ORIGINAL ARTICLE Indian J Allergy Asthma Immunol 2009; 23(2) : 79-82

Comparative study of long acting -2 agonist and low dose inhaled corticosteroid combination versus medium dose inhaled corticosteroid in therapy of moderate persistent asthma
R.K.Gupta1, S. Kumar1, A. Shukla1, A.K.Nigam2, R. Singh1
1Department

of Tuberculosis and Respiratory Diseases, 2Department of Postgraduate Medicine, S.N. Medical College, Agra, India
Abstract Asthma is a immune inflammatory disorder in which airway hyper-responsiveness leads to recurrent wheezing, breathlessness, and coughing. Treatment with an inhaled corticosteroid (ICS) is the first line of therapy. In patients receiving ICS whose asthma is not fully controlled, guidelines recommend increasing the dose of ICS or using the combination of LABA and ICS. The present study was aimed to compare the effects of the combination of low dose of ICS+LABA and the medium dose of ICS in moderate persistent asthma. Here 59 cases were studied for 12 weeks and all the patients were prescribed one of the treatment twice daily- salmeterol 25g+fluticasone propionate 125 g, formoterol 6 g + budesonide 200 g, fluticasone propionate 250 g and or budesonide 400 g. Analysis of the results was performed in 12, 14, 16 and 17 patients in treatment groups namely salmeterol+fluticasone, formoterol+budesonide, fluticasone propionate, and budesonide. At the end of 12 weeks, the mean values of FEV1 increased to 3.32+/-0.52, 3.41+/-0.48, 2.97+/-0.68, 3.26+/-0.63(L/sec) from baseline FEV1 2.25+/-0.72, 2.28+/-0.62, 2.14+/-0.52 and 2.38+/-0.49, respectively in different groups. No significant difference was found in end mean values among them. In total 12 weeks, the mean number of exacerbations were 0.87 +/- 2.37, 0.96 +/- 2.57, 1.21+/- 2-83 and 1.18 +/- 3-02 and there was no significant difference in any of the two groups in number of exacerbations. But number of exacerbations were less in combination therapy. Also the patient receiving combination therapy (LABA+ICS) responded sooner than ICS alone. In conclusion, the combination therapy is slightly more efficacious than higher dose ICS in treatment of asthma.

Key Words: LABA, Inhaled corticosteroid, Asthma

INTRODUCTION Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated
Address for correspondence: Dr. R.K.Gupta. Professor, Department of Tuberculosis and Respiratory Diseases. S.N.Medical College, Agra, Uttar Pradesh, India IJAAI, 2009, XXIII (2) p 79-82. 79

with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning1. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment. Effective control of asthma symptoms and maintenance of optimal lung function are critical for the long-term management of

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INDIAN J ALLERGY ASTHMA IMMUNOL 2009; 23(2)

patients with persistent asthma. Treatment with an inhaled corticosteroid (ICS) is usually the first line of therapy 2 . For patients whose asthma is poorly controlled on ICS therapy alone, current management guidelines recommend add-on therapy with a long acting 2-agonist(LABA), or alternatively a leukotriene receptor antagonist. However, the long term increase in dose of ICS increases the risk of local side effects3 due to oropharyngeal deposition like hoarseness of voice, dysphonia, sore throat, oropharyngeal candidiasis etc3 as well as systemic side effects4 like adrenal suppression, decreased bone density growth retardation4. Whereas the regular use of LABA has been challenged due to their potential to mask the progression of airway inflammation and thereby worsen asthma 5 . Studies suggest that combination therapy of LABA and ICS is significantly more effective than similar dose of ICS alone, in controlling asthma symptoms and exacerbations6-10. But few studies are there to compare the efficacy of low dose of ICS with LABA against medium dose of ICS. The study was undertaken to compare the effects of the combination of low dose of ICS+LABA and the medium dose of ICS to relate these effects to changes in lung function, and the need of rescue medication. MATERIAL AND METHODS Selection of Patients: Diagnosed cases of moderate persistent asthma, aged over 14 years, visiting out patient Department of Tuberculosis and Respiratory Diseases and Department of Postgraduate Medicine, S.N.Medical College, Agra, were included in the study. Smokers either active or passive, history of lower respiratory tract infection within one month,

history of exposure to occupational sensitizer, pregnancy, patients with known case of chronic obstructive pulmonary disease, cardiac illness and hypertension were not included in the study. Methodology to diagnose moderate persistent asthma: included- daily symptoms, exacerbation that may affect activity and sleep, nocturnal symptoms more than once a week, FEV1 or PEF 60-80% predicted and FEV1 or PEF variability >30%. Study Design: Study was started from 05-01-2007 and the data collected till 31-12-2007. The present study was randomized control trial. At the end of study, the data was assembled and results were analyzed using students t test. Baseline values were recorded about symptoms, FEV1, PEF through spirometry. Sixty nine cases were prescribed one of the treatment twice daily salmeterol 25g + fluticasone propionate 125 g, formoterol 6 g + budesonide 200 g, fluticasone propionate 250 g and budesonide 400 g. The drugs were administered through metered dose inhaler with spacer. All rescue medications were replaced by inhaled levosalbutamol during exacerbations. The patients were followed up weekly for 12 weeks. At the end of 12 weeks, spirometry was performed again on each patient and results were compared with base line values. RESULTS Out of total 69 cases59 patients followed the strict protocol. So only the results of 59 cases were analyzed. Statistically significant (p value < 0.01) increase in FEV1 was recorded at the end of 12weeks in each group compared to baseline values (Table 1).

Table 1: Mean of FEV1(L/sec) at baseline and at 12th week Treatment Group Salmeterol+Fluticasone Formoterol+Budesonide Fluticasone propionate Budesonide No. of Cases 12 14 16 17 FEV1 at Baseline 2.25+/-0.72 2.28+/-0.62 2.14+/-0.52 2.38+/-0.49 FEV1 at 12th week 3.32+/-0.52 3.41+/-0.48 2.97+/-0.68 3.26+/-0.63 P Value 0.0004 0.0001 0.0004 0.0001

FEV1: forced expiratory volume in one second

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But no significant difference was found in FEV1 values at 12th week (p value>0.05) among these four treatment groups (Table 2). Whereas no significant difference (p value > 0.05) was found in the number of exacerbations in any of two treatment groups, in 12 week study period (Tables 3&4). DISCUSSION The present study compared the effects of treatment with a combination of low dose ICS with LABA against medium dose ICS in asthma. The results are based on a small exploratory study and should be considered as hypothesis generating rather than definitive. Statistically significantly increases in FEV 1 at the end of 12 weeks in each treatment group was recorded compared to baseline values but no significant

difference was found in FEV1 values at 12th week among these four groups. There was no significant difference in any of the two treatment groups in number of exacerbations. However, number of exacerbations were less in combination therapy. Apart from this, patients receiving combination therapy respond sooner than ICS alone. Our findings are similar to VanNoord et al,11 who used salmeterol 50mcg and fluticasone propionate 250mcg against 500mcg fluticasone propionate twice daily. They found that increase in FEV1 was higher in combination group than fluticasone alone group at the end of 4 weeks but not after 12 weeks. The salmeterol group also showed lesser the need for rescue medication. Similar findings were also observed by Matz et al12. Kips and Pauwels13 got similar results in budesonide and formoterol combination Vs increased dose of budesonide alone.

Table 2: Significance of difference in FEV1%among treatment groups at 12th week. Treatment Group Salmeterol+Fluticasone Formoterol+Budesonide Fluticasone Formoterol+Budesonide P value = 0.65 P value = 0.54 Fluticasone P value = 0.145 Budesonide P value = 0.78 P value = 0.47 P value = 0.21

Table 3: Mean number of exacerbations in 12 weeks Treatment Group Salmeterol+Fluticasone Formoterol+Budesonide Fluticasone propionate Budesonide Mean number of exacerbations in 12 weeks 0.87 +/- 2.37 0.96 +/- 2.57 1.21+/- 2-83 1.18 +/- 3-02

Table 4: Significance of difference in mean number of exacerbations in 12 weeks. Treatment Group Salmeterol+Fluticasone Formoterol+Budesonide Fluticasone Formoterol+Budesonide P value = 0.93 P value = 0.80 Fluticasone P value = 0.74 Budesonide P value = 0.77 P value = 0.83 P value = 0.98

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INDIAN J ALLERGY ASTHMA IMMUNOL 2009; 23(2) in a new powder inhalation device for the treatment of asthma: a randomized, double blind, placebo controlled trial. Am J Respir Crit Care Med 2000; 161: 527-34 7. Aubier M, Pieters WR, Schlsser NJ, Steinmetz KO. Salmeterol/fluticasone propionate (50/500 g) in combination in a. Diskus inhaler (Seretide) is effective and safe in treatment of steroid dependent asthma. Can Respir J 1999; 6: 45-51. Shapiro G, Lumry W, Wolfe J, Given J, White MV, Woodring A, et al. Combined salmeterol 50 g and fluticasone propionate 250 g in the Diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000; 161: 527-534. Weersink EJ, Douma RR, Postma DS and Koeter GH. Fluticasone propionate, salmeterol xinafoate, and their combination in the treatment of nocturnal asthma. Am J Respir Crit Care Med. 1997; 155(4): 12411246.

Condemi et al 14 and Pearlman. 15 found the combination therapy of fluticasone 88mcg and salmeterol 42 mcg significantly better than fluticasone 220mcg alone in terms of FEV1%, PEFR and use of rescue medicine. Kelsen et al16 observed similar finding with salmeterol 42mcg+ beclomethasone 168 mcg versus beclomethasone 336mcg. The difference observed in various studies may be due to difference in patient selection criteria like -level of asthma (mild persistent /moderate persistent/ severe) and difference in drugs doses and mode of drug delivery. In conclusion, the results of present study suggest that combination therapy (salmeterol+ fluticasone, formoterol+ budesonide) is slightly more efficacious and the control is rapid than medium dose ICS (fluticasone, budesonide) in treatment of moderate persistent asthma (though statistically not proved). So it is advisable that patients of moderate persistent asthma should be treated by combination of ICS+LABA initially and maintenance therapy may be higher dose of ICS to avoid worsening of asthma associated with long term use of LABA. Whereas patients on high risk of developing ICS induced side effects (old age, immunocompromised state, AIDS etc.) should be treated with combination therapy of LABA and ICS. REFERENCES
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