1. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report. NIH Publication number 02-3659, 2002.

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Pulmicort - place in therapy : 2. Inhaled corticosteroids and mild asthma
Pulmicort and asthma of different degrees of severity
2. What is the difference between mild intermittent and mild persistent asthma?

GINA Guidelines

Patients with mild intermittent asthma have symptoms less frequently; <1 time a week whereas patients with mild persistent asthma have symptoms ≥1 time a week but not every day.

Mild intermittent asthma is characterised by night-time symptoms ≤2 times a month, whereas patients with mild persistent asthma may have night-time symptoms >2 times a month.

All patients with mild asthma have a normal airway function between attacks; i.e. PEF values >80% predicted normal. Patients with mild intermittent asthma have a PEF variability <20% (the difference between evening and morning PEF values), whereas patients with mild persistent asthma may have a PEF variability of 20-30%.

1. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report. NIH Publication number 02-3659, 2002.

GINA Guidelines

O´Byrne et al performed a study in patients whom the treating primary care physicians regarded as having mild intermittent asthma and according to Guidelines not requiring treatment with anti-inflammatory medication (1). Fifty-seven patients were randomized to treatment for 16 weeks with Pulmicort 200 µg b.i.d., 400 µg b.i.d. or placebo. Pulmicort was delivered via a pMDI attached to a large volume spacer (Nebuhaler®).
Patients treated with Pulmicort showed a mean improvement in morning PEF before bronchodilation of approximately 70 L/min (Fig.1). Early morning and night-time symptoms as well as asthma exacerbations decreased significantly.

The study showed improved asthma control. The asthma severity of the patients was obviously misclassified. The reduction in exacerbations and no emergency room visits in the Pulmicort groups resulted in a cost-benefit advantage for Pulmicort.

Fig.1: ´Morning pre-bronchodilator´ shows the effect of Pulmicort before the use of bronchodilator in the morning. ´Morning post-bronchodilator´ shows the additional gain in lung function 10 min after the use of a bronchodilator (from Reference 1).

Reference:

1. O´Byrne PM et al. Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice.
Can Respir J 1996; 3: 169-175.

Patients with mild persistent asthma also exhibit exacerbation, often in association with an upper respiratory tract viral infection or when exposed to high amounts of environmental trigger factors or allergens. This has been seen in children with asthma (1,2,3) as well as in adult patients (2,3). The rate of severe exacerbations has been around one per patient per year and is of the same magnitude as in patients with moderate severe asthma (4). The 3-year START study in 7241 randomized patient with mild persistent asthma showed 159 exacerbations in 117 patients receiving Pulmicort 200-400 µg once daily in addition to their regular treatment compared to 271 exacerbations in 198 patients receiving placebo (2).

START: severe exacerbations in mild asthma

In the 1-year OPTIMA study the rate was 0.77 severe exacerbations per patient per year in the steroid naïve patient group and 0.92-0.96 in patients already treated with a low dose of inhaled steroids but still fulfilling the criteria of having mild persistent asthma (3).

Similarly, in a 16-week study by O´Byrne et al in 57 patients considered by their primary care physicians to have mild asthma seven patients in the placebo group had a severe asthma exacerbation or emergency room visit during this short period of time (Fig. 2) (4).

Exacerbations in "mild" asthmatics

References:

1. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063.

2. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen Y-Z, Ohlsson SV et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trail. Lancet 2003; 361: 1071-76 and Eur Respir J 2002; 20, suppl 38: 305s.

3. O´Byrne PM, Barnes PJ, Rodriques-Roisin R, et al. Low dose inhaled budesonside and formoterol in mild persistent asthma. Am J Respir Crit Care Med 2001, 164: 1392-1397.

4. O´Byrne PM et al. Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice. Can Respir J 1996; 3: 169-175.

A study in patients with newly diagnosed, untreated asthma, investigated the efficacy of Pulmicort Turbuhaler 200 µg and 800 µg daily (1). During the 12-week treatment period there were no differences between the dose groups in PEF, FEV₁, asthma symptoms or use of rescue ß₂-agonists. During the short study period the 800 µg dose showed, however, higher efficacy on bronchial hyper-responsiveness, blood eosinophils and inflammatory markers in sputum (ECP, EPX).

Recently a much larger 1-year study was reported in patients with mild persistent asthma (2). The OPTIMA (Oxis and Pulmicort Turbuhaler in the management of patients with asthma) study was performed in two groups of patients: group A, which had not previously been treated with corticosteroids, and group B, which was on treatment with Pulmicort Turbuhaler ≤400 µg per day or its equivalents. The aim of the study was to investigate whether the addition of Oxis (formoterol) Turbuhaler 4.5 µg b.i.d. to a low dose of budesonide would improve asthma control. The primary variable was the risk of having a severe asthma exacerbation.

The results of the A group are relevant when evaluating the efficacy of a low dose of Pulmicort. These patients not treated earlier with inhaled corticosteroids were randomized into three groups: they received placebo or Pulmicort Turbuhaler 100 µg b.i.d. with or without the addition of Oxis 4.5 µg b.i.d.

Except for airway function, which improved slightly more in the combination treatment group, all other variables showed no differences between Pulmicort alone and Pulmicort plus Oxis. Both treatments were significantly superior to placebo (see: Pulmicort in mild asthma : 8. What did the CAMP study tell us?)

It was obvious that a low dose of Pulmicort alone is an effective and sufficient treatment for patients with mild persistent asthma.

References:

1. Tukiainen H, Taivainen A, Majander R, et al.: Comparison of high and low dose of the inhaled steroid, budesonide, as an initial treatment in newly detected asthma. Respir Med 2000; 94: 678-683.

2. O´Byrne PM, Barnes PJ, Rodriques-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. Am J Respir Crit Care Med 2001; 164: 1392-1397.

Studies in adult patients with mild persistent asthma have investigated the clinical efficacy of once vs twice daily dosing of Pulmicort Turbuhaler. In adults with mild-to-moderate asthma the studied daily dose range has been 100 to 800 µg and in children 100 to 400 µg.

Mintz et al (1) included 288 patients with mild asthma receiving treatment with BDP, 200-250 µg daily by pMDI prior to entry into a 12-week placebo-controlled study comparing 200 µg once daily vs 100 µg b.i.d. of Pulmicort Turbuhaler. No differences were found for any of the clinical variables: airway function, asthma symptoms or use of rescue ß₂-agonists. Both treatments were significantly superior to placebo (Fig.1).

Jónasson et al (2) studied 163 children, aged 7 to 16 years, with mild asthma for 12 weeks and found that Pulmicort Turbuhaler 100 µg and 200 µg once daily were as effective as 100 µg b.i.d. All three dosing regimens were significantly superior to placebo treatment.

Once daily vs twice daily in mild asthma

References:

1. Mintz S, Alexander M, Li JHS, Mayer PV. Once-daily administration of budesonide Turbuhaler was as effective as twice-daily treatment in patients with mild to moderate asthma. J Asthma 2002; 39: 203-210.

2. Jónasson G, Carlsen K-H, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998; 12: 1099-1104.

The placebo-controlled START (inhaled Steroid Treatment As Regular Therapy in early asthma) study investigated the efficacy and safety of once-daily Pulmicort Turbuhaler, 200 µg in children <11 years old and 400 µg in other patients with newly onset asthma; i.e. with mild persistent asthma for less than 2 years and not previously treated with glucocorticosteroids (3). The investigational drug (Pulmicort or placebo) was given in addition to the patients´ regular treatment. During the study whatever type of additional asthma medication could be added depending on the clinical situation. 7241 patients from 32 countries were randomized to treatment and 7165 patients completed the 3 year study.

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 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). 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.

Patients treated with Pulmicort used significantly less additional inhaled, oral, or systemic corticosteroids (31% vs 45%). At the same time airway function improved, asthma symptoms decreased as well as the need for additional non-steroid rescue or maintenance anti-asthma therpy. No safety concerns were raised.

The START study verified previous studies in smaller number of patients showing that a low dose of budesonide should represent first-line treatment of patients with mild persistent asthma.

References

1. 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.

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.

3. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen Y-Z, Ohlsson SV et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trail. Lancet 2003; 361:1071-76 and Eur Respir J 2002; 20, suppl 38: 305s.

Read more:
Early intervention with Pulmicort
Safety of Pulmicort Turbuhaler
START study

For the primary variable there was no difference between the treatments with all three groups showing mean values between 100 and 105 percent predicted normal after bronchodilation (indicating normal lung growth). For all other variables - FEV₁ before bronchodilation, PC₂₀ methacholine, asthma symptoms, use of rapid-acting bronchodilators as needed, symptom-free days, health outcome, rates of hospitalisation and emergency visits budesonide treatment showed superiority.

An analysis of the relationship between duration of asthma and asthma severity before treatment (2) showed that asthma duration was associated with lower lung function, greater methacholine responsiveness, more asthma symptoms, and greater use of as-needed salbutamol.

The data support the early use of an inhaled steroid (budesonide) in early childhood asthma.

CAMP: lung function and asthma severity

References:

1. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063.

2. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999; 103: 376-387.

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Early Intervention with Pulmicort
Paediatric asthma

Group A.
Patients were randomized into three groups: they received placebo or Pulmicort Turbuhaler 100 µg b.i.d. with or without the addition of Oxis 4.5 µg b.i.d. The addition of Oxis to Pulmicort significantly improved airway function, but not other variables in the study. Pulmicort alone was as good as the Pulmicort-Oxis combination to reduce the risk of exacerbations. Both were significantly superior to placebo (Fig.1).

Group B.
The patients were randomized into four treatment groups: Pulmicort Turbuhaler 100 µg or 200 µg b.i.d. with or without Oxis 4.5 µg b.i.d.
The addition of Oxis to both doses of Pulmicort significantly reduced the risk of a severe asthma exacerbation, which were approximately halved (Fig.2). Airway function and use of ß₂-agonists also decreased significantly with the addition of Oxis.

OPTIMA A: Rate of severe exacerbations

Reference:

1. O´Byrne PM, Barnes PJ, Rodriques-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. Am J Respir Crit Care Med 2001, 164: 1392-1397.

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OPTIMA
Oxis

Haahtela et al (2) included 103 patients with newly detected asthma into a double-blind 2-year study treating the patients with Pulmicort or Bricanyl (terbutaline) delivered via pMDIs attached to large volume spacers (Nebuhaler®). The Pulmicort group improved significantly more in terms of airway function, bronchial hyperresponsiveness, asthma symptoms and need of rescue ß₂-agonists. Thereafter the terbutaline-treated patients received for a third treatment year an identical therapy with Pulmicort as the other group had had from the beginning (3). The difference between the groups was only that treatment with Pulmicort was started with a delay of two years in the latter group.

The initially terbutaline-treated patients improved when receiving Pulmicort for the third year but they never reached the same level of asthma control as those treated early with Pulmicort (3).

Delay in starting treatment with an inhaled corticosteroid may result in less good asthma control and a sub maximal airway function.

Early intervention with budesonide

Early intervention and bronchial hyperresponsiveness

References:

1. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339: 1194-1200.

2. 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.

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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Early intervention with Pulmicort

Airway function improved significantly more with the inhaled corticosteroid than with the bronchodilator treatment (Fig. 1). Similarly the improvements in bronchial hyper-responsiveness measured as PC ₁₅ histamine improved significantly more with Pulmicort compared with terbutaline.

Budesonide vs regular terbutaline

Reference:

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.

In a 6-week study Molema et al (1) treated patients with a low dose of Pulmicort, 100 µg q.i.d. or DSCG 2 mg q.i.d. Treatment with Pulmicort significantly improved FEV₁ as shown in Fig. 1.

Patients also had exercise tests. The last doses of medications were given in the evening the day before the exercise tests. As shown in Fig. 2. there was no remaining effect after treatment with DSCG, which have to be given immediately before a provocation in order to show a preventive effect.

Budesonide vs DSCG

The risk of having an acute asthma exacerbation when treated initially with Pulmicort or with DSCG was investigated in the Helsinki Early Intervention Childhood Asthma study (HEICA) (2).

The children were randomized to initial treatment with Pulmicort, 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. The time to the first asthma exacerbation was also significantly shorter in the DSCG group compared with the Pulmicort groups.

First-line therapy with Pulmicort was thus significantly superior to induction treatment with DSCG.

References:

1. Molema J, van Herwaarden CL, Folgering HT. Effects of long-term treatment with inhaled cromoglycate and budesonide on bronchial hyper-responsiveness in patients with allergic asthma. Eur Respir J 1989; 2: 308-316.

2. 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.

Read more:
Pulmicort in mild asthma : 10. What are the consequences if patients with mild asthma don't get treatment with inhaled corticosteroids?

As compared with placebo-treated children, those assigned to receive Pulmicort had a significantly smaller decline in the FEV₁/FVC ratio before bronchodilation, lower responsiveness to methacholine, fewer hospitalizations, fewer visits to a caregiver, greater reductions in the use of rescue medication, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medication was needed. Nedocromil only reduced urgent care visits and the number of courses of prednisone compared with placebo. No formal statistical tests compared the Pulmicort and nedocromil groups.

CAMP: Budesonide vs nedocromil

1. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063.