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| 1. What do we mean by early intervention? |
| In the 1970s and early 1980s the traditional asthma treatment did not include inhaled corticosteroids as a main treatment option. Inhaled corticosteroids were given as a last treatment possibility to patients with severe persistent asthma, often as a replacement for oral corticosteroids. Asthma was looked upon as a disease of the bronchial smooth muscle with airway obstruction as the main clinical sign. When it became obvious that also patients with mild newly detected asthma had inflammatory lesions in their airways (1) clinical studies comparing the efficacy of first-line treatment with bronchodilators or inhaled corticosteroids were initiated (2). It was found that treatment with inhaled steroids was superior to treatment with bronchodilators. The study by Haahtela et al (2) showed that a delay of 2 years in starting treatment with inhaled corticosteroids resulted in less good results in terms of airway function, bronchial responsiveness, asthma symptoms and use of rescue bronchodilators compared with initial treatment with a bronchodilator, terbutaline. Based on this study "Early intervention" has been interpreted as starting treatment when patients have had asthma for less than 2 years. The benefits of early intervention with an inhaled corticosteroid
compared with other anti-asthma treatments are: Delay in anti-inflammatory treatment |
 Fig. 1. PC15 values in patients with early asthma starting treatment with Pulmicort within 12 months from diagnosis or with a 2-year delay. From Ref. 2. |
References: 1. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized double-blind, parallel-group controlled study. J Allergy Clin Immunol 1992; 90: 32-42. 2. Haahtela T, Järvinen M, Kava T, et al. Effect of reducing or
discontinuing inhaled budesonide in patients with mild asthma. N Engl
J Med 1994; 331: 700-705. |
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| 2. Why should treatment with inhaled corticosteroids in asthma be started early? |
Several clinical studies with Pulmicort have shown the importance of early intervention with inhaled corticosteroids. Compared with other types of asthma treatment, early introduction with inhaled steroids results in significantly better airway function and asthma control than treatment with alternative medications, such as beta-agonists, disodium cromoglycate or theophylline. In a study by Selroos et al (1) patients were divided into groups depending on for how long they had had symptoms of asthma when starting treatment with an inhaled corticosteroid for the first time in life: <6 months, 6-12 months, 1-2 years, 2-5 years, 5-10 years and >10 years. The improvements in airway function (morning PEF, FEV1 at clinic visits) showed a statistically significant negative correlation between symptom duration and improvement in airway function. Patients with the shortest duration of symptoms showed the best increases in PEF and FEV1, respectively. The three groups with a duration of symptoms <2 years showed all clinically important improvements. Early intervention with budesonide |
 Fig. 1. Mean improvements in morning PEF in asthma patients with different duration of asthma symptoms. Similar results have been found in studies in children with asthma
(2) (Fig.2.) |
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There is also some evidence that early treatment with inhaled corticosteroids
can prevent airway remodelling. Even if the results of only a few biopsy
studies are available a prevailed post-bronchodilator FEV1
is a good sign of absent airway remodelling. Early use of inhaled steroids
has certainly resulted in the best possible post-bronchodilator airway
function. 1. Selroos O, Pietinalho A, Löfroos A-B, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234. 2. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373-381. |
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| 3. What are the immediate consequences of delayed treatment? |
| If treatment with inhaled corticosteroids is started when patients have
had asthma symptoms for more than 2 years the improvements in airway function
are significantly inferior to those seen with earlier initiated treatment
(1). The possibilities to normalize or significantly improve the non-specific
bronchial hyperresponsiveness are also greater when treatment is started
early.
For a long time it has been stated that treatment with inhaled steroids does not change the thickness of the reticular basement membrane. However, a recent study (2) showed that early treatment with inhaled steroids may even reduce the thickness of the reticular basement membrane and thereby reduce the degree of bronchial hyperresponsiveness. With delayed treatment the bronchial hyperresponsiveness may remain within the abnormal range resulting in asthma symptoms when patients are exposed to environmental irritants. Early intervention with budesonide |
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References: 1. Selroos O, Pietinalho A,Löfroos A-B, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234. 2. Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159(4):1043-1051. |
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| 4. What are the late consequences of delayed treatment? |
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If treatment with inhaled corticosteroids is started when patients have had asthma symptoms for more than 2 years, the response is inferior compared to treatment started earlier (1). In order to be well controlled, patients with delayed treatment also require higher maintenance doses of inhaled corticosteroids, which means a less costly treatment (2). The need for additional medications, e.g. inhaled long-acting beta-agonists, theophylline or leukotriene modifiers, is also higher over the years when treatment with inhaled corticosteroids is delayed. |
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| Fig. 1. Maintenance doses of Pulmicort Turbuhaler to control asthma
and need for additional treatment in patients starting treatment early
(within 2 years after the first symptoms of asthma) or later (median time
of asthma symptoms in the delayed therapy group was 5 years). From Ref
2.
In the study by Haahtela et al (3) patients with early asthma were
treated with Pulmicort pMDI and spacer when they had had asthma for
less than one year, or with a 2-year delay (these patients received
terbutaline regularly for the first 2 years). When the delayed treatment
group started treatment with Pulmicort they improved in terms of airway
function, bronchial reactivity and symptoms, but they did not reach
the same levels of control as those patients treated early. References: 1. Selroos O, Pietinalho A, Löfroos A-B, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234. 2. Selroos OB, Löfroos A-B,. Niemistö M, et al. Early introduction with inhaled steroids in asthma results in achievements of treatment goals. Am J Respir Crit Care Med 1999; 159: A627. 3. Haahtela T, Järvinen M, Kava T, et al. Effect of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994; 331: 700-705. |
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| 5. What dose of Pulmicort should be used when treatment is started early? |
In most cases a daily dose of 200 µg to 400 µg is sufficient to control early asthma, which in the majority of cases is mild or moderately severe. This dose can be given once daily or in two divided doses over the day, i.e. 100 µg or 200 µg twice daily. In patients with mild asthma (FEV1 and/or PEF >80% predicted normal) no difference in efficacy was seen between a low starting dose of Pulmicort (200 µg) or a high dose (800 µg) (1). In a double-blind, placebo-controlled study by Selroos et al (2) two groups of patients were randomised to treatment with Pulmicort: patients who had had asthma symptoms for less than one year, and patients with symptoms for more than 2 years. They received Pulmicort Turbuhaler 100 µg twice daily or 400 µg twice daily. In the group of patients with symptoms for less than one year no difference in response was seen between the two doses of Pulmicort. In the group with a duration of asthma symptoms for more than 2 years the higher dose was significantly more efficacious. Low vs high starting dose |
 Fig.1. No difference in daytime asthma symptom scores in patients treated with 200 mg Pulmicort Turbuhaler once daily as follow-up after low or high dose twice-daily treatment (from Ref. 1.). References: 1. van der Molen T, Meyboom-de Jong B, Mulder HH, Postma DS. Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment. Am J Respir Crit Care Med 1998; 158: 121-125. 2. Selroos O, Löfroos A-B, Niemistö M. A double-blind, randomized, dose-response study with budesonide in asthma patients with short or long duration of symptoms. Am J Respir Crit Care Med 1999; 159: A627. |
| 6. Is there a difference long-term in the amount per year of Pulmicort and other asthma medications depending on when treatment has been started? |
| One would expect that starting early with a medication would result
in a higher total cumulative dose long term. Results of clinical follow-up
studies have, however, given a different picture.
In a Danish study in 268 children with asthma Agertoft and Pedersen found a difference between the group of children who started treatment with Pulmicort early (<2 years after asthma debut) compared to those starting late (>2 years after asthma debut) (1,2). After treatment for 4.5 years the children treated early had a statistically significantly higher mean FEV1 despite the fact that their mean accumulated dose of Pulmicort was lower compared to the group of children starting treatment late (p<0.01). Fig.1. Total (cumulative) dose of Pulmicort received over 4.5 years and mean FEV1 at 4.5 years in the patients subdivided by stage at which they started to receive treatment with inhaled Pulmicort. Cumulative doses |
 Fig.1. Total (cumulative) dose of budesonide received over 4.5 years and mean FEV1 at 4.5 years in the patients subdivided by stage at which they started to receive treatment with inhaled budesonide. From Ref. 2.
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1. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373-381. 2. Jackson W. Act early in asthma. A conference report (edit A Woolcock), Health Science Press, London 1995; 32-35. 3. Selroos OB, Löfroos A-B,. Niemistö M, et al. Early introduction with inhaled steroids in asthma results in achievements of treatment goals. Am J Respir Crit Care Med 1999; 159: A627. |
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| 7. What is the evidence that early treatment is safe long-term? |
| Asthma treatment guidelines state that one of the treatment goals would
be that the medication is free of side effects.
The safety aspects in relation to long-term use of inhaled corticosteroids have been focused on local side effects, growth retardation, suppression of the HPA-axis and effects on bone metabolism (osteoporosis and risk for fractures). Although differences exist between inhaled steroids and individuals may have varying susceptibility to develop side effects it can be stated that in general treatment with inhaled steroids in approved doses has been found safe. Regarding Pulmicort, children with asthma have been treated until they have reached adulthood and final heights (1). It was found that the children achieve their predicted final heights. It should be noticed, however, that treatment over the first 3-6 months may slow down growth, but during continuous treatment catch-up in growth will be seen. Final height |
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| Fig.1. Final height in 142 children treated with Pulmicort for 3-13
years (mean duration 9.2 years), mean daily dose 412 µg (range 110-877
µg).
Regarding local side effects no signs of airway atrophy or malignant transformation have been found. For potential systemic side effects see Safety of Pulmicort Turbuhaler
1. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343: 1064-1069. Read more. |
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| 8. What are the differences in efficacy between Pulmicort and a ß2-agonist when used as first-line treatment of early asthma? |
| In the early 1980s regular or as needed treatment with inhaled ß2-agonists
were first-line treatment of asthma. In the early 1990s it became obvious
that asthma was a chronic inflammatory disease of the airways, and that
inflammatory lesions were present already in early mild disease.
In a 2-year double-blind, randomised, parallel-group study Haahtela et al (1) compared treatment with Pulmicort, 600 µg twice daily delivered via a large volume spacer, with regular twice-daily treatment with inhaled terbutaline, in patients with newly detected asthma. Treatment with Pulmicort was significantly superior to treatment with the ß2-agonist in terms of airway function, bronchial responsiveness, asthma symptoms and need of rescue bronchodilator treatment. In a double-blind, randomised, parallel-group placebo-controlled 20-month study in children, van Essen-Zandvliet et al (2) compared treatment with Pulmicort, 600 µg daily + salbutamol 600 µg daily with salbutamol alone. Treatment with Pulmicort was associated with a progressive improvement in bronchial reactivity whereas no change was seen in the salbutamol group (see Fig. 1). Long-term airway responsiveness |
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| Fig.1. Airway responsiveness (PD20 histamine) over 20 months
in children treated with budesonide and salbutamol, or with salbutamol
alone. (From Ref. 2.)
1. Haahtela T, Järvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide in newly detected asthma. N Engl J Med 1991; 325: 388-392. 2. van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and asthma symptoms in children with asthma. Am Rev Respir Dis 1992; 146: 547-554. Read more: |
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| 9. What are the differences in
efficacy between Pulmicort and disodium cromoglycate
(DSCG) when used as first-line treatment of early asthma? |
| DSCG has been widely used as first-line treatment of especially children
with asthma. However, the long-term efficacy of DSCG has been questioned.
Turpeinen et al performed an 18-month study in children with newly detected asthma (1), the so called HEICA study. The children were randomized to initial treatment with Pulmicort Turbuhaler, 800 µg per day for 1 month, followed by 400 µg per day for 5 months and 200 µg per day for 12 months. Another group of children received Pulmicort as above for 6 months but after that placebo treatment and Pulmicort only during exacerbations. A third group received disodium cromoglycate (DSCG) openly 10 mg three times a day. Severe asthma exacerbations were the primary variable of efficacy. The number of asthma exacerbations per patient was 2.7 in the group of patients receiving DSCG treatment, compared with 1.27 (p<0.001) in the group of children receiving regular treatment with Pulmicort, and 1.92 (p=0.044) in the group receiving placebo treatment following the induction therapy with Pulmicort (see Fig.1.). The time to the first asthma exacerbation was also significantly shorter in the DSCG group compared with the Pulmicort groups (see Fig.2.). First-line therapy with Pulmicort was thus significantly superior to induction treatment with DSCG. Budesonide vs DSCG |
 Fig.1. Exacerbation rates in the three treatment groups in the HEICA study. Budesonide vs DSCG |
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| Fig. 2. Time to first asthma exacerbation in the three study groups
in the HEICA study.
1. Turpeinen M for the Helsinki Early Intervention Childhood Asthma study (HEICA): Inhaled budesonide halved the number of asthma exacerbations compared with inhaled disodium cromoglycate during 18 months of treatment. Eur Respir J 2000; 16, suppl 31: 311s |
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| 10. What is the START study? |
| The START (inhaled Steroid Treatment As Regular Therapy in early asthma)
study was a randomized double-blind, placebo-controlled 3-year study in
7241 patients from 32 countries, aged 5 to 66 years, having mild persistent
asthma for less than 2 years and no previous treatment with glucocorticosteroids
(1). Data on 7165 patients was available for analysis. The 3-year study
was completed by 5155 patients. The drop-out rate and the mean time in
the study were comparable for the budesonide and placebo groups. The age
of the patients (mean ± SD) was 24±15 years. 27% of them
were 6-10 years old, 17% 11-17 years old and the rest 18 years or older. The patients had symptoms, such as wheeze, cough, dyspnoea, and chest tightness at least weekly, but not as often as daily, during 3 months prior to entering the study. In addition to their usual asthma medications the patients in the study received once-daily Pulmicort or placebo. The Pulmicort dose was 200 µg once daily for children under 11 years and 400 µg once daily for others. Treatments other than the study medication could be changed during the study depending on the degree of asthma control. The primary outcome was the time to the first severe asthma-related event, defined as events requiring hospitalization or emergency treatment due to worsening of asthma or death due to asthma. Emergency treatment was defined as treatment of acute airway obstruction with systemic glucocorticosteroids and nebulized or parenteral bronchodilators given at health care institutions. Patients were seen by the investigators after treatment for 3, 12, 24 and 36 months when spirometry and reversibility tests were performed and adverse events recorded. Asthma medications and daily symptoms were recorded during 6-week periods preceding the clinic visits. Patients used a notebook between the visits for notification of asthma-related events and asthma control.
1. Pauwels RA, Busse WW, O´Byrne PM et al. The inhaled steroid treatment as regular therapy in early asthma (START) study: rationale and design. Contr Clin Trials 2001;22:405-19. |
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| 11. What were the main results of the START study? |
| The primary outcome in the START study was the time to the first severe
asthma-related event, defined as events requiring hospitalization or emergency
treatment due to worsening of asthma or death due to asthma. Emergency
treatment was defined as treatment of acute airway obstruction with systemic
glucocorticosteroids and nebulized or parenteral bronchodilators given
at health care institutions. Patients were seen by the investigators at
6 and 12 weeks after randomisation, and then every 3 months for 3 years,
when spirometry and reversibility tests were performed and adverse events
recorded. Asthma medications and daily symptoms were recorded during 6-week
periods preceding the clinic visits. Patients used a notebook between
the visits for notification of asthma-related events and asthma control.
Pulmicort reduced the risk of a first severe asthma exacerbation by 44% (95% CI: 29%-55%, p<0.001) (Fig.1.) (1). There were 271 exacerbations in 198 placebo-treated patients versus 159 in 117 Pulmicort-treated patients (p<0.001). Pulmicort also increased asthma control, the number of symptom-free days and prebronchodilator FEV1 at 12 and 36 months. Pulmicort was comparably effective for the 60% of the patients that had a prebronchodilator FEV1 >80% and were not on any glucocorticosteroid therapy at entry. The study also evaluated cost-effectiveness of the early intervention with Pulmicort. The significant reductions in hospitalisations (69%), emergency room visits (67%) and absence from school or work (36%), coupled with an additional 14 symptom-free days gained per year, showed significant cost-effectiveness (Fig. 2.) (2) The START study thus confirmed previous results that an inhaled corticosteroid should be first-line treatment of patients with newly detected mild asthma. START: Severe asthma events |
 Fig. 1. Risk of severe asthma-related events (SARE) in the START study (from Ref. 1). START: Cost-effectiveness |
 Fig. 2. Gain in symptom-free days and reductions in hospitalisation, emergency room visits etc in the START study. (From Ref. 2.)
1. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071-76 and Eur Respir J 2002; 20, suppl 38: 305s. 2. Sullivan SD, Buxton M, Andersson LF, et al. Cost-effectiveness of early intervention with budesonide once daily: results from the START study. Eur Respir J 2002; 20, suppl 38: 43s. |
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