Do inhaled corticosteroid/long-acting beta 2 -agonist fixed combinations provide superior clinical benefits compared with separate inhalers? A literature reappraisal Peter J. Barnes, M.D., 1 Gabriele Nicolini, Ph.D., 2 Andrea Bizzi, Pharm.D., 2 Monica Spinola, Ph.D., 2 and Dave Singh, M.D. 3 ABSTRACT Current asthma management guidelines emphasize the importance of disease control. Although effective drug therapies are available, real-life data indicate that the general level of asthma control is still low. Fixed-dose combinations of inhaled corticosteroids/long-acting beta 2 -agonists (ICS/LABAs) are now increasingly used in the management of asthma. A number of studies have compared the clinical benefits of ICS/LABA fixed combinations with the monocomponents administered using two separate inhalers. We conducted a database search to identify all published studies that have assessed whether fixed-dose combinations achieve greater asthma control compared with administration by separate inhalers. Among fixed combinations, only extrafine beclomethasone/formoterol provided significantly greater asthma control compared with separate inhalers administered as larger aerosol particles. This greater effect may be explained by increased delivery to the small airways by the extrafine formulation. (Allergy Asthma Proc 33:140 144, 2012; doi: 10.2500/aap.2012.33.3512) Asthma is characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Asthma affects both the large and the small airways and there is growing evidence showing correlation between small airways impairment and poor asthma control. 1 Several randomized controlled trials have indicated that the addition of a long-acting 2 -agonist (LABA) is more beneficial in terms of improving asthma control and pulmonary function and reducing exacerbation rates compared with increasing the dose of inhaled corticosteroids (ICSs) in patients on low-to-medium doses of ICS. 2 6 ICS/LABA fixed-dose combinations are now increasingly used in asthma because they are more convenient for patients and the co-deposition of the two drugs can increase synergy at the molecular level. 7 A number of studies have compared the clinical benefits of ICS/LABA fixed combinations with From the 1 National Heart and Lung Institute, Imperial College, London, United Kingdom, 2 Chiesi Farmaceutici S.p.A., Parma, Italy, and 3 Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, University of Manchester, Manchester, United Kingdom PJ Barnes has served on Scientific Advisory Boards of AstraZeneca, Boehringer- Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, Teva and UCB and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Daiichi-Sankyo, GlaxoSmithKline, Mistubishi-Tanabe, Novartis, and Pfizer. D Singh has received lectures fees, support for conference attendance, advisory board fees, and research grants from a range of pharmaceutical companies including GSK, Chiesi Pharmaceuticals, AstraZeneca, CIPLA, Novartis, Forest, MSD, Boehringer, and Allmiral. G Nicolini, A Bizzi, and M Spinola are full time employees of Chiesi Farmaceutici S.p.A. Address correspondence and reprint requests to Monica Spinola, Ph.D., Chiesi Farmaceutici S.p.A., via Palermo 26/A, 43122, Parma, Italy E-mail address: m.spinola@chiesigroup.com Copyright 2012, OceanSide Publications, Inc., U.S.A. the administration of the monocomponents using two separate inhalers. We performed a literature review of all published studies that have assessed whether fixed-dose combinations achieve greater asthma control compared with the monocomponents administered as separate inhalers. METHODS The Medline database was searched using the following terms: asthma control, fixed combination, separate inhalers, fluticasone salmeterol, budesonide formoterol, beclomethasone formoterol, and fluticasone formoterol. Searches were last updated on February 2011. Randomized controlled trials in asthma patients evaluating the effects of an ICS/LABA combination administered via a single inhaler compared with two separate inhalers were identified. The level of asthma control was assessed using different parameters in these studies. The most frequently used parameter was the percentage of asthma control days (defined as days without asthma symptoms, nocturnal awakenings, or rescue medication use). Other parameters included the proportion of days without asthma symptoms, the proportion of patients with 75% of days without asthma symptoms, and the Asthma Control Questionnaire (ACQ) score. 8 Data reported in the selected articles were extracted and used to calculate the increase in asthma control in fixed combinations when compared with separate inhalers. Percentage increase in asthma control (AC) was calculated as follows: 140 March April 2012, Vol. 33, No. 2
Table 1 Summary of randomized controlled trials comparing patients treated with ICS/LABA fixed combination or two separate inhalers Study AC increase (%) Patients No.; Age Baseline Mean FEV 1 (% predicted normal) (AC fixed combination AC separate components) AC separate components Duration (mo) Daily Dosage ( g) Fixed vs Separate Beclomethasone/formoterol Huchon et al. 9 645; 18 yr 65 6 extrafine 400/ 24 vs larger particles 1000/24 Fluticasone/salmeterol Bateman et al. 10 244; 12 yr 76 3 200/100 vs 200/100 Chapman et al. 11 371; 12 yr 76 3 500/100 vs 500/100 Aubier et al. 12 503; 12 yr 73 3 1000/100 vs 1000/100 Budesonide/formoterol Zetterstrom et al. 13 362; 18 yr 74 3 vs Rosenhall et al. 14 586; 18 yr 95 6 vs Rosenhall et al. 15 # 321; 18 yr 95 12 vs Jenkins et al. 16 456; 12 yr 66 3 1600/48 vs 1600/48 Chervinsky et al. 17 553; 18 yr 68 3 vs Fluticasone/formoterol Bodzenta-Lukaszyk 620; 18 yr 58 2 1000/40 vs et al. 18 1000/48 Measured Outcome Difference (fixed separate) AC days (%) 7.7* Patients with 75% symptom-free days (%) Patients with 75% symptom-free days (%) Symptom-free days (%) RESULTS Articles were available for all ICS/LABA fixed combinations used as key terms for a database search. The list of randomized controlled trials in patients with asthma comparing the effects of different ICS/LABA combinations administered via a single inhaler or two separate inhalers is presented in Table 1. 9 18 The studies using fluticasone/salmeterol used symptom-free days to assess AC. Studies of other fixed combination inhalers used either AC days or the ACQ score as an index of AC. The three studies of fluticasone/salmeterol showed that both the fixed combination inhaler and the separate inhalers increased the number of patients with 75% symptom-free days 10,11 and the percentage of symptom-free days versus baseline. 12 There was no significant difference between the treatment groups. 3 0 0 AC days (%) 1.6 ACQ score ACQ score 0 0 AC days (%) 0.2 AC days (%) 0.1 AC days (%) 0.6 *p 0.005. #This study reports follow-up data of the study by Rosenhall et al. 14 Estimated from graph. AC asthma control; ACQ asthma control questionnaire; FEV 1 forced expiratory volume in 1 s; ICS/LABA inhaled corticosteroid/long-acting 2 -agonist. Allergy and Asthma Proceedings 141
Studies using budesonide/formoterol (F) showed similar improvements in the percentage of AC days observed in the fixed combination and separate inhaler groups. 13,16,17 Similarly, both the fixed combination and the separate inhalers provided a comparable decrease in the ACQ score at 6 and 12 months. 14,15 Jenkins et al. showed a trend toward a lower risk of mild exacerbations in the fixed combination inhaler versus the separate inhaler group (p 0.13). 16 Bodzenta-Lukaszyk et al. studied fluticasone/f and found that both the fixed combination and the separate inhalers provided a similar increase in AC days versus baseline, with no significant difference between treatments. 18 Huchon et al. studied extrafine beclomethasone/f and found that the fixed combination provided significantly greater AC compared with separate inhalers. 9 It should be noted that the beclomethasone and F separate inhalers delivered larger particle sizes, and that the ICS dose was greater in the separate treatment compared with the fixed treatment (1000 g versus 400 g, respectively). A post hoc analysis showed that combination therapy results in a 50.0% increase in the percentage of days with AC, which increased from 15.4% with separate inhalers to 23.0% with combination therapy (p 0.005; Fig. 1). 9 DISCUSSION AND CONCLUSIONS ICSs are the mainstay for anti-inflammatory therapy for patients with persistent asthma. Several randomized controlled trials have shown that addition of a LABA is more beneficial in terms of AC and pulmonary function than increasing the dose of corticosteroids in patients not fully controlled on lowto-medium doses of ICS. 2 6 Although the clinical benefits of combined ICS plus LABA therapy can be achieved with separate inhalers, fixed combination Figure 1. Asthma control changes in fixed combinations versus separate components. Percentage increase was calculated as described in the Materials and Methods section. Asthma control was defined in each study as detailed in Table 1. inhalers are more convenient for patients and they are likely to increase adherence to therapy by reducing the number of inhalers that patients need to take. Additionally, given the potential risks associated with the use of LABAs without an inhaled steroid, 19 fixed inhalers would reduce the concern about patients using LABAs only and ensure continuation of ICS therapy. A meta-analysis showed that the fluticasone/salmeterol fixed combination had a greater effect on morning peak expiratory flow compared with separate component inhalers (difference 5.4 l/min; p 0.006). 20 However, this small difference in lung function did not translate into symptomatic benefits in terms of the number of symptom-free and relieverfree days and nights. Such data question whether fixed combinations have clinically important benefits in terms of symptom control compared with separates. We therefore performed a systematic literature review to assess whether fixed-dose combinations achieve greater AC than separate inhalers. Studies were found for the ICS/LABA fixed combinations fluticasone/salmeterol, budesonide/f, beclomethasone/f, and fluticasone/f. There was a statistically significant improvement in AC only for the fixed combination of extrafine beclomethasone/f compared with its separate components. For the other fixed combinations, there were no differences compared with separates. Extrafine beclomethasone/f was administered using less than one-half the steroid dose of the separate ICS inhaler (400 g versus 1000 g, respectively). The key difference was the small particle size of the beclomethasone/f combination, allowing increased drug delivery to the distal airways compared with the larger particle size of the ICS separate inhaler. The extrafine formula- 142 March April 2012, Vol. 33, No. 2
tion of the fixed combination allows more particles to reach and treat the small airways, 21 23 and this may result in greater clinical benefit when compared with larger particles. Another fixed combination is currently being developed that contains mometasone furoate (MF) and F. Recent studies have shown that MF/F is superior to mometasone alone or F alone in improving AC and reducing nocturnal symptoms. 24 26 However, no data are available comparing MF/F versus its two monocomponents administered concurrently via two separate inhalers. Additional studies are warranted to understand whether AC is different when administering MF and F with a single inhaler or two separates. It has been reported that AC correlates better with measurements of small airway function than with conventional spirometric indices. 1 The role of small airways in asthma pathogenesis is recognized and there is growing evidence that airway obstruction and inflammatory processes affect both large and small airways. 27,28 The data from Huchon et al. indicate that a significant clinical benefit can be gained by the use of extrafine formulations that target the small airways. 9 Jenkins et al. found no difference in the number of AC days when budesonide/f was administered as a fixed combination compared with separate inhalers, but there was a trend toward reduction in exacerbations using the combination inhaler. 16 This highlights that results may vary between asthma end points, as was the case for the meta-analysis of the fluticasone/salmeterol fixed combination, which had a greater effect on morning peak expiratory flow compared with separate inhalers but no benefit in terms of symptoms. 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