INTRODUCTION

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Inhaled corticosteroids are very effective to control symptoms in the treatment of asthma (1, 2). Current guidelines on the management of asthma advocate inhaled corticosteroid therapy as soon as more than 3 doses per week of an inhaled bronchodilator are needed for symptom relief (3). General practitioners in many countries have adopted these guidelines and early treatment of asthma with inhaled corticosteroids has become the golden therapy standard. Most guidelines suggest a step-up treatment, i.e., to start at a low dose and increase the dose progressively until asthma control is achieved (3). The suggested starting doses are based on clinical studies with conflicting outcome with regard to a dose-related effect of inhaled corticosteroids (6). The new British guidelines on the treatment of asthma (9, 10) advocate a step-down treatment with inhaled corticosteroids starting with 800 µg of inhaled corticosteroids daily in patients with asthma, including patients with mild asthma as detected in a general practitioner setting. This recommendation stems from clinical practice and common sense, and just as with a step-up treatment it is not based on the outcome of clinical studies (9, 11). Until now no formal trials have been published to assess whether step-down treatment is effective. Support for the step-down approach originates only from studies that demonstrate that the dose of inhaled steroids can be reduced once control is achieved (12, 13).

We designed a study to investigate whether step down treatment with inhaled corticosteroids (starting with 400 µg budesonide twice a day in contrast to 100 µg budesonide twice a day), in steroid-naive asthma patients would be more effective in improving lung function and symptoms. Additionally, we aimed to investigate whether a maintenance treatment with 200 µg of inhaled corticosteroids, inhaled once daily, could maintain the induced effect of the previous treatment. We consider this to be the step-down treatment of inhaled corticosteroids in contrast to low-dose maintenance treatment.

	METHODS

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Patients

Patients were selected in 25 general practices. They were diagnosed as having asthma according to the definition of the Dutch College for General Practice by their general practitioner (3). All patients were between 18 and 50 yr of age, had a prebronchodilator PEF and FEV₁ > 50% of predicted, and reported a weekly need for 3 doses or more of an inhaled bronchodilator in the month before enrollment. Excluded were patients with a smoking history of more than 20 pack-years, those who received steroid treatment or had an exacerbation of their asthma in the 2 mo prior to enrollment as well as patients with serious concomitant disease. The study protocol was reviewed and approved by the medical ethics committee of the University Hospital of Groningen.

All patients were informed orally and in writing of the purpose of the study and signed an informed consent form.

Study Design

The study had a double-blind, randomized, parallel design. A total of 91 patients were selected from July 1994 to May 1995. After a run-in period of 1 wk on bronchodilator therapy (terbutaline via Turbuhaler, 250 µg per dose) if needed, patients were either randomized to double-blind treatment with 400 µg budesonide via Turbuhaler (Astra Pharmaceutica, Zoetermeer, The Netherlands) twice daily or to 100 µg budesonide twice daily for 4 wk. Hereafter, all patients were treated with 200 µg budesonide once daily (in the morning) for another 8 wk.

Inhaled bronchodilators were only used when needed. Throughout the study, patients completed a diary twice daily, recording PEF (standing, best of three attempts; mini-Vitalograph, absolute scale; Vitalograph, Buckingham, UK), daytime symptoms (0 = none; 1 = mild, aware of symptoms, but easily tolerated; 2 = moderate, some discomfort, causing interference with daily life; 3 = severe, incapacitating, inability to work or do usual activities), nighttime symptoms (0 = not waking up because of asthma; 1 = awoke because of asthma and/or a bronchodilator had to be used at night), and medication use. Before and after the run-in period and after 1, 4, 8, and 12 wk of treatment the general practitioner measured the patient's lung function (FEV₁, vital capacity [VC], and PEF, by Microspiro 3300; Sensor Medics, Bilthoven, The Netherlands), at approximately the same time of day. Lung function data are expressed as percentage of predicted normal (14). On all five visits, the physician asked the patient to report adverse events.

Analysis

The primary objective of the study was to assess the efficacy of the different dosages of budesonide. The primary efficacy variable was morning PEF, recorded at home. All assessments were analyzed by a two-way fixed effects analysis of variance of the change from baseline. The original 25 centers were pooled into seven new centers of approximately the same size. For all diary assessments (morning PEF, evening PEF, PEF fall overnight, terbutaline use, daytime and nighttime symptoms) means were calculated over the last 7 d before each visit. FEV₁ values obtained at randomization are the baseline values in the analyses.

For each patient the time to reach optimal asthma control was calculated, defined as the number of days after randomization until at least three of the five following criteria were met during a period of 7 consecutive days: (1) no symptoms at night; (2) > 50% reduction in daytime asthma symptoms compared with run-in; (3) > 50% reduction in terbutaline use compared with run-in; (4) morning PEF values > 120% of run-in; (5) fall in PEF overnight < 75% of run-in. p Values refer to two-sided significance levels. All calculations were based on the "all patients treated" approach. Results are expressed as mean ± SD and with 95% confidence intervals (CI). Compliance with medication intake was calculated from the notations in the diary cards. The patient was considered to be compliant, if 75% to 125% of the doses were reported to have been used. Power analysis prior to the study revealed that with 80 patients in the study a clinically relevant difference of 30 L/min in morning PEF could be detected with a power of 80% at the p = 0.05 level, assuming a SD in the change from baseline in PEF of 50 L/min.

	RESULTS

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Of the 91 enrolled patients, seven were not randomized, three because they were not compliant, two because of a deterioration of asthma, and two because of withdrawal of consent. Characteristics of the 40 patients randomized to the 100 µg budesonide twice daily starting dose and of the 44 patients to the 400 µg budesonide twice daily starting dose are shown in Table 1. Twelve patients used additional medication besides an inhaled bronchodilator prior to the study, mainly cromoglycate. Six patients in the 400 µg twice daily and five patients in the 100 µg twice daily group did not complete the study according to the protocolfour because of unwillingness to continue, two because of adverse events, two because of deterioration of asthma, one ran away from home, one did not attend the visits on the scheduled times, and in one case an error was made in dispensing the study medication. Compliance with study drug intake was good. On average 93% of the morning doses and 91% of the evening doses were reported to have been taken in the first 4 wk of the treatment period. In the next 8 wk with once daily treatment compliance was 89%. No patient was noted to have used more than 125% of prescribed budesonide doses, but 16 patients reported less than 75% reported doses on one or more periods. Five patients started to use nonallowed medication, in three cases because of an asthma exacerbation. Pharmacologically predictable adverse events were infrequently reported, i.e., a mild hoarseness by one patient in each group, other throat complaints by three patients starting with 400 µg twice a day and by two patients starting with 100 µg twice a day. Oropharyngeal candidiasis was not observed. No serious adverse events were reported.

Diary

Morning PEF increased slightly during the first week with 400 µg budesonide twice daily treatment (4 L/min), but significantly more during 100 µg budesonide twice a day (24 L/min), mean difference being 20.6 L/min, 95% CI 3.4 to 37.9 L/min, p = 0.02 (Figure 1). In the fourth week of treatment there was no significant difference in the change from baseline value in morning PEF (27 respectively 38 L/min, p = 0.30). Also in the next 8 wk of once-daily treatment, no significant difference between both groups was found. Evening PEF values were less increased than morning values, and changes from baseline were not significantly different between groups. PEF variation decreased similarly in the two groups.

View larger version (13K): [in this window] [in a new window]   Figure 1.   Changes in morning PEF from run-in period after 1 wk and 4 wk of treatment with 100 µg budesonide and 400 µg budesonide twice daily, after 8 wk and 12 wk of treatment on 200 µg budesonide once daily.

During the run-in period, patients were mildly symptomatic with average daytime asthma symptoms 1.1 on a scale from 0 to 3. Patients nevertheless reported nocturnal awakenings and/or nocturnal medication intake in 27% of the nights. Both treatment groups reported fewest nocturnal complaints in the fourth treatment week (in 13% of the nights) with a small deterioration over the ensuing 8 wk (difference between groups not significant). Daytime symptoms were approximately reduced by 50% after 4 wk of treatment, and stayed low throughout the remainder of the study (difference between groups not significant) (Figure 2). In the run-in period, patients were observed to have used 1.5 doses of bronchodilator per day. During treatment with budesonide this was reduced by 38% compared with the run-in period, in patients starting with 400 µg budesonide twice a day and by 48% in those starting with 100 µg budesonide twice a day (difference between groups not significant) (Figure 3).

View larger version (11K): [in this window] [in a new window]   Figure 2.   Changes in daytime symptoms from baseline during run-in period, after 1 wk and 4 wk of treatment with 100 µg budesonide twice daily and 400 µg budesonide, after 8 wk and 12 wk of treatment on 200 µg budesonide once daily.

View larger version (11K): [in this window] [in a new window]   Figure 3.   Changes in bronchodilator use from baseline during run-in period, after 1 wk and 4 wk of treatment with 100 µg budesonide twice daily and 400 µg budesonide twice daily, after 8 wk and 12 wk of treatment on 200 µg budesonide once daily.

The time to reach optimal asthma control could not be calculated in 25 patients, because they either never had a period of 7 consecutive days with completed diary data or never reached this predetermined optimal control (Figure 4). Median time to reach optimal asthma control was 15 d in the 400 µg budesonide twice daily group (n = 26) and 20 d in the 100 µg budesonide twice daily group (n = 33, difference not significant).

View larger version (9K): [in this window] [in a new window]   Figure 4.   Proportion of patients and time of reaching asthma control according to predetermined criteria in two treatment groups of 100 µg budesonide twice daily, 400 µg budesonide twice daily, and maintenance treatment period on 200 µg once daily.

Spirometry

At enrollment, mean FEV₁, measured by the GPs in their offices, was 84% of predicted. One-week treatment induced an increase in FEV₁ predicted of 2.2% with 400 µg budesonide twice a day and 1.2% with 100 µg budesonide twice a day. The maximal effect on FEV₁ was reached after 4 wk, with no changes thereafter. All differences between the two treatments were not statistically significant.

	DISCUSSION

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In the present study, we show no advantage of starting treatment with 400 µg budesonide twice a day above 100 µg budesonide twice a day in steroid-naive asthmatic patients recruited in general practice. This finding is very important for day-to-day asthma management in general practice and contrasts with U.K. guidelines on the treatment of asthma, advocating a step-down treatment in steroid-naive asthma patients (10). The present study shows that 200 µg daily of budesonide as starting and maintenance dose is sufficient to control asthma in the majority of steroid-naive asthma patients. A minority of patients, equally divided (27%) over both treatment groups, did not reach optimal asthma control following the predetermined criteria. The explanation for this phenomenon is that three of the five criteria were related to marked improvements in morning PEF to 120% of baseline, a 50% reduction in daytime asthma symptoms, and a 50% reduction in terbutaline use as compared with the run-in period. These improvements were difficult to meet in patients already experiencing few symptoms and near-normal baseline values during run-in. Other patients failed to complete sufficient diary data to complete a period of 7 consecutive days during the treatment period in which they reached the predetermined criteria. With other criteria, a higher number of sufficient asthma control could be shown, but without changing the main conclusion of the study that both treatment strategies were equally effective in this group of patients.

These findings seem to be in contrast to a number of other studies showing a clear dose-dependent treatment effect on airway hyperresponsiveness, and a smaller dose dependent effect on symptoms and lung function (15). In a study from Kraan and coworkers (6), starting inhaled corticosteroids with a high dose (400 µg budesonide twice daily) induced a more rapid and larger improvement in bronchial hyperresponsiveness than a lower dose (100 µg budesonide twice daily) in a group of patients with mild asthma (mean FEV₁ 84% predicted) who were referred to a hospital outpatient clinic. However, symptom scores did not differ between the groups. In patients with more severe asthma (mean FEV₁ 62% predicted), a dose-related effect on lung function and symptom scores has been observed (18). In a study by Lorentzson (8) in an outpatient setting patients with mild asthma (mean morning PEF around 80% predicted) benefitted from 200 µg budesonide once daily. These studies indicate that the dose-related effect of inhaled corticosteroids on symptoms and lung function depends partly on the severity of asthma and disappears in mild or moderate asthma. However, the effect of inhaled corticosteroids on bronchial hyperresponsiveness seems to be dose-related even in relatively mild asthma (7).

There has been much debate about the potency of different inhaled corticosteroids and the influence of the inhalation device on the effect of inhaled corticosteroids (19). Due to possible differences in potency between beclomethasone diproprionate, budesonide, and fluticasone (20, 21), it is hard to establish a standardized starting dose for all three steroids. However, there is evidence that the inhalation device has an important influence on the lung deposition and the effect of inhaled corticosteroids (19). The lung deposition of the dry powder inhaler Turbuhaler is twice that from pressurized metered dose inhalers (PMDI) (22). The 100 µg budesonide twice daily via turbuhaler used in this study possibly could therefore be as potent as 200 µg twice daily via PMDI, the starting dose advocated by current guidelines (3, 5).

After changing from either dose in the first month, 400 µg budesonide twice daily and 100 µg twice daily, to 200 µg budesonide once daily there was no deterioration detectable in diary parameters or lung function. Our patients, with mild asthma as judged from their FEV₁ being 84% predicted, still benefitted from inhaled corticosteroid treatment because the increase in PEF was 25 to 30 L/min (8 to 9% above baseline values). This improvement was as large as the increase in PEF, seen during the reversibility test at enrollment in the study. Symptom scores and concomitant medication use were greatly diminished within weeks, even though the lung function parameter FEV₁, as measured at the visits to the GP, improved only to a small extent. Thus, low-dose inhaled corticosteroids, 200 µg budesonide once daily, was enough in the treatment of our asthma patients. Further studies are needed to determine whether this is the lowest dosage to establish an effective treatment in patients with mild to moderate asthma.

We conclude that in general practice most newly treated asthma patients react with quick control of asthma symptoms on low-dose inhaled corticosteroids (100 µg budesonide twice a day). Furthermore, the patients in our study did not experience an extra benefit from an initial high dose of inhaled corticosteroids (400 µg budesonide twice daily).