| 1.The logic step for a combination inhaler |
Based on the favourable results when budesonide and formoterol were administered via separate inhalers to patients with mild-to-moderate persistent asthma (48,50) it was a logic step to develop a combination inhaler (Symbicort®).
One of the first studies in patients with moderate persistent asthma showed that budesonide/formoterol in one inhaler improved airway function numerically slightly more than the same amount of medication delivered via two inhalers, but significanly more than budesonide alone (57).
Inhaled corticosteroids have for a long time been used in an adjustable way in case of deteriorating asthma. An old advice has been to ask patients to double the dose of the inhaled corticosteroid when more asthma symptoms appear, e.g. in association with an acute respiratory infection. However, more recent controlled studies have shown that in order to prevent an asthma exacerbation doubling the dose of the inhaled corticosteroid was not enough. The dose has to be increased four times (48,58,59). In a study by Foresi et al (60) patients were equally well controlled on a low dose budesonide, 100 µg b.i.d., with additional medication (200 µg q.i.d.) when symptoms occurred, compared to a fixed higher dose of budesonide, 400 µg b.i.d.
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| 2. Adjustable maintenance treatment with budesonide/formoterol |
Based on these observations a series of clinical studies in patients with moderate persistent asthma were performed comparing a fixed dose of budesonide/formoterol with an adjustable dosing regimen. During the run-in phase all patients used two doses twice daily. The adjustable regimen allowed stable patients to reduce the dose to one dose of budesonide/formoterol twice daily but to increase the dose to four inhalations twice daily for a week or two if, e.g., more symptoms and an increased need for reliever medication occurred or PEF had decreased in a defined way on two consecutive mornings.
By using this adjustable treatment regimen some 20 studies have been performed including appr 25 000 patients. The studies have shown that compared with a fixed dose of either budesonide/formoterol (61,62) or salmeterol/fluticasone (SeretideTM) (63) adjustable maintenance treatment has reduced the risk of severe asthma exacerbations and improved asthma control, but with a lower total dose of medication and a lower corticosteroid burden. The adjustable maintenance dosing regimen has consequently been found very cost-effective.
The reductions in exacerbations with less use of medication in the three first studies are shown in Figures 42 and 43.
Fig. 42. Daily doses of budesonide/formoterol with fixed or adjustable maintenance dosing and resulting reduction in exacerbations. From Refs Ref. 61.
Fig. 43. Reductions in exacerbations with adjustable maintenance dosing of budesonide/formoterol. From refs 62 and 63.
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| 3. Symbicort Maintenance And Reliever Therapy (SMART) |
Because of the clear dose-response for both components in Symbicort Turbuhaler, budesonide and formoterol, and the rapid onset of action of formoterol (64,65) it was postulated that treatment of patients with moderate persistent asthma possibly could be taken one step further: from adjustable maintenance therapy to treatment with only one inhaler. This single inhaler approach means that patients have the same inhaler (Symbicort) for both maintenance therapy and for as-needed use (SMART).
The principle behind SMART can be illustrated as in Fig. 44.
Fig. 44. Immediate intervention with budesonide/formoterol within the Symbicort SMART concept.
The early intervention for prevention of an asthma exacerbation means that the patient has already developed predefined criteria for deterioration, i.e. a defined change in airway function, symptom scores or need for reliever medication. The immediate intervention, as in the SMART approach, means that the patient takes the combination inhaler as soon as the first need for an additional reliever dose is apparent. There is information available that already at this state, when the patient feels the need for bronchodilation, there is a mini-exacerbation with an increase in exhaled nitric oxide and in eosinophils in induced sputum (66). It therefore seems logical that the patient already at this time point should have not only a bronchodilator but also additional anti-inflammatory medication. A recent clinical study comparing terbutaline, formoterol and budesonide/formoterol as reliever medication in patients on identical maintenance therapy with budesonide/formoterol also clearly showed the advantage of giving an inhaled steroid when the patients needed a reliever (67).
A series of controlled clinical studies have investigated the usefulness of Symbicort SMART. AstraZeneca has also obtained regulatory approval within EU and in some other countries for SMART. For further data related to SMART the reader is advised to check in on the Symbicort Product Information.
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