Comparative Evaluation of Fixed Dose Combinations of Fluticasone/ Formoterol and Budesonide/ Formoterol in Patients of Mild- Moderate Bronchial Asthma

Introduction

Asthma is a chronic disease with recurrent episodes of breathlessness, wheeze, cough and expectoration and is defined as “chronic inflammatory disorder of airways” characterized b [1] airway obstruction that is reversible either spontaneously or with treatment; [2] airway inflammation an [3] airway hyper-responsiveness to a variety of stimuli [1]. Its prevalence is rising worldwide with 10–12% of adults and 15% of children affected presently (more than 300 million people) and it is estimated that 100 million more people may be affected by 2025 [2]. The overall prevalence in India is 2.38%. Female sex, advancing age, urban residence, lower socio- economic status, history of atopy, asthma in a first degree relative and all forms of tobacco smoking are associated with significantly higher odds of having asthma [3]. Asthma can have a considerable impact on the quality of life of patients and their caregivers. The vast economic burden comprises both direct costs, such as emergency care, hospitalizations and medications, and indirect costs, largely driven by absenteeism and reduced productivity [4, 5]. It is diagnosed as reversibility of airflow obstruction in response to inhaled bronchodilator, with spirometer demonstrating a 12% improvement and 200 ml increase in forced expiratory volume in 1 second (FEV1) [6]. The efficacy of inhaled corticosteroids (ICS) in reducing airway inflammation and hyper-responsiveness has led to their widespread use as initial therapy in the treatment of patients with moderate-to-severe asthma, especially those requiring daily beta-2 adrenoceptor agonists [7]. These drugs are highly efficacious in reducing symptoms, frequency and severity of exacerbations and risk of a life- threatening attack. ICSs drastically improve lung function and asthma quality of life (AQLQ) of asthmatic patients [8, 9, 10]. An aerosolized short acting β 2-agonist (SABA) is the bronchodilator of choice as a symptom-reliever in acute, severe asthma and a long acting β 2-agonist (LABA) in combination with inhaled corticosteroid (ICS) is used as disease-controller in chronic asthma [11]. ICS and LABA in conjunction effectively achieve a higher level of asthma control and reduce exacerbations and asthma-related hospitalizations [12, 13] .There is a strong rationale of combining ICS and LABA as they optimize each others’ beneficial actions in the airways. Corticosteroids increase the transcription of beta- 2 receptors which protects against the down-regulation of beta-2 receptors in response to long-term exposure to LABAs. LABAs potentiate the molecular mechanism of corticosteroid actions, with increased nuclear localization of glucocorticoid receptors and a synergistic suppression of inflammatory mediator release [14]. Currently accepted goal of asthma care [15] is to achieve and maintain control of the clinical manifestations for prolonged periods so that patients can prevent most attacks, avoid troublesome symptoms day and night and keep physically active. In the present study, two ICS & LABA combinations i.e. fluticasone/ formoterol and budesonide/ formoterol were compared, both administered through a metered dose inhaler (MDI) with a spacer, for achieving and maintaining asthma control, improving symptoms, quality of life and pulmonary function tests, over 12 weeks in patients of mild to moderate bronchial asthma. The main parameters used to compare the said combination inhalers were: a. Asthma control scoring (according to the GINA definition of "control" b. Pulmonary function tests – FEV1, Peak expiratory flow rate (PEFR) c. Standardized Asthma Quality of Life Questionnaire [AQLQ(S)] d. Adverse effect profile

Results

The two treatment groups were well-matched with respect to all key demographic characteristics and other variables at baseline as shown in Table 1.

History revealed that an acute exacerbation of asthma was triggered by multiple factors and most patients had exacerbations due to more than one trigger. The common factors were as shown in Figure 1.

Fluticasone/ Formoterol (n=40)

Budesonide/ Formoterol (n=40)

0 10 20 30 40 34 38

27 23 33 37

Click to enlarge

Pulmonary function tests improved over baseline values and percent predicted values in both treatment groups during the course of the study and this change was highly significant (p= 0.000). The inter-group differences in FEV1 and PEFR change from baseline was not statistically significant as depicted in table 2.

Over the 12 weeks duration, groups a (fluticasone/ formoterol) and group B (budesonide/ formoterol) were compared with respect to 5 domains of asthma control scoring (Table 3).

During the treatment period, the number of additional salbutamol puffs (rescue bronchodilator) taken by the patient were noted as given in Table 4.

No. of patients in

No. of

Fluticasone/

Salbutamol

Formoterol group

puffs used (n=40) 4 5 0 5 (6.3%)

6 23 0 23 (28.7%) 7 1 0 1 (1.3%)

8 8 4 12 (15%) 10 2 6 8 (10%)

12 1 16 17 (21.3%) No. of patients in Budesonide/

Total

Formoterol group

(n=40)

Table 4: Patients using rescue bronchodilator during treatment Mean number of salbutamol puffs used by group A (fluticasone/ formoterol) and group B (budesonide/ formoterol) was 6.53 ± 1.68 and 12.35 ± 2.43 respectively and this difference was highly significant (p= 0.000). Mean AQLQ(S) scores divided into four domains (symptoms, activity limitation, emotional function and environmental stimuli) were compared between the two groups. Both combinations i.e. fluticasone/ formoterol and budesonide/ formoterol significantly improved (p= 0.000) all the domain scores throughout the study period. There was no significant difference in score improvement between the two groups except for emotional function, which improved significantly in fluticasone/ formoterol group (p=0.029) at 6 weeks (Table 5).

Mean total AQLQ(S) score for group a (fluticasone/ formoterol) was 118 ± 12.1 at baseline that improved to 191 ± 12.29 at the end of the study. For group B (budesonide/ formoterol) this value increased from 121 ± 10.58 at baseline to 190 ± 13.15 at 12 weeks. There was no significant difference in total scores of groups A and B at any time of the study [p= 0.08 (6 weeks); p= 0.73 (12 weeks)].

Percent improvement in quality of life at 6 weeks and 12 weeks was also compared between the two groups. For group A (fluticasone/ formoterol), AQLQ(S) score increased by 45.38 ± 14.97 percent and for group B (budesonide/ formoterol), it increased by 37.16 ± 10.56 percent at 6 weeks. This difference among the two groups was statistically significant (p value < 0.05). At the end of 12 weeks quality of life increased by 62.95 ± 20.11

percent for group A and 57.02 ± 12.06 percent for group B. But this difference was not significant statistically. There was no significant difference in adverse effect profile between the two groups. In fluticasone/ formoterol group, 2 patients suffered from sore throat, 3 from hoarseness of voice, 1 had or pharyngeal candidacies and 2 had upper respiratory tract infection. In budesonide/ formoterol group, 2, 1, 1 and 3 patients suffered these adverse effects respectively.

Discussion

Comparison between the two groups on the basis of improvement in pulmonary function tests (FEV1 and PEFR) demonstrated no significant change at the end of the study period as depicted in previous studies. [22, 23] In concordance with past studies, fluticasone/ formoterol provided a more rapid and greater improvement in percent predicted PEFR [24, 25]. Symptom control was achieved by most patients at the end of the study. Significant differences were seen at 6 weeks, when nocturnal symptoms were better controlled in budesonide/ formoterol and a higher control was seen in fluticasone/ formoterol in terms of daytime symptoms and need for rescue therapy analogous to the results of another study [26]. During the course of therapy, the average number of rescue bronchodilator puffs (salbutamol 200 mcg per puff) required by patients in fluticasone/ formoterol group was significantly lower than that for budesonide/ formoterol group. Therefore fluticasone/ formoterol was better in controlling asthma symptoms for a longer time as recorded by a double – blind, randomized, parallel study where percent days without the use of additional bronchodilator was significantly more in fluticasone/ formoterol group as compared to budesonide/ formoterol group [27]. AQLQ(S) scoring did not differ significantly between the two groups, except for the emotional function at 6 weeks, which improved more in fluticasone/ formoterol group. Also the overall percent improvement at 6 weeks was higher with fluticasone than with budesonide. In a similar study done previously, there were significant treatment differences in favor of fluticasone in three of the four domains - activity limitations, symptoms, and emotional function [28]. Both the treatments were well tolerated and there was no significant difference in incidence of side effects between them.

Conclusion

This study concludes that fixed dose combinations MDIs containing fluticasone/ formoterol and budesonide/ formoterol are very effective in elevating pulmonary functions, controlling & relieving symptoms and revamping the quality of life in patients of bronchial asthma. Fluticasone/ formoterol were better in providing a more rapid and greater improvement in percent predicted PEFR, in controlling daytime symptoms for a longer time and reducing the need for rescue therapy.