III. The ICS used included budesonide (262 patients [45%]), beclomethasone (142 patients [24%]), fluticasone (175 patients [30%]), and flunisolide (2 patients [<1%]). The mean baseline ICS dose was 959 pg/d (not corrected for beclomethasone equivalents) (Table IV).
Table II. Study protocol for increasing inhaled corticosteroid (ICS) dose based on current ICS use. Current ICS Dose (puffs/d) 0-6 8-12 14-18 20-22 -->24
Dose Increase (puffs/d) 2 4 6 8 10
(1 (2 (3 (4 (5
in AM, 1 in AM, 2 in AM, 3 in AM, 4 in AM, 5
in in in in in
PM) PM) PM) PM) PM)
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Table III. Demographic characteristics of enrolled patients (N = 581)* at baseline. Characteristic
Age, y, mean (SD) Age distribution, no. (%) <18 y 18-65 y >65 y Sex, no. (%) Male Female Race, no, (%) White Asian Black Other Duration of ICS therapy, no. (%) <1 y --1 y Dose of ICS at baseline, no. (%)~ -<800 pg >800 to <1200 pg 1200 to <1500 IJg 1500 to 2000 IJg >2000 IJg FEV1, mean % predicted (SD) Beta-agonist use, mean (SD) puffs/d Smoking history, no. (%) Smoked Never smoked
41.0 (1 3.5) 10 (2) 551 (95) 20 (3) 249 (43) 332 (57) 567 5 4 5
(98) (<1) (<1) (<1)
21 7 (37) 364 (63) 233 158 34 132 23 85.1 3.0
(40) (27) (6) (23) (4) (12.0) (4.1)
207 (36) 374 (64)
ICS = inhaled corticosteroid; FEV1 = forced expiratory volume in 1 second. *Efficacy data unavailable for 1 patient. tBeclomethasone equivalent dose; dose unknown for 1 patient.
Week 12 After 12 weeks of treatment with montelukast, the mean ICS dose was reduced to 172 pg/d, representing a significant (P < 0.001) mean reduction of 82.3% (95% CI, 80.0-84.7) from baseline (Figure 1). At week 12, 345 patients (59.5%) completely stopped ICS therapy (95% CI, 55.4-63.5); 90.9% (527/580) of patients were able to reduce their ICS dose by at least 50%, and 77.1% (447/580) by at least 75%. Week 48
After 48 weeks of treatment with montelukast, the mean dose was reduced to 178 pg/d, representing a significant (P< 0.001) mean reduction of 81.3% (95% CI, 78.5-84.0) from baseline (Figure 1). A total of 356 patients (61.3%) completely
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Table IV. Mean baseline and last tolerated dose by type of inhaled corticosteroid (ICS).
ICS Type
No. of Patients
Baseline Dose (IJg/d) (range)
142 261 2 175
1026 (800-2000) 1033 (400-3200) 1250 (1000-1500) 792 (300-2000)
Beclomethasone Budesonide Flunisolide Fluticasone
Last Tolerated Dose (IJg/d) (range) 142 208 250 163
(0-1500) (0-2133) (0-500) (0-1333)
stopped ICS therapy by week 48 (95% CI, 57.3-65.3). By week 48, 89.5% (519/580) of patients were able to reduce their ICS dose by at least 50%, and 79.0% (458/580) by at least 75%. Seventy-seven patients (13.3%) did not respond to rescue doses (ie, CPS = 0 at 2 consecutive visits). Of the cases in which ICS doses were increased 0e, rescues), 78.9% were successful 0e, CPS at the next visit = 1 or 2). Only 2 patients required more rescues than tapers, whereas 97.2% of patients had more tapers than rescues. To assess the relation between baseline asthma control level and tapering success, tapering was also analyzed based on baseline beta-agonist use (ie,
-0- FEV, -II- Beta-agonist use -~- ICS dose 1000
300
100,
2so
800
-0
8o u_
2oo 6oo
6o
•~ 0
150
400 100
2OO
so
0
0
N
2o 0
;
I
6
1'2
I
1'8 24
3'0
I
3'6 42
I
48
Weeks
Figure 1. Effect of montelukast administration on dose of inhaled corticosteroid (ICS), beta-agonist use, and forced expiratory volume in 1 second (FEV~) among patients with established asthma (N = 581). Values are weekly means.
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>100 pg/d or <100 pg/d). Among patients using >-100 lag/d, the mean ICS dose was tapered from 984 lag/d to 189 lag/d (80.2%, P < 0.001). Among those patients using <100 pg/d at baseline, mean ICS dose was tapered from 925 lag/d to 158 lag/d (82.9%, P < 0.001). During the study, beta-agonist use decreased significantly (P < 0.001) by -30% (Figure 1). This decrease occurred early and remained stable throughout the study. Among patients whose beta-agonist use at baseline was excessive according to asthma guidelines (ie, >200 lag/d albuterol), the median reduction in beta-agonist use was 48.3% (from 490 pg/d to 260 pg/d). A small but significant 2.7% decrease (P < 0.001) in percent predicted FEV~ occurred during the study (Figure 1). The percentage reduction in ICS dose was similar across all subgroups, irrespective of sex, race, age, duration of previous ICS therapy (>1 year vs <1 year), type of ICS, and dose of ICS at baseline (>1500 pg/d, 81.7% reduction; <1500 pg/d, 80.2% reduction). There was a high correlation between the degree of ICS tapering observed at 12 weeks and at 48 weeks (Figure 2). For example, 368 patients (63%) had identical reductions at week 12 and week 48. Despite the ICS tapering, the peripheral blood eosinophil concentration remained stable (baseline mean, 0.24 x 109 cells/L; treatment period mean, 0.27 x 109 cells/L). Montelukast was generally well tolerated. The most frequent clinical adverse events over the 48 weeks were upper respiratory infection (43% [250/581]), 100 80 60 0
40
~J ! ._=
20
e-
0 -20
e-
u
-4O -60 -8O -100 Week 12
Week48
Figure 2. Treatment effect (degree of tapering) at 12 weeks versus 48 weeks in a randomly selected subset representing 20% of treated patients. Values represent mean percentage of tapering of inhaled corticosteroid (ICS) dose.
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asthma worsening (27% [154/581]), and headache (26% [ 149/581]). Forty-six patients (8%) discontinued after 12 weeks and 130 patients (22%) after 48 weeks. Fifty-one patients (9%) discontinued due to clinical adverse events (most commonly asthma worsening [25 patients] and dyspnea [3 patients]). Of the 25 patients who discontinued with worsening asthma, 1 was hospitalized. In addition, 6 patients discontinued due to pregnancy, 1 due to a laboratory adverse event (liver function abnormality), 14 due to insufficient therapeutic response, and 58 for other miscellaneous reasons (protocol deviations [10 patients], lack of response to increased ICS dose or need for additional medication [15 patients], loss to follow-up [I 1 patients], uncooperative behavior or patient request for withdrawal [22 patients]). Responses to the baseline questionnaire suggested that >50% of participants had an average of at least 1 unscheduled visit to a physician for asthma in the past year. Only 27% of patients reported asthma-related adverse events during the study.
DISCUSSION Montelukast has been shown to enable ICS tapering at a rate significantly greater than placebo in a traditional clinical trial population drawn mainly from secondary care. n Clinical effectiveness studies, however, require the inclusion of patients representative of those who will actually be treated while maintaining the rigor of a clinical trial. This study therefore examined a large primary care population of asthma patients prescribed higher than ideal doses of ICS and used an open-label design to closely mimic actual clinical practice. We found that treatment with montelukast was associated with significant reductions in ICS doses without negatively affecting asthma control. This reduction occurred within the first 12 weeks and persisted throughout the 48-week treatment period. The percentage change from baseline in ICS dose was substantial, and >60% of patients were able to stop 1CS therapy completely. It may be argued that those patients for whom ICS doses were substantially reduced had a form of asthma that is especially leukotriene dependent. In fact, concomitant treatment with a leukotriene receptor antagonist with subsequent tapering of ICS therapy may be a way to identify these patients. In this trial, ICS therapy was tapered while maintaining the clinical stability of the patients. Patients were clinically stable at randomization and were able to have their ICS dose tapered despite a significant reduction in beta-agonist use. Although spirometry showed a statistically significant decrease in FEV1, the magnitude of the decrease (2.7%) was small and of questionable clinical relevance. Inclusion of a placebo group in this study was considered ethically unacceptable since results from a previous study of montelukast with ICS tapering showed that the placebo group had an increased risk of loss of asthma control. H With no placebo group, it is impossible to quantitate the placebo effect of tapering. Thus, the conclusions drawn must be tentative. However, in a
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previous study, 11 the placebo response in the run-in and treatment phases was -57%. The -80% reduction seen in the present study would appear to be greater than what might be expected from placebo alone. One might hypothesize that these patients were overtreated and that most did not actually require ICS. However, the fact that patients taking ->100 pg/d of beta-agonist at baseline (and thus not completely controlled with ICS) and those taking <100 pg/d had their doses tapered to a similar extent (81% vs 83%) would support the premise that the results were not all due to placebo effect and that these patients were not overtreated with ICS. A significant proportion of therapeutic responses in an office setting may, in fact, be due to a placebo response. Even so, this does not limit the utility of therapeutic interventions in clinical practice, especially since there is significant evidence that steroid tapering is not being actively implemented by health care professionals. 16 Evidence for complementary activity of leukotriene modifiers and ICS is growing. Several studies have demonstrated that steroid therapy does not decrease leukotriene levels in vivo, 17A8 and the results of some studies suggest a potential upregulation of the 5-1ipoxygenase enzyme responsible for leukotriene generation. 19 In addition, clinical studies have demonstrated additive effects of leukotriene receptor antagonists and ICS, providing clinical evidence that leukotrienes are present even in steroid-treated patients. 1°'11'2°'21 It is also possible that patients taking high doses of ICS require these doses because they have a significant leukotriene component to their asthma that is not being addressed by ICS therapy. Thus, the steroid dose may be increased with marginal benefit. Patients taking lower doses of ICS at baseline had percentage reductions in ICS dose similar to those taking higher doses, suggesting that overtreatment alone does not explain the excessive ICS dose used in these patients. The results of this study are consistent with another study in which treatment with the leukotriene receptor antagonist pranlukast allowed significant tapering of ICS therapy. 22 The importance of tapering ICS doses has been increasingly recognized in national guidelines as well as in recent statements by the US Food and Drug Administration and the Committee on Safety of Medicines (United Kingdom) concerning the safety of higher ICS doses. 23 The present study suggests that ICS tapering by -25% every 2 to 6 weeks can be carried out both safely and faster than current international asthma guidelines recommend, with the high correlation between reduction at 12 weeks and 48 weeks supporting the feasibility of this approach. This method of steroid tapering at a faster rate than currently recommended in guidelines and using 2 parameters of asthma control--lung function and beta-agonist use---may be useful in broader clinical practice. Montelukast therapy was generally well tolerated. It is difficult to fully interpret the safety profile in this study without a control group. However, the adverse-event profile of montelukast in this study is similar to that seen in controlled clinical trials, in which no difference from placebo was observed. 8-~2
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CONCLUSIONS The addition of montelukast to a regimen containing ICS was associated with significant reductions in ICS doses while maintaining clinical stability in patients with established asthma. The degree of tapering was significant and sustained. Montelukast may be useful in the process of ICS tapering recommended by asthma treatment guidelines. The clinical performance score may be a useful way of assessing the ability to taper ICS, and steroid tapering may be conducted faster than current guidelines recommend.
ACKNOWLEDGMENTS
This study was supported by a grant from Merck & Co, Inc, Whitehouse Station, New Jersey. We thank Veerle Coenen for coordination of study data and Joris Menten for statistical analysis and advice. We also gratefully acknowledge the excellent study monitors, investigators, and patients. The members of the Montelukast/ Inhaled Steroid Taper Study Group are as follows: Atmtralia: D. Campbell, C. Jenkins, A. Rubinfeld, R. Ruffin, and P. Thompson; Austria: M. Flicker, W. Janistyn, L. Leitner; Belgium: C. Bonnet, M. De Jonghe; Canada: G.T. Ford, P.S.F. Man, R. Paterson, M.M. Yeung, and N. Zamel; Germany: P. Boelcskei, U. Costabel, E. Daume, H. Fabel, K.-G. Hissnauer, R. Huber, C. Kroegel, B. Kroemer, A. Linnhoff, A. Overlack, K.-H. Ruehle, B. Schmorell, W. Schuette, M. Setzkorn, U. Steinhauser, C. Vogelmeier, T.O.F. Wagner, J. Weidemann, K. Werdermann, and H. Worth; Ireland: P. Maher; The Netherlands: R. Aalbers, T. Bantje, P.B. Luursema, S.J.M. Mol, H. Mulder, H.E.J. Sinninghe Damste, P.W.C. Van Barneveld, and A.M.J. Wever; Norway: E. Eivindson, S. Fosse, E. Gloersen, F.N. Kjeldsberg, T. Kristiansen, P.A. Lier, T. Oien, A. Ostrem, O. Petterson, T. Sandnes, E. Scheel, O. Storro, A. Sundset, G. Vea, and R. Walstad; Switzerland: A. Helbling, T.C. Medici, M. Pons, and M. Soler; United Kingdom: I. Ballin, R. Cook, I.S. Farmer, P.R. Harvey, J. Pittard, T.P. Rees, D. Sills, P. Stephenson, A. Wade, M. Waldron, and J. Zachariah.
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21. Christian Virchow J, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med. 2000; 162:578--585. 22. Tamaoki J, Kondo M, Sakai N, et al, for the Tokyo Joshi4dai Asthma Research Group. Leukotriene antagonist prevents exacerbation of asthma during reduction of highdose inhaled corticosteroid. Am J Respir Crit Care Med. 1997;155:1235-1240. 23. The safety of inhaled and nasal corticosteroids. Curr Probl Pharmacovig. 1998;24:510.
Address correspondence to: David B. Price, MB, BChir, MRCGP, DRCOG Department of General Practice and Primary Care University of Aberdeen ForesterhiU Health Centre Westburn Road Aberdeen AB25 2AY United Kingdom E-mail: [email protected]
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Use of Montelukast in Tapering Inhaled Corticosteroid Therapy: An Open-Label, 48-Week Trial David B. Price, MB, BCh, 1 Michel Y. Rouleau, MD, 2 Christopher P. Fletcher, MB, 3 Piyush Patel, MD, 4 Ronald Olivenstein, MD, s Leiv Myhr, MD, 6 J. Christian Virchow, Jr, MD, 7 W.R. Cameron Aitchison, MB, 8 Ernst R. Omenaas, MD, PhD, 9 Pam S. Dellea, BS,1° Martino Laurenzi, MD, 1° Jonathan A. Left, MD, 1° and the Montelukast/Inhaled Steroid Taper Study Group*
1Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom, 2H6pital du St.-Sacrement, Quebec, Canada, 3Woolwell Medical Centre, Woolwell, Plymouth, United Kingdom, 4Clinical Immunology, Allergy & Asthma, Mississauga, Ontario, Canada, 5Montreal Chest Institute, Montreal, Quebec, Canada, 6LovisenbergHospital, Oslo, Norway, 7Department of Pneumology, Medical University Clinics, Freiburg, Germany, 8The Surgery, Renfrewshire, United Kingdom, 9Universityof Bergen, Bergen, Norway, and Z°Merck and Co, Inc, Whitehouse Station, New Jersey
ABSTRACT
Background: International asthma treatment guidelines recommend tapering inhaled corticosteroid (ICS) therapy to the lowest dose that provides the maximum effect. Montelukast, a leukotriene receptor antagonist with complementary anti-inflammatory actions, has been shown in a tightly controlled trial to allow effective tapering of ICS therapy. Objectives: The purpose of this naturalistic study was to assess whether administration of montelukast could assist in the tapering of ICS therapy in patients with established asthma and whether the reduced dose achieved at 12 weeks could be maintained at 48 weeks without loss of asthma control. Methods: Patients with proven chronic asthma who were being treated with moderate to high doses of ICS (beclomethasone equivalent of 600 to 3200 pg/d) and required, according to their physician, the prescribed dose to maintain asthma control, were given open-label oral montelukast (10 mg/d at bedtime) for 48 weeks. Patients who were clinically stable, based on a composite clinical performance score, had their ICS dose reduced by -25% at 2-week intervals for 12 weeks and at 6-week intervals for the remaining 36 weeks. The percentage *Members of the Montelukast/Inhaled SteroidTaper StudyGroup are listed in the Acknowledgments.
AcceptedforpublicationSeptember18, 2001.
Printed in the USA.Reproduction in whole or part is not permitted.
0011-393X/01/$19.00
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reduction in final ICS dose associated with clinical stability was the primary end point of the study. Results: Five hundred eighty-one patients were enrolled (57% female; mean age, 41 years). At 12 weeks, the mean ICS dose had been tapered by 82.3% (from 959 IJg/d to 172 IJg/d) and a total of 345 patients (59.5%) had completely stopped ICS. At 48 weeks, mean ICS dose had been tapered by 81.3% (from 959 IJg/d to 178 pg/d; P < 0.001), and 356 patients (61.3%) had completely stopped ICS. During tapering, patients remained clinically stable despite a significant -30% reduction in beta-agonist use (P < 0.001). There was a small but significant 2.7% decrease in forced expiratory volume in 1 second (P < 0.001). The extent of tapering was similar regardless of the ICS used (fluticasone, budesonide, beclomethasone, or flunisolide) and independent of baseline betaagonist use. Montelukast was generally well tolerated. Fifty-one patients (9%) discontinued due to clinical adverse events. Conclusion: In patients with chronic asthma treated with ICS, the addition of montelukast to assist in ICS tapering can be applied in clinical practice without loss of asthma control. Key words: inhaled steroids, leukotriene receptor antagonists, montelukast, asthma, steroid sparing, steroid tapering. (Curr Ther Res Clin Exp. 2001;62:743-
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INTRODUCTION Although inhaled corticosteroids (ICS) are effective in the treatment of bronchial asthma, chronic administration of moderate to high doses of ICS may cause side effects such as cataract formation, oral thrush, dysphonia, and skin bruising. ~-6 International guidelines, therefore, recommend that the ICS dose be minimized whenever possible. 7 It may be useful to develop new strategies that will help reduce ICS dose requirements to the lowest dose while providing the maximum benefit. Montelukast sodium* is a specific and potent leukotriene (CysLT1) receptor antagonist with demonstrated efficacy in the treatment of chronic asthma in adults and children. 8-x5 The benefits of montelukast therapy have been demonstrated in patients who have not been treated with ICS and also have been found to be additive in patients receiving ICS.1° In a randomized, placebo-controlled trial, H montelukast enabled a 47% reduction of ICS doses over a 12-week treatment period compared with 30% for placebo. Although this study was well designed, it was a classic efficacy study in which patients had to meet inclusion criteria not representative of the "real-life" target population, had to make numerous study visits, and tended to be highly compliant with administered therapy. Thus, while this study may provide data on absolute efficacy of the drug in an *Trademark: Singuiair® (Merck & Co, Inc, Whitehouse Station, New Jersey).
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ideal scenario and in a relatively homogeneous patient population, it yields limited information about the actual effectiveness of the drug in clinical practice. The present study was therefore designed to assess whether the method of tapering used in the previous clinical trial ]~ could be safely and effectively extended to an actual clinical practice setting and whether short-term reductions in ICS dose could be maintained over a longer period of time. We conducted a multicenter, open-label study in patients with proven asthma who required moderate to high ICS doses to assess whether tapering of ICS therapy could be undertaken according to a protocol of beta-agonist use and lung function monitoring in conjunction with montelukast therapy. We also determined whether the tapering achieved at 12 weeks could be maintained at 48 weeks and assessed its impact on asthma control. The inclusion of a placebo arm was considered unethical, considering the duration of the study and results from a previous study H that showed greater loss of asthma control and a 30% discontinuation rate in the placebo arm. PATIENTS AND METHODS Patients Patients 15 to 70 years of age with clinically stable asthma were enrolled from 10 countries--Australia, Austria, Belgium, Canada, Germany, Ireland, the Netherlands, Norway, Switzerland, and the United Kingdom. Eligible patients had a history of persistent and currently stable asthma. Asthma was demonstrated by either (1) a >12% increase in forced expiratory volume in 1 second (FEV1) or 15% increase in peak expiratory flow after beta-agonist administration or (2) airway hyperresponsiveness as defined by a ->20% reduction in FEV] in response to methacholine or histamine <4 mg/mL (determined either during the run-in period or within 1 year of study entry). In addition, patients had to be nonsmokers for at least 1 year, with a smoking history of -<20 pack-years. Stability of asthma was demonstrated by an FEV] ->70% of the predicted value before beta-agonist use. Excluded were patients who had had emergency treatment for asthma within 1 month of the first visit, hospitalization for asthma within 3 months, an unresolved upper respiratory tract infection within 3 weeks of study entry, or sinus infection within 1 week of study entry. Patients required, according to their physician, treatment with an ICS for at least 3 months at any dose, and at the following stable daily doses for at least 1 month before the study: fluticasone 300 to 1600 pg/d, beclomethasone or budesonide 800 to 3000 pg/d, flunisolide 1000 to 3000 pg/d, or triamcinolone 1200 to 3200 pg/d. Patients used a daily average of -<6 puffs of inhaled betaagonist as needed (measured on a diary card) during the baseline period (ie, between visits 1 and 2). Thus, although clinically stable, many patients could still show clinical improvement in terms of reduced beta-agonist use. Patients were in good health except for their asthma. The following asthma medications were excluded: oral, intravenous, or intramuscular corticosteroids
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within 1 month; cromolyn sodium or nedocromil within 1 month; leukotriene receptor antagonists or theophylline within 2 weeks; and long-acting inhaled or oral beta-agonists or inhaled anticholinergic agents within 1 week of the first visit. Nasal corticosteroids and nasal cromolyn sodium were allowed as needed. Inhaled albuterol and short-acting antihistamines were allowed as needed, but were withheld for at least 6 and 48 hours, respectively, before s t u d y visits. The ethical review committees of all participating centers approved the protocol, and written informed consent was obtained from all participants.
Study Design The study consisted of 3 periods over 50 weeks. Period 1 was a 2-week screening period that included the administration of a questionnaire regarding the stability of asthma over the preceding year. Period 2 was a 12-week treatment phase in which ICS dosage could be adjusted at clinic visits every 2 weeks. Period 3 was a 36-week treatment phase in which ICS dosage could be adjusted at 6-week intervals. During period 1 (visits 1 and 2), patients maintained their usual dose and formulation of ICS. During periods 2 and 3, patients took montelukast sodium (one 10-mg film-coated tablet daily at bedtime). At visit 2 (ie, week 0), the dose of ICS was tapered by 1 step (Table I) for all patients. Beginning at visit 3, ICS doses were tapered, increased, or maintained based on a clinical performance score (CPS).
Clinical Performance Score and Taper Method The CPS was calculated based on the FEV~ recorded at the clinic visit and beta-agonist use recorded during the 7 days immediately preceding the visit (determined from patient diary cards). This was based on the scoring methodology of the previous steroid taper study using montelukast. H One point was given if FEV~ was ---90% of the pre-beta-agonist baseline (average of values at visits 1 and 2), and 1 point was given if beta-agonist use did not exceed 135% of the baseline value (average daily use on days between visits 1 and 2). The CPS therefore ranged between 0 (worst outcome) and 2 (best outcome). The ICS
Table I. Study protocol for tapering inhaled corticosteroid (ICS) dose based on current ICS use. Current ICS Dose (puffs/d)
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2-10
2 (1 in AM, 1 in PM)
12--18
4 (2 in AM, 2 in PM)
20-26 28-32 34-40
6 (3 in AM, 3 in PM) 8 (4 in AM, 4 in PM) 10 (5 in AM, 5 in PM)
D.B. Price et eL
dose was tapered for patients with a score of 2, maintained for those with a score of 1, and increased (Table II) for those with a score of 0. Therapy was not tapered for patients whose dose had been increased at the previous visit, even if they had a CPS of 2. Patients receiving increased ICS doses who subsequently did not restabilize (ie, CPS = 0 at 2 consecutive clinic visits) were withdrawn from the study at the discretion of the investigator.
End Points The primary end point was the percentage reduction in ICS dose from baseline to the last tolerated dose at week 12. The last tolerated dose was defined as the last dose at which the CPS was 1 or 2. Other end points included the percentage of patients who did not require any ICS therapy by weeks 12 and 48, the percentage reduction in ICS dose at week 48, and the change in daily beta-agonist use.
Statistical Analysis The efficacy analysis was performed on the intent-to-treat population, that is, all patients with a baseline measurement and at least 1 postbaseline measurement. At each visit, the number of patients whose therapy was tapered and the number (percentage) of successful tapers (CPS score at next visit of 1 or 2) were summarized. The percentage reduction in ICS dose was analyzed with a 1-sample t test, and 95% CIs were constructed around the mean dose reduction. Statistical significance was set at P -< 0.05.
RESULTS A total of 581 patients were enrolled. Baseline characteristics of the patients are listed in Table III. The ICS used included budesonide (262 patients [45%]), beclomethasone (142 patients [24%]), fluticasone (175 patients [30%]), and flunisolide (2 patients [<1%]). The mean baseline ICS dose was 959 pg/d (not corrected for beclomethasone equivalents) (Table IV).
Table II. Study protocol for increasing inhaled corticosteroid (ICS) dose based on current ICS use. Current ICS Dose (puffs/d) 0-6 8-12 14-18 20-22 -->24
Dose Increase (puffs/d) 2 4 6 8 10
(1 (2 (3 (4 (5
in AM, 1 in AM, 2 in AM, 3 in AM, 4 in AM, 5
in in in in in
PM) PM) PM) PM) PM)
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Table III. Demographic characteristics of enrolled patients (N = 581)* at baseline. Characteristic
Age, y, mean (SD) Age distribution, no. (%) <18 y 18-65 y >65 y Sex, no. (%) Male Female Race, no, (%) White Asian Black Other Duration of ICS therapy, no. (%) <1 y --1 y Dose of ICS at baseline, no. (%)~ -<800 pg >800 to <1200 pg 1200 to <1500 IJg 1500 to 2000 IJg >2000 IJg FEV1, mean % predicted (SD) Beta-agonist use, mean (SD) puffs/d Smoking history, no. (%) Smoked Never smoked
41.0 (1 3.5) 10 (2) 551 (95) 20 (3) 249 (43) 332 (57) 567 5 4 5
(98) (<1) (<1) (<1)
21 7 (37) 364 (63) 233 158 34 132 23 85.1 3.0
(40) (27) (6) (23) (4) (12.0) (4.1)
207 (36) 374 (64)
ICS = inhaled corticosteroid; FEV1 = forced expiratory volume in 1 second. *Efficacy data unavailable for 1 patient. tBeclomethasone equivalent dose; dose unknown for 1 patient.
Week 12 After 12 weeks of treatment with montelukast, the mean ICS dose was reduced to 172 pg/d, representing a significant (P < 0.001) mean reduction of 82.3% (95% CI, 80.0-84.7) from baseline (Figure 1). At week 12, 345 patients (59.5%) completely stopped ICS therapy (95% CI, 55.4-63.5); 90.9% (527/580) of patients were able to reduce their ICS dose by at least 50%, and 77.1% (447/580) by at least 75%. Week 48
After 48 weeks of treatment with montelukast, the mean dose was reduced to 178 pg/d, representing a significant (P< 0.001) mean reduction of 81.3% (95% CI, 78.5-84.0) from baseline (Figure 1). A total of 356 patients (61.3%) completely
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Table IV. Mean baseline and last tolerated dose by type of inhaled corticosteroid (ICS).
ICS Type
No. of Patients
Baseline Dose (IJg/d) (range)
142 261 2 175
1026 (800-2000) 1033 (400-3200) 1250 (1000-1500) 792 (300-2000)
Beclomethasone Budesonide Flunisolide Fluticasone
Last Tolerated Dose (IJg/d) (range) 142 208 250 163
(0-1500) (0-2133) (0-500) (0-1333)
stopped ICS therapy by week 48 (95% CI, 57.3-65.3). By week 48, 89.5% (519/580) of patients were able to reduce their ICS dose by at least 50%, and 79.0% (458/580) by at least 75%. Seventy-seven patients (13.3%) did not respond to rescue doses (ie, CPS = 0 at 2 consecutive visits). Of the cases in which ICS doses were increased 0e, rescues), 78.9% were successful 0e, CPS at the next visit = 1 or 2). Only 2 patients required more rescues than tapers, whereas 97.2% of patients had more tapers than rescues. To assess the relation between baseline asthma control level and tapering success, tapering was also analyzed based on baseline beta-agonist use (ie,
-0- FEV, -II- Beta-agonist use -~- ICS dose 1000
300
100,
2so
800
-0
8o u_
2oo 6oo
6o
•~ 0
150
400 100
2OO
so
0
0
N
2o 0
;
I
6
1'2
I
1'8 24
3'0
I
3'6 42
I
48
Weeks
Figure 1. Effect of montelukast administration on dose of inhaled corticosteroid (ICS), beta-agonist use, and forced expiratory volume in 1 second (FEV~) among patients with established asthma (N = 581). Values are weekly means.
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>100 pg/d or <100 pg/d). Among patients using >-100 lag/d, the mean ICS dose was tapered from 984 lag/d to 189 lag/d (80.2%, P < 0.001). Among those patients using <100 pg/d at baseline, mean ICS dose was tapered from 925 lag/d to 158 lag/d (82.9%, P < 0.001). During the study, beta-agonist use decreased significantly (P < 0.001) by -30% (Figure 1). This decrease occurred early and remained stable throughout the study. Among patients whose beta-agonist use at baseline was excessive according to asthma guidelines (ie, >200 lag/d albuterol), the median reduction in beta-agonist use was 48.3% (from 490 pg/d to 260 pg/d). A small but significant 2.7% decrease (P < 0.001) in percent predicted FEV~ occurred during the study (Figure 1). The percentage reduction in ICS dose was similar across all subgroups, irrespective of sex, race, age, duration of previous ICS therapy (>1 year vs <1 year), type of ICS, and dose of ICS at baseline (>1500 pg/d, 81.7% reduction; <1500 pg/d, 80.2% reduction). There was a high correlation between the degree of ICS tapering observed at 12 weeks and at 48 weeks (Figure 2). For example, 368 patients (63%) had identical reductions at week 12 and week 48. Despite the ICS tapering, the peripheral blood eosinophil concentration remained stable (baseline mean, 0.24 x 109 cells/L; treatment period mean, 0.27 x 109 cells/L). Montelukast was generally well tolerated. The most frequent clinical adverse events over the 48 weeks were upper respiratory infection (43% [250/581]), 100 80 60 0
40
~J ! ._=
20
e-
0 -20
e-
u
-4O -60 -8O -100 Week 12
Week48
Figure 2. Treatment effect (degree of tapering) at 12 weeks versus 48 weeks in a randomly selected subset representing 20% of treated patients. Values represent mean percentage of tapering of inhaled corticosteroid (ICS) dose.
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asthma worsening (27% [154/581]), and headache (26% [ 149/581]). Forty-six patients (8%) discontinued after 12 weeks and 130 patients (22%) after 48 weeks. Fifty-one patients (9%) discontinued due to clinical adverse events (most commonly asthma worsening [25 patients] and dyspnea [3 patients]). Of the 25 patients who discontinued with worsening asthma, 1 was hospitalized. In addition, 6 patients discontinued due to pregnancy, 1 due to a laboratory adverse event (liver function abnormality), 14 due to insufficient therapeutic response, and 58 for other miscellaneous reasons (protocol deviations [10 patients], lack of response to increased ICS dose or need for additional medication [15 patients], loss to follow-up [I 1 patients], uncooperative behavior or patient request for withdrawal [22 patients]). Responses to the baseline questionnaire suggested that >50% of participants had an average of at least 1 unscheduled visit to a physician for asthma in the past year. Only 27% of patients reported asthma-related adverse events during the study.
DISCUSSION Montelukast has been shown to enable ICS tapering at a rate significantly greater than placebo in a traditional clinical trial population drawn mainly from secondary care. n Clinical effectiveness studies, however, require the inclusion of patients representative of those who will actually be treated while maintaining the rigor of a clinical trial. This study therefore examined a large primary care population of asthma patients prescribed higher than ideal doses of ICS and used an open-label design to closely mimic actual clinical practice. We found that treatment with montelukast was associated with significant reductions in ICS doses without negatively affecting asthma control. This reduction occurred within the first 12 weeks and persisted throughout the 48-week treatment period. The percentage change from baseline in ICS dose was substantial, and >60% of patients were able to stop 1CS therapy completely. It may be argued that those patients for whom ICS doses were substantially reduced had a form of asthma that is especially leukotriene dependent. In fact, concomitant treatment with a leukotriene receptor antagonist with subsequent tapering of ICS therapy may be a way to identify these patients. In this trial, ICS therapy was tapered while maintaining the clinical stability of the patients. Patients were clinically stable at randomization and were able to have their ICS dose tapered despite a significant reduction in beta-agonist use. Although spirometry showed a statistically significant decrease in FEV1, the magnitude of the decrease (2.7%) was small and of questionable clinical relevance. Inclusion of a placebo group in this study was considered ethically unacceptable since results from a previous study of montelukast with ICS tapering showed that the placebo group had an increased risk of loss of asthma control. H With no placebo group, it is impossible to quantitate the placebo effect of tapering. Thus, the conclusions drawn must be tentative. However, in a
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previous study, 11 the placebo response in the run-in and treatment phases was -57%. The -80% reduction seen in the present study would appear to be greater than what might be expected from placebo alone. One might hypothesize that these patients were overtreated and that most did not actually require ICS. However, the fact that patients taking ->100 pg/d of beta-agonist at baseline (and thus not completely controlled with ICS) and those taking <100 pg/d had their doses tapered to a similar extent (81% vs 83%) would support the premise that the results were not all due to placebo effect and that these patients were not overtreated with ICS. A significant proportion of therapeutic responses in an office setting may, in fact, be due to a placebo response. Even so, this does not limit the utility of therapeutic interventions in clinical practice, especially since there is significant evidence that steroid tapering is not being actively implemented by health care professionals. 16 Evidence for complementary activity of leukotriene modifiers and ICS is growing. Several studies have demonstrated that steroid therapy does not decrease leukotriene levels in vivo, 17A8 and the results of some studies suggest a potential upregulation of the 5-1ipoxygenase enzyme responsible for leukotriene generation. 19 In addition, clinical studies have demonstrated additive effects of leukotriene receptor antagonists and ICS, providing clinical evidence that leukotrienes are present even in steroid-treated patients. 1°'11'2°'21 It is also possible that patients taking high doses of ICS require these doses because they have a significant leukotriene component to their asthma that is not being addressed by ICS therapy. Thus, the steroid dose may be increased with marginal benefit. Patients taking lower doses of ICS at baseline had percentage reductions in ICS dose similar to those taking higher doses, suggesting that overtreatment alone does not explain the excessive ICS dose used in these patients. The results of this study are consistent with another study in which treatment with the leukotriene receptor antagonist pranlukast allowed significant tapering of ICS therapy. 22 The importance of tapering ICS doses has been increasingly recognized in national guidelines as well as in recent statements by the US Food and Drug Administration and the Committee on Safety of Medicines (United Kingdom) concerning the safety of higher ICS doses. 23 The present study suggests that ICS tapering by -25% every 2 to 6 weeks can be carried out both safely and faster than current international asthma guidelines recommend, with the high correlation between reduction at 12 weeks and 48 weeks supporting the feasibility of this approach. This method of steroid tapering at a faster rate than currently recommended in guidelines and using 2 parameters of asthma control--lung function and beta-agonist use---may be useful in broader clinical practice. Montelukast therapy was generally well tolerated. It is difficult to fully interpret the safety profile in this study without a control group. However, the adverse-event profile of montelukast in this study is similar to that seen in controlled clinical trials, in which no difference from placebo was observed. 8-~2
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CONCLUSIONS The addition of montelukast to a regimen containing ICS was associated with significant reductions in ICS doses while maintaining clinical stability in patients with established asthma. The degree of tapering was significant and sustained. Montelukast may be useful in the process of ICS tapering recommended by asthma treatment guidelines. The clinical performance score may be a useful way of assessing the ability to taper ICS, and steroid tapering may be conducted faster than current guidelines recommend.
ACKNOWLEDGMENTS
This study was supported by a grant from Merck & Co, Inc, Whitehouse Station, New Jersey. We thank Veerle Coenen for coordination of study data and Joris Menten for statistical analysis and advice. We also gratefully acknowledge the excellent study monitors, investigators, and patients. The members of the Montelukast/ Inhaled Steroid Taper Study Group are as follows: Atmtralia: D. Campbell, C. Jenkins, A. Rubinfeld, R. Ruffin, and P. Thompson; Austria: M. Flicker, W. Janistyn, L. Leitner; Belgium: C. Bonnet, M. De Jonghe; Canada: G.T. Ford, P.S.F. Man, R. Paterson, M.M. Yeung, and N. Zamel; Germany: P. Boelcskei, U. Costabel, E. Daume, H. Fabel, K.-G. Hissnauer, R. Huber, C. Kroegel, B. Kroemer, A. Linnhoff, A. Overlack, K.-H. Ruehle, B. Schmorell, W. Schuette, M. Setzkorn, U. Steinhauser, C. Vogelmeier, T.O.F. Wagner, J. Weidemann, K. Werdermann, and H. Worth; Ireland: P. Maher; The Netherlands: R. Aalbers, T. Bantje, P.B. Luursema, S.J.M. Mol, H. Mulder, H.E.J. Sinninghe Damste, P.W.C. Van Barneveld, and A.M.J. Wever; Norway: E. Eivindson, S. Fosse, E. Gloersen, F.N. Kjeldsberg, T. Kristiansen, P.A. Lier, T. Oien, A. Ostrem, O. Petterson, T. Sandnes, E. Scheel, O. Storro, A. Sundset, G. Vea, and R. Walstad; Switzerland: A. Helbling, T.C. Medici, M. Pons, and M. Soler; United Kingdom: I. Ballin, R. Cook, I.S. Farmer, P.R. Harvey, J. Pittard, T.P. Rees, D. Sills, P. Stephenson, A. Wade, M. Waldron, and J. Zachariah.
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21. Christian Virchow J, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med. 2000; 162:578--585. 22. Tamaoki J, Kondo M, Sakai N, et al, for the Tokyo Joshi4dai Asthma Research Group. Leukotriene antagonist prevents exacerbation of asthma during reduction of highdose inhaled corticosteroid. Am J Respir Crit Care Med. 1997;155:1235-1240. 23. The safety of inhaled and nasal corticosteroids. Curr Probl Pharmacovig. 1998;24:510.
Address correspondence to: David B. Price, MB, BChir, MRCGP, DRCOG Department of General Practice and Primary Care University of Aberdeen ForesterhiU Health Centre Westburn Road Aberdeen AB25 2AY United Kingdom E-mail: [email protected]
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