| 1. Patients with moderate persistent asthma benefit from combination therapy |
Formoterol is a ß2-agonist originally developed by Yamanouchi as an oral bronchodilator. Given orally formoterol has a duration of action similar to that of oral salbutamol and terbutaline; it is short-acting. Löfdahl and Svedmyr in Sweden discovered that formoteral after inhalation had a prolonged duration of bronchodilation (44). Two years later the same group published the first results with salmeterol, another long-acting inhaled ß2-agonist (45). Astra Pharmaceuticals decided to develop formoterol in Turbuhaler.
At this time it was known that regular maintenance treatment with a short-acting ß2-agonist administered four times daily could result in tolerance development for the bronchoprotective effects, increase in bronchial responsiveness and less good asthma control (14-16). Also tachyphylaxis to the bronchodilating effects was discussed. It was therefore postulated that introduction of long-acting inhaled ß2-agonists might make the situation even worse.
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| 2. The FACET study |
When planning the FACET study two trials comparing BDP plus salmeterol with a higher dose of BDP had been published (46,47). These studies showed that a lower dose of BDP plus salmeterol reduced asthma symptoms and need of reliever medication, and improved airway function, more than doubling the dose (47) or giving a 2½ times higher dose of BDP (46). The studies were also of only 6 months´ duration and could therefore not conclusively evaluate the effect of the combination therapy on asthma control and exacerbations. The FACET study was therefore designed as a 12-month study. It was a double-blind trial evaluating the effects of adding twice daily formoterol (9 µg twice daily) to a low dose budesonide, 100 µg twice daily, or a four times higher dose of budesonide, 400 µg twice daily (48). The hypothesis was that adding formoterol to budesonide would improve airway function and reduce asthma symptoms but also not to cause a decrease in overall asthma control over the time priod of one year.
A total of 1114 patients with moderate severe asthma entered a 4-week run-in phase during which they received high-dose therapy in order to optimize their asthma condition. This treatment consisted of budesonide Turbuhaler 800 µg b.i.d. plus formoterol Turbuhaler 9 µg b.i.d. The aim was thereafter to evaluate to what degree the patients remained well controlled on the four different treatments. The primary variable was the risk of having a severe asthma exacerbation defined as an investigator-defined need for a course with oral corticosteroids or a drop during two consecutive days in morning PEF of more than 30% from baseline. Those 852 patients who were stable in their asthma during the last 10 days of the run-in period could be randomized (Fig. 24).
Fig. 24. Study design for the FACET study
As expected, the patients treated with the combination, improved significantly in their airway function compared with patients treated with budesonide alone (Fig. 25). Similarly, asthma symptoms decreased as did the need for short-acting reliever medication. Adding formoterol, both to the low dose and to four times higher dose of budesonide significantly reduced the risk of having a severe asthma exacerbation (Fig. 26). It should be noted, however, that increasing the dose of budesonide from 200 µg per day to 800 µg per day reduced the risk of having a severe asthma exacerbation more than adding formoterol to 200 µg budesonide (Fig. 26). Increasing the dose of budesonide reduced the exacerbation risk by 49%, adding formoterol by 26%.
The FACET study thus showed that adding regular treatment with a long-acting ß2-agonist twice daily to regular maintenance treatment with an inhaled corticosteroid did not result in a decrease in asthma control or increase in severe asthma exacerbations.
Fig. 25. Increase in FEV1 as percent predicted In the FACET study. From Ref. 48.
Fig. 26. Number of severe asthma exacerbations per patient per year in the FACET study. From Ref. 48.
However, one important question remained to be answered. Could it be so that treatment with formoterol masked the underlying airway inflammation?
To answer that question the "Little FACET study" was performed (49). The study had the same design as the FACET study but included only two treatment arms: 100 µg budesonide b.i.d. plus formoterol and 400 µg budesonide b.i.d. A number of inflammatory markers were studied and it was found that addition of formoterol did not mask the underlying airway inflammation. Fig. 27 shows the number of eosinophils in sputum in the two treatment groups.
Fig. 27. Sputum eosinophils in patients treated with low dose budesonide plus formoterol or four times higher dose of budesonide. From Ref 49.
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| 3. The OPTIMA study |
The FACET study had included patients with moderate persistent asthma and the obvious question with the FACET study results available was whether the results were applicable also on patients with mild persistent asthma. To answer that question the 12-month OPTIMA study was performed (50). The study had two patient populations: group A consisting of patients with mild persistent asthma not previously treated with inhaled corticosteroids, and group B, patients already using a low dose of inhaled corticosteroids but not being well controlled on that treatment. Group A patients (698 randomized patients) were treated with budesonide Turbuhaler 100 µg b.i.d. with or without formoterol 4.5 µg b.i.d., or placebo (Fig. 28), group B patients (1272 randomized patients) with budesonide Turbuhaler 100 µg or 200 µg b.i.d. with or without formoterol 4.5 µg b.i.d. (Fig. 29). The primary outcome was again the risk of having a severe asthma exacerbation.
Fig. 28. Study design in OPTIMA group A. From Ref. 50.
Fig. 29. Study design in OPTIMA group B From Ref. 50.
The study showed that in both groups the addition of formoterol improved airway function. However, in group A the addition of formoterol did not reduce the proportion of patients having a severe asthma exacerbation (Fig. 30). In group B, the results were of the same type as in the FACET study: adding formoterol to both 200 µg and 400 µg daily of budesonide Turbuhaler significantly reduced the proportion of patients having severe asthma exacerbations (Fig. 31).
Fig. 30. Proportion of patients in group A the OPTIMA study having severe asthma exacerbations. From Ref. 50.
Fig. 31. Proportion of patients in group B in the OPTIMA study having severe asthma exacerbations. From Ref. 50.
Based on the results of the OPTIMA study it was concluded that patients with mild persistent asthma, i.e. patients with persistent asthma symptoms but normal airway function (FEV1 or PEF 80% predicted normal) and not treated with an inhaled corticosteroid, should be first treated with an inhaled corticosteroid alone (and a rapid-acting bronchodilator as reliever medication to be used as needed), whereas patients with mild persistent asthma using an inhaled corticosteroid but still being symptomatic, could benefit from the combination therapy with a long-acting inhaled ß2-agonist.
It was also obvious that the development of a combination inhaler with both budesonide and formoterol could be of benefit and improve patients´ compliance with treatment.
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4. Formoterol can also be used as needed
The RELIEF study |
Inhaled formoterol is a unique ß2-agonist bronchodilator as it combines the rapid onset of action with the long duration. In the global asthma guidelines (GINA) it therefore has its own place among the ß2-adrenoceptor agonists (Fig. 32).
Fig. 32. Classes of ß2-agonist bronchodilators.
The rapid onset of action of inhaled formoterol indicated that it could also be used "as needed", especially as a comparative cross-over study in asthma patients with two doses of salbutamol and three doses of formoterol and investigating both bronchodilation (FEV1) and systemic activity (serum potassium) in the same patients, indicated that formoterol had a 2.5 times more favourable ratio between wanted and unwanted activities than the standard inhaled rapid-acting bronchodilator, salbutamol (51). High-dose studies in patients with stable (52) as well as in acute unstable condition (53,54) showed that doses up to 90 µg of formoterol Turbuhaler were well tolerated.
As an example, the use of formoterol as as-needed medication was investigated in a series of clinical studies. Tattersfield et al (55) included 362 randomized patients for 6 months into a double-blind trial with patients using an inhaled corticosteroid. As reliever medication the patients could use either formoterol 4.5 µg as needed or terbutaline 0.5 mg as needed, both administered by Turbuhaler. The primary variable was the risk of having a severe asthma related event. The study showed that patients treated with formoterol as needed had a significantly lower risk of getting a severe asthma exacerbation than patients using terbutaline (Fig. 33).
Fig. 33. Risk of having a severe asthma exacerbation when using formoterol or terbutaline as reliever medication in patients using inhaled corticosteroids From Ref. 55 .
These results of this study, as well as results of other studies, led to the largest asthma study performed so far, the RELIEF study (56). This was an open 6-month study in more than
18 000 randomized patients and it was conducted at 1139 centres in 24 countries. Patients from the age of four years and patients representing all severities of asthma could be included. The only inclusion criterion was that the patient required a rapid-acting bronchodilator to be used as needed in addition to whatever other asthma medication. The distribution of patients according to ashma severity is shown in Fig. 34. The study design is shown in Fig. 35. Patients were randomized to as-needed treatment with formoterol by Turbuhaler or salbutamol by pMDI or a powder inhaler. The primary variable of efficacy was the risk of having a severe asthma related event.
Fig. 34. Proportion of asthma patients in the RELIEF study according to disease severity. From Ref. 56.
Fig. 35. Study design of the RELIEF study. From Ref. 56.
The time to the first exacerbation was significantly longer in patients using formoterol as needed compared to those using salbutamol as needed (Fig. 36). The total number of exacerbations is shown in Fig. 37.
Fig. 36. Time to first exacerbation in patients treated with formoterol or salbutamol as needed. From Ref. 56.
Fig. 37. Proportion of patients with exacerbation in the RELIEF study. From Ref. 56.
During the study patients could change their asthma medication. In patients treated with formoterol 6.8% of the patients increased their medication during the study whereas 14.4% decreased their medication (Fig. 38). In the salbutamol as-needed group a higher proportion of patients increased their medication and less patients could decrease it. The difference in shifts between the groups was statistically significant (Fig.39).
Fig. 38. Changes in the level of asthma medications in patients treated with formoterol as needed. From Ref. 56.
Fig. 39. Difference in change of asthma medication in the formoterol as needed and salbutamol as needed groups. From Ref. 56.
Both as-needed treatments were well tolerated without statistically significant differences in adverse events between the treatments (Fig. 40). Treatment with formoterol as needed resulted in a number of benefits and advantages with no or minimal cost increase (depending on price levels in different countries (Fig. 41).
Fig. 40. Adverse events in patients treated with formoterol or salbutamol as needed. From Ref. 56.
Fig. 41. Costs and benefits in patients treated with formoterol as needed compared with salbutamol as needed. From Ref. 56.
Based on these study results formoterol by Turbuhaler has become widely used not only as a long-acting bronchodilator in combination with inhaled corticosteroids, but also as reliever medication in the treatment of patients with asthma of all degrees of severity.
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