Allergy Asthma Immunol Res.  2015 Sep;7(5):440-448. 10.4168/aair.2015.7.5.440.

Addition of Montelukast to Low-Dose Inhaled Corticosteroid Leads to Fewer Exacerbations in Older Patients Than Medium-Dose Inhaled Corticosteroid Monotherapy

• Ye YM
• Kim SH
• Hur GY
• Kim JH
• Park JW
• Shim JJ
• Jung KS
• Lee HY
• Park HS
• PRANA Group

• KMID: 2147952
• DOI: http://doi.org/10.4168/aair.2015.7.5.440

Abstract

PURPOSE
There have been few reports regarding the efficacy of antiasthmatics in older patients. To compare the efficacy of the addition of montelukast to low-dose inhaled budesonide (MON-400BUD) versus increasing the dose of inhaled steroid (800BUD) on asthma control in older asthmatics.
METHODS
A randomized, open-label, parallel-designed trial was conducted for 12 weeks. The primary endpoint was the rate of patients who reached "well-controlled asthma status" after the 12-week treatment period. Additionally, asthma exacerbations, sputum inflammatory cells, asthma control test (ACT) and physical functioning scale (PFS), and adverse reactions were monitored.
RESULTS
Twenty-four (36.9%) and 22 (34.9%) subjects in the MON-400BUD (n=65) and 800BUD (n=63) groups had well-controlled asthma at the end of the study, respectively. The numbers of asthma exacerbations requiring oral corticosteroid treatment (20 vs 9, respectively, P=0.036) and the development of sore throat (22 vs 11, respectively, P=0.045) were significantly higher in the 800BUD group than in the MON-400BUD group. Body mass index and changes in ACT, FEV1%, 6-min walk distance and PFS from baseline were all significant determinants for distinguishing subjects with well-controlled and partly controlled asthma from those with uncontrolled asthma (P<0.05) at the end of the study.
CONCLUSIONS
The efficacy of 12-week treatment with MON-400BUD in older asthmatics was comparable to that of 800BUD on asthma control but associated with reduced frequency of asthma exacerbations requiring oral steroids and sore throat events. Changes in ACT and PFS can be useful predictors of asthma control status in older patients.

Keyword

Asthma control; older; leukotriene receptor antagonist; inhaled corticosteroid; physical activity; asthma exacerbation

MeSH Terms

Anti-Asthmatic Agents
Asthma
Body Mass Index
Budesonide
Humans
Motor Activity
Pharyngitis
Sputum
Steroids
Anti-Asthmatic Agents
Budesonide
Steroids

Figure

• 

  Fig. 1 CONSORT chart detailing the enrollment of subjects in the present study.

• 

  Fig. 2 The proportion of the patients who achieved well-controlled asthma in week 12. The proportion test (one-sided) for proving non-inferiority of MON-400BUD vs 800BUD in per-protocol population without the last observation carried forward (LOCF) approach and intention-to-treat set with LOCF, with a predetermined non-inferiority margin of -17.2% for the difference in the rates of well-controlled asthma between treatments. MON-400BUD, montelukast added to low-dose inhaled budesonide; 800BUD, medium-dose inhaled budesonide; PP, per-protocol; ITT, intention-to-treat; LOCF, last observation carried forward; CI, confidence interval.

• 

  Fig. 3 The proportions of asthma control status in the MON-400BUD (A) and 800BUD (B) groups during the study period. MON-400BUD, montelukast added to low-dose inhaled budesonide; 800BUD, medium-dose inhaled budesonide.

• 

  Fig. 4 (A) Asthma Control Test (ACT) scores in the 2 groups. The error bars indicate standard deviation of the means. (B) The proportion of patients with ACT <20 at each time point.

Reference

1. Gibson PG, McDonald VM, Marks GB. Asthma in older adults. Lancet. 2010; 376:803–813.

2. Kim YK, Kim SH, Tak YJ, Jee YK, Lee BJ, Kim SH, et al. High prevalence of current asthma and active smoking effect among the elderly. Clin Exp Allergy. 2002; 32:1706–1712.

3. Hwang EK, Jin HJ, Nam YH, Shin YS, Ye YM, Nahm DH, et al. The predictors of poorly controlled asthma in elderly. Allergy Asthma Immunol Res. 2012; 4:270–276.

4. Enright P. The diagnosis of asthma in older patients. Exp Lung Res. 2005; 31:Suppl 1. 15–21.

5. Park J, Kim TB, Joo H, Lee JS, Lee SD, Oh YM. Diseases concomitant with asthma in middle-aged and elderly subjects in Korea: a population-based study. Allergy Asthma Immunol Res. 2013; 5:16–25.

6. Holgate ST. Mechanisms of asthma and implications for its prevention and treatment: a personal journey. Allergy Asthma Immunol Res. 2013; 5:343–347.

7. Global Initiative for Asthma (US). Global strategy for asthma management and prevention [Internet]. Vancouver (WA): Global Initiative for Asthma;2010. updated 2010. cited 2011 Feb. Available from: http://www.ginasthma.com.

8. Ducharme FM, Lasserson TJ, Cates CJ. Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2006; CD003137.

9. O'Byrne PM, Rennard S, Gerstein H, Radner F, Peterson S, Lindberg B, et al. Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids. Respir Med. 2012; 106:1487–1493.

10. Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med. 2001; 345:941–947.

11. Wang JJ, Rochtchina E, Tan AG, Cumming RG, Leeder SR, Mitchell P. Use of inhaled and oral corticosteroids and the long-term risk of cataract. Ophthalmology. 2009; 116:652–657.

12. Reed CE. Asthma in the elderly: diagnosis and management. J Allergy Clin Immunol. 2010; 126:681–687.

13. Lee YH, Lee KJ, Han GS, Yoon SJ, Lee YK, Kim CH, et al. The development of physical functioning scale for community-dwelling older persons. Korean J Prev Med. 2002; 35:359–374.

14. Bae JN, Cho MJ. Development of the Korean version of the Geriatric Depression Scale and its short form among elderly psychiatric patients. J Psychosom Res. 2004; 57:297–305.

15. Enright PL. The six-minute walk test. Respir Care. 2003; 48:783–785.

16. Kwon HS, Lee SH, Yang MS, Lee SM, Kim SH, Kim DI, et al. Correlation between the Korean version of Asthma Control Test and health-related quality of life in adult asthmatics. J Korean Med Sci. 2008; 23:621–627.

17. Kim MA, Ye YM, Park JW, Lee JH, Lee SK, Kim CW, et al. A computerized asthma-specific quality of life: a novel tool for reflecting asthma control and predicting exacerbation. Int Arch Allergy Immunol. 2014; 163:36–42.

18. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004; 170:836–844.

19. Israel E, Chervinsky PS, Friedman B, Van Bavel J, Skalky CS, Ghannam AF, et al. Effects of montelukast and beclomethasone on airway function and asthma control. J Allergy Clin Immunol. 2002; 110:847–854.

20. Virchow JC, Mehta A, Ljungblad L, Mitfessel H. MONICA study group. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: the MONtelukast In Chronic Asthma (MONICA) study. Respir Med. 2010; 104:644–651.

21. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998; 17:873–890.

22. FitzGerald JM, Foucart S, Coyle S, Sampalis J, Haine D, Psaradellis E, et al. Montelukast as add-on therapy to inhaled corticosteroids in the management of asthma (the SAS trial). Can Respir J. 2009; 16:Suppl A. 5A–14A.

23. Joos S, Miksch A, Szecsenyi J, Wieseler B, Grouven U, Kaiser T, et al. Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review. Thorax. 2008; 63:453–462.

24. Song WJ, Kim SH, Lim S, Park YJ, Kim MH, Lee SM, et al. Association between obesity and asthma in the elderly population: potential roles of abdominal subcutaneous adiposity and sarcopenia. Ann Allergy Asthma Immunol. 2012; 109:243–248.

25. Epstein TG, Ryan PH, LeMasters GK, Bernstein CK, Levin LS, Bernstein JA, et al. Poor asthma control and exposure to traffic pollutants and obesity in older adults. Ann Allergy Asthma Immunol. 2012; 108:423–428.e2.

26. Thomas M, Kay S, Pike J, Williams A, Rosenzweig JR, Hillyer EV, et al. The Asthma Control Test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey. Prim Care Respir J. 2009; 18:41–49.

27. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol. 2002; 109:410–418.

28. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. 1999; 159:941–955.

29. Zhao JJ, Rogers JD, Holland SD, Larson P, Amin RD, Haesen R, et al. Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers. Biopharm Drug Dispos. 1997; 18:769–777.

30. Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R, Arnold A, et al. The 6-min walk test: a quick measure of functional status in elderly adults. Chest. 2003; 123:387–398.

31. Weatherall M, James K, Clay J, Perrin K, Masoli M, Wijesinghe M, et al. Dose-response relationship for risk of non-vertebral fracture with inhaled corticosteroids. Clin Exp Allergy. 2008; 38:1451–1458.

32. Ernst P, Baltzan M, Deschênes J, Suissa S. Low-dose inhaled and nasal corticosteroid use and the risk of cataracts. Eur Respir J. 2006; 27:1168–1174.