Despite the availability of effective anti-asthma drugs, many patients with bronchial asthma (BA) of disease control remains sub-optimal. Often, patients relying on short-acting bronchodilators, anti-inflammatory therapy is neglected, thus increasing the risk of asthma exacerbation.
In the February issue of the journal Chest published results of the first of its kind randomized, double-blind study of new therapeutic strategies based on the use of glucocorticoid (GC), budesonide (B) and β2-agonist formoterol (F) contained in a single inhaler (B + F). Since F begins to act as quickly as salbutamol, a new approach is consistent with the current guidelines, according to which persistent asthma patients should receive daily anti-inflammatory treatment with a rapid increase in the dose of drugs at the time of symptoms and enhance contrast, reduce the dose when restoring a good control of the disease.
Methods and progress of studies
The study was conducted in 77 centers in 9 countries (Argentina, Brazil, Denmark, Indonesia, Spain, China, Norway, Philippines, Sweden). Included patients aged 12 to 80 years with a diagnosis of persistent asthma mild to moderate set of at least 6 months. Forced expiratory volume in 1 second (FEV1) of patients had to be 60 to 100% of the normal value in 15 minutes after the inhalation of 1 mg terbutaline (T) increase in FEV1 ≥ 12%, and for adults, in addition, an increase in FEV1 ≥ after inhalation of 200 ml of β-agonist. In the absence of these criteria, the reversibility of airflow obstruction in the study participants could be included with the variability of peak expiratory flow (PEF) ≥ 12% for at least 3 days in the last 10 days. All patients received a dose of inhaled GC 200-500 mg / day for at least 3 months during the last month.
Exclusion criteria were: use of systemic GC or Cromones during the previous month; respiratory infections, control violating the disease during the month; severe comorbidities; smoking (with a history of> 10 years-Packaging). The use of anticholinergics and xanthine are not allowed, except for the period of hospitalization.
During open introductory study period (14-18 days), all subjects received inhaled B at 100 mg twice a day, if necessary, at 0.5 T g. The number of inhalations β-agonist had to be not less than 7 during the last 10 days, but less than 10 per day for every day of the run-in period. Thus, participants with severe asthma exacerbations were excluded from the study.
Patients were randomized into groups: the use of B + P (constant intake of 80 mg / 4.5 mg to 2 inhalations in the evening (inhaler number 1) + inhalation “on demand” (inhaler number 2)) for 6 months – treatment group; the use of double doses of B (160 mcg 2 inhalations for the evening (inhaler number 1)) + T inhalation (0.4 mcg (inhaler number 2)) “on demand” – a comparison group. It is allowed to receive a maximum of 10 inhalations “on demand” in the day, otherwise it was a question of the extension study. Thus, in group B + F participants can receive the maximum daily dose of B / F 960/54 ug.
To monitor the effectiveness of interventions to patients daily inhalation in the morning and evening peak flow meter was measured using PSV. Control Spirometry was performed at 1, 3 and 6 months of the study. The severity of daytime and nighttime asthma symptoms assessed separately on a 4-point scale (where 0 points – the absence of symptoms, 3 points – severe symptoms) and then summed.
Calculating the percentage of days without asthma symptoms, the percentage of days without inhalation “on demand”, for a total of the number of days of asthma control. Exacerbations of the disease were considered as severe in the case of hospitalization, the need to assign system HA reduction ≥ 30% of PSV for 2 consecutive days. Patients with severe exacerbations of prednisone orally received 30 mg / day for 10 days. The need to further prednisone was seen as a re-aggravation. Patients who needed 3 or more courses of systemic GC, were excluded from the study.
Total randomized 697 patients (mean age 38 years; 270 men). The group P + P included 355 people, a group of a double dose of B – 342 participants. Before randomization, 95% of participants had symptoms of asthma, including 43% – nocturnal symptoms. Initially groups were comparable for clinical and demographic characteristics and the number of used “on demand” dose: an average of 1.6 vs. 1.8 inhalations per day. Adherence to treatment was high in both groups (> 97% of participants). Eliminated from the study of 27 patients in the treatment group and 31 patients in the comparison group.
Patients from group B + P compared with group B noted a significant improvement in morning PEF (34.5 l / min versus 9.5 l / min; p <0.001) and evening PEF (25 l / min to 7 l / min ; p <0, 001), which appeared at the beginning of the study and remained to the end. The same trend is observed and dynamic assessment of FEV1: 0.210 l vs. 0.062 L, respectively (p <0.001).
Patients from group B + F reported better control of the disease: the scale of asthma severity (score 0.73 versus 0.94; p <0.001) in the number of asymptomatic days (55.1 vs. 46.4%; p = 0.004) , the number of days without inhalation “on demand” (55.3 vs. 45.4%; p <0.001) and in the percentage of asthma control days (47.4 vs. 38.8%, respectively; p = 0.0012).
The risk of severe asthma exacerbations was 54% lower in the intervention group (43 vs. 94, respectively aggravation; p = 0.0011). Also, there was a decrease by 76% the frequency of exacerbations that required hospitalization or application of the system of the Civil Code (14 cases vs. 57; p <0.001), and 90% – the risk of emergency hospital admissions (1 case vs. 10, respectively; p = 0.026). In general, the risk of developing at least one severe exacerbation was lower in group B + F by 70% (p <0.001), which when extrapolated to 1 year of therapy was 27 fewer exacerbations per 100 patients treated.
Greater efficiency in the intervention group B + F was achieved using a lower dose of inhaled GC (240 mg / day to 320 mg / day in group B). In addition, patients in the intervention group 77% less likely to have received oral HA (114 days versus 498 days in the control group), and also less likely to use inhaled “on demand” (1.04 / day compared to 1.48 / day; p <0.001 ).
Both modes of therapy were well tolerated. Adverse reactions were mostly mild or moderate in intensity, with the same frequency in groups. Clinically significant between-group differences in ECG, haematological and biochemical parameters were observed.
The new approach of management of patients with asthma, which consists in the use of low maintenance dose of P + F in a single inhaler, with additional doses of B + F “on demand”, improves and simplifies the control of the disease compared with conventional therapy.
Application B + F reduces hospitalization and use of the system frequency at a lower dose of HA HA inhalation, thereby improving the ratio of the risk / benefit compared to a fixed dose B.
The authors suggest that these results call into question the need for the traditional use of short-β-agonists for relief of symptoms of the disease and may contribute to the revision of the existing recommendations on the management of patients with asthma.