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ABSTRACT |
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Dose-dependent effects of inhaled corticosteroids have been described. Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently (stepdown approach), no clinical studies have assessed this strategy. We compared two different dosage schedules of inhaled fluticasone propionate (FP) in chronic persistent childhood asthma with respect to efficacy (airways hyperresponsiveness [PD20], lung function, exhaled nitric oxide [eNO]) and safety (height). During this double-blind study, children with asthma (aged 6-10 yr) were randomized to receive either FP 200 µg/d (constant dose approach) or to start with 1000 µg/d with two monthly reductions to 500, 200, and 100 µg/d (stepdown approach). PD20 improved in both approaches during treatment with FP, with a significantly better PD20 after 2 mo of 1000 µg/d followed by 500 µg/d in the stepdown approach versus 200 µg/d in the constant dose approach. No significant differences in PD20 or other efficacy parameters were found after 1 yr. Changes in standing height were similar in both treatment approaches. This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma.
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Keywords: asthma; children; fluticasone; growth; hyperreactivity
Current guidelines for the management of childhood asthma focus on the use of maintenance therapy with antiinflammatory agents, in particular inhaled corticosteroids (ICS) (1). In these guidelines, increasing the dose of ICS is advised during periods with increased symptoms. This advice is based on the concept that ICS have a dose-dependent effect on reduction of airway inflammation. Although some studies have failed to do so, the majority of recent studies appear to support the hypothesis of a dose-dependent relationship of ICS on markers of effectiveness in childhood asthma (5). As a result, it has become established practice to start ICS therapy in childhood asthma with relatively high doses, in order to reduce airway inflammation aggressively, and to reduce the dose of ICS subsequently in a stepwise fashion to the lowest effective dose (3, 4, 11, 12). Popular as this stepdown strategy may be, there is little, if any, published evidence from clinical trials to support it. The only clinical trial comparing the stepdown approach with a constant dose in childhood asthma that we are aware of is a study of nebulized budesonide suspension in preschool children (aged 6 mo to 3 yr) (13). In this study, the stepdown approach yielded a significantly earlier improvement in asthma symptoms, which was sustained during follow-up, when compared with a constant low dose. No objective assessments of lung function or airway hyperresponsiveness was carried out. In addition, the short duration of both the high-dose starting period (less than 1 wk) and total follow-up (10 wk) limits the generalizability of these study results to clinical practice.
Systemic side-effects, in particular reduction of growth rate, are a matter of concern in children with asthma when treated with ICS. Limited data are available on the effect of fluticasone propionate (FP) on growth in children with asthma. Although two recent studies showed no effect on linear growth in children during 1-yr treatment with FP 100 µg/d, treatment with a dose of 200 µg/d was associated with a reduction in growth when compared with placebo (14). Reassuring results showing normal adult height after long-term treatment with ICS have recently been published (17, 18).
The aim of our study was to compare a stepdown approach (1000 µg/d tapering off to 100 µg/d) with a constant dose approach (of 200 µg/d) in school children with asthma for a period of 12 mo. Symptoms, exacerbations, lung function, and airway hyperresponsiveness were primary efficacy variables, and height was the primary safety variable.
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INTRODUCTION
METHODS
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Subjects
Children aged 6-10 yr with chronic persistent asthma were recruited
for the study. None used > 800 µg of inhaled budesonide or beclomethasone, or inhaled FP > 400 µg. No long acting 
2-agonists or antileukotriene therapy were allowed during the study. Patients with
major other illness and those who had used systemic corticosteroids during the previous 6 wk, or had a respiratory tract infection during
the preceding 4 wk, were excluded. Informed consent was obtained
from all children and their parents. The study was approved by the
medical ethics committees of the three participating centers.
Study Design
After a run-in period of 6 wk, during which patients used FP 200 µg/d by dry powder inhaler (Diskhaler; GlaxoWellcome, Zeist, The Netherlands), patients entered a period of 2-8 wk during which no ICS or other antiinflammatory drugs, but only inhaled salbutamol 200 µg by Diskhaler on demand were used. During this period, patients returned to the clinic every 2 wk (or earlier if symptoms worsened, but before a full-blown exacerbation developed) for measurement of airway hyperresponsiveness. Those subjects whose provocative dose (PD20) did not drop below 80 µg during the 8-wk wash-out were withdrawn from the study (19). When a PD20 < 80 µg was found, the patient was randomized either to the stepdown (FP 1000 µg/d with two monthly reductions to 500, 200, and 100 µg/d) or the constant dose approach (Figure 1). Randomization was performed with stratification for age, sex, duration of prior ICS use, and PD20. All patients received standardized instructions on the correct use of the Diskhaler and were required to demonstrate a correct inhalation maneuver at each follow-up visit. Patients were allowed to use salbutamol by Diskhaler on demand during the whole study.
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The time schedule of assessments is given in Figure 1. At the randomization visit, blood was drawn for total and specific immunoglobulin E (IgE) to house dust mite, grass and tree pollen, and cat and dog dander (Pharmacia MasterCap analysis, Pharmacia & Upjohn, Uppsala, Sweden). Lung function (flow-volume curves) was measured according to ERS guidelines, using a Jaeger Masterlab pneumotachograph (Erich Jaeger GmbH, Würzburg, Germany) (20). Airway hyperresponsiveness to methacholine was measured using a dosimeter method as published previously (21). Exhaled nitric oxide was measured using a tidal breathing method (22). Height was measured by trained technicians, using a Harpenden stadiometer. Bone age was determined at randomization and after 1 yr using the Tanner & Whitehouse method by a single blinded investigator (T.dV.). Tanner's pubertal stages were scored at each follow-up visit (23).
Patients kept a diary card of symptom scores (score 1 to 10), use of salbutamol, and peak expiratory flow (PEF) for 2 wk prior to each follow-up visit. All patients received a new mini Wright PEF meter (Clement Clarke, Harlow, UK) and standardized instructions on how to use it. PEF was recorded each morning and evening in triplicate; the highest value was recorded in the diary. At each follow-up visit, a standardized short symptom questionnaire was administered to each patient (24). Patients were asked to bring along all used and unused medication at each follow-up visit. Adherence to treatment was assessed by counting the blisters used.
Statistical Analysis
All calculations of PD20 were performed on a log-transformed basis, thereby normalizing the distribution. The analyses were performed using SAS 6.12 and SPSS 9.0. Differences between groups were analyzed at individual time points, both when differences in ICS dosages between groups were large (first months of the study) and when they were small (Figure 1). To determine trends over time, a linear mixed effects model (SAS Proc Mixed) was used.
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RESULTS |
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Patients
Fifty-five children completed the 1-yr study. During the study,
four children were withdrawn: three from the constant dose approach (one due to exacerbation of asthma and two because
of insufficient asthma control) and one from the stepdown approach (because of adverse event: abnormal bone density).
This difference was not significant. Baseline characteristics
were similar in both treatment approaches (Table 1). Mean
2-agonist use was 0.1 dosages/d (range 0.0-1.0) in both
groups during the wash-out period. The (geometric) mean
time between end of the run-in period and randomization for
the constant dose approach was 22.8 d and 24.3 d for the stepdown approach.
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Airway Hyperresponsiveness
Airway hyperresponsiveness improved in both approaches after randomization to treatment with inhaled FP (PD20 change from 30 to 346 µg in constant dose approach, and from 30 to 477 µg in stepdown approach; Figure 2). Only at 4 mo was the difference in PD20 between study approaches significant (geometric mean [range] PD20 200 µg/d versus PD20 500 µg/d: 430 [264-700 µg] versus 940 µg [571-1548 µg], respectively, p = 0.03). No significant difference was found when comparing the area under the log PD20 curve between the stepdown approach and the constant dose approach after 1 yr.
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Lung Function, Exhaled Nitric Oxide, and Peakflow
FEV1% predicted deteriorated during the wash-out period (Figure 3). After randomization both treatment approaches improved (mean from 92.1% to 106.4% in the stepdown approach, and from 89.4% to 102.6% in the constant dose approach; Figure 3). No significant differences were found between the two dosage schedules at any time point.
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Levels of exhaled nitric oxide (eNO) increased after withdrawal of FP and decreased in both treatment approaches after randomization (Table 2). During follow-up, no significant differences were detected between the two treatment schedules.
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Results of morning and evening PEF (Table 2) and diurnal and day-to-day PEF variation (data not shown) did not differ between the treatment schedules during the study.
Symptom Scores and Exacerbations
Symptoms increased after withdrawal of FP and decreased during therapy with both dosage schedules of FP, without any significant difference between the two schedules.
The number of asthma exacerbations requiring prednisolone courses was low (0.4 exacerbations/patient year) and evenly distributed between the two approaches (10 and 11 exacerbations in the constant dose and stepdown approach, respectively). The incidence of exacerbations was stable throughout the study period. The number of prednisolone courses in both treatment groups was the same (seven in each) during the first 6 mo of the study, when differences in dosages of FP between study groups were largest. There were no deaths and no patients were admitted to intensive care during the study.
Because the dose of FP differed most between groups during the first 6 mo of therapy, all analyses of the differences between groups were made for the first and second 6 mo of the study separately. This did not change the results: the only significant difference found was between the log PD20 levels mentioned above.
Height
At baseline patients in the stepdown approach were taller (mean 3.3 cm) compared with those treated according to the constant approach (Table 1). This difference remained stable throughout the study (Figure 4), and no significant differences in changes of standing height over time were found between children treated according to the stepdown approach or the constant dose approach. Changes in bone age were similar in the two study approaches during 1-yr treatment (stepdown approach from 8.2 to 9.4 yr, constant dose approach from 8.0 to 9.1 yr).
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Adherence
Mean adherence to treatment was 95.4% in the stepdown and 92.7% in the constant dose group, and remained stable throughout the 12-mo study period. There were no patients with compliance less than 84.6%.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
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DISCUSSION
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This is the first study comparing a constant dose approach of ICS (FP) to a stepdown dosing approach in childhood asthma. Apart from a temporarily larger improvement in airway hyperresponsiveness in the stepdown approach, the effects of the dosage schedules on the measured disease parameters (symptom scores, exacerbation rates, PEF, FEV1, PD20, and eNO) were very similar even when differences in FP doses between treatment groups were largest (first 4 mo of the study). Thus, the results of our study do not support the hypothesis of a superior effect of a stepdown approach (with a high starting dose of ICS, tapered off to a low dose) when compared with a fixed dose schedule over a 1-yr treatment period in children with chronic persistent asthma. It is important to point out that our study population did not include patients with mild intermittent asthma (who would not show airway hyperresponsiveness within 4 wk of withdrawing ICS), or those with severe persistent asthma (who would not have been able to complete the wash-out period without ICS maintenance therapy). We feel, however, that our study population is representative of a large group of children with mild to moderate chronic persistent asthma, characterized by moderate to severe airway hyperresponsiveness.
The degree of airway hyperresponsiveness, a cardinal feature of asthma, was the primary end point of the study. It has been shown previously that ICS improve airway hyperresponsiveness in a dose-dependent way (7). In our study, the only evidence of a dose-dependent effect of FP on airway hyperresponsiveness was the significant difference in PD20 between the two study approaches after 4 mo of treatment (FP 500 µg/d versus FP 200 µg/d; Figure 2). We suspect that the significant difference after 4 mo of follow-up is due to a "carryover" effect of the high dose (1000 µg/d) given during the first 2 mo of follow-up.
Previous studies have shown that airway hyperresponsiveness continues to improve for many months on end during treatment with a fixed dose of budesonide or beclomethasone, which was also seen with FP in the constant dose approach in our study (Figure 2) (25). The lack of difference in airway hyperresponsiveness after 2 mo of treatment between FP 1000 µg/d and FP 200 µg/d is probably caused by a too short duration of treatment with this high dose of inhaled FP, preventing an optimal response on airway hyperresponsiveness after 2 mo. Indeed, a recent study, comparing two different dosage schedules of FP, only showed a significant dose-dependent effect on airway hyperresponsiveness after treatment for 6 mo, suggesting a slow dose-dependent effect on airway inflammation (7). However, our results suggest that this dose-dependent effect of FP on airway hyperresponsiveness is not maintained when a high dose is tapered off in the stepdown fashion so popular in contemporary asthma management.
We found no difference in airway hyperresponsiveness when in both approaches patients were treated with inhaled FP 200 µg/d (after 6 mo). Previous studies in adults (using FP and budesonide) are consistent with this finding (28, 29). Even more important, no superior effect of the stepdown approach on airway hyperresponsiveness was found after 1 yr of treatment, although the cumulative dose of FP was 1.7 times higher in the stepdown approach (120 mg) than in the constant dose approach (73 mg). This suggests that the effects of ICS on airway inflammation in patients with asthma are independent of the cumulative dose of ICS used, but rather depend on the dose presently being used. The results of previous studies showing rapid recurrence of airway hyperresponsiveness after withdrawal of ICS demonstrate that the effect of even a high dose of ICS on both airway inflammation and airway hyperresponsiveness is only temporary, if ICS are not continued (29, 30).
Although all participating children had been using ICS before entering the study, the FEV1 % predicted improved during the run-in period in both approaches. We propose that this is due to improved adherence to treatment, caused by participation in the clinical trial. During the wash-out period, the FEV1 decreased significantly as expected, to improve again rapidly after reinstitution of ICS therapy (Figure 3). Although in some studies the effect of ICS on FEV1 was dose dependent at the group level, we did not find significant differences between the two treatment approaches at any moment during the study (6, 7, 9, 29). Previous studies have shown that the improvement in FEV1 quickly levels off after introducing these drugs (11, 25, 26, 31). This suggests that the lack of finding a dose-dependent response on the FEV1 is possibly due to the relative insensitivity of this parameter to changes in the dose of ICS within the individual patient.
Cross-sectional studies have shown that children with asthma have higher levels of eNO than healthy control children (22, 32, 33). In addition, ICS decrease eNO levels in subjects with asthma (34). We found that eNO levels increased after withdrawal and decreased after reinstitution of FP, but without a significant effect of the dose of FP on eNO levels (Table 2). It is unlikely, therefore, that eNO levels will be useful to titrate the ICS dose in childhood asthma.
Previous studies have shown that PEF increases, and symptoms and use of rescue medication decrease after institution of ICS. In accordance with our results, other studies have shown little, if any, effect of the dose of ICS on the improvement of those parameters (6, 37). In addition, a recent study in adult subjects with asthma, comparing two different dosage schedules of ICS, also failed to detect differences in PEF and symptoms (38). The difference between changes during therapy in these variables on the one hand, and changes in airway hyperresponsiveness in which a slight dose-dependent effect of ICS was observed on the other, is in accordance with earlier work (39, 40).
Although children treated according to the stepdown approach cumulatively received almost twice the amount of inhaled FP as those treated according to the constant dose approach, this had no significant effect on linear height over a 1-yr period (Figure 4). This does not, however, exclude an effect of FP per se on height. A previous study, comparing FP 100 µg/d for 1 yr with cromoglycate, showed no significant effect of FP on height growth of children with asthma (14). In a placebo-controlled trial, treatment for 1 yr with FP 200 µg/d, however, was associated with reduced height growth, as has been observed with beclomethasone and budesonide (15, 16, 18, 26, 41, 42). Reassuring results of long-term treatment with budesonide have recently been published, showing no effect on adult height (17, 18). Although it is likely that this is also the case for FP, long-term prospective studies are needed to test this hypothesis.
The power of our study to detect significant differences between groups was somewhat reduced (to 84%) because it was difficult to recruit patients with a sufficient amount of airway hyperreponsiveness into our study (19). Because the differences in disease parameters between study groups were absent or very small, we feel it is unlikely that increasing the power would have changed the results.
In conclusion, this study showed no superior clinical effect of FP given in a stepdown approach for 1 yr when compared with a constant dose strategy in children with asthma. Only a small and temporary dose-dependent effect on airway hyperresponsiveness was found. These results raise doubt as to the validity of the popular stepdown strategy of dosing ICS in moderate to severe childhood asthma. Further studies are needed to evaluate the effects of constant and stepdown dosing strategies in mild asthma.
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Footnotes |
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Correspondence and requests for reprints should be addressed to P.L.P. Brand, Department of Pediatrics, Isala Klinieken/Weezenlanden Hospital, P.O. Box 10500, 8000 GM Zwolle, The Netherlands. E-mail: P.L.P.Brand{at}isala.nl
(Received in original form March 15, 2001 and accepted in revised form September 25, 2001).
Acknowledgments:
This study was supported by GlaxoSmithKline B.V., The Netherlands, University
Hospital Groningen, and the University of Groningen.
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References |
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 M.J. Visser, E. van der Veer, D.S. Postma, L.R. Arends, T.W. de Vries, P.L.P. Brand, and E.J. Duiverman Side-effects of fluticasone in asthmatic children: no effects after dose reduction Eur. Respir. J., September 1, 2004; 24(3): 420 - 425. [Abstract] [Full Text] [PDF]
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L. Prieto, L. Bruno, V. Gutierrez, S. Uixera, C. Perez-Frances, A. Lanuza, and A. Ferrer Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects Chest, October 1, 2003; 124(4): 1325 - 1333. [Abstract] [Full Text] [PDF]
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 M. J. TOBIN Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 619 - 630. [Full Text] [PDF]
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