Comparison of the efficacy and safety of mometasone furoate to other inhaled steroids for asthma: a metaanalysis

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1 Original article Comparison of the efficacy and safety of mometasone furoate to other inhaled steroids for asthma: a metaanalysis Danlei Yang, Jianmiao Wang, Hansvin Bunjhoo, Weining Xiong, Yongjian Xu and Jianping Zhao Summary Background: It has been of great interest whether mometasone furoate (MF) is better than other inhaled corticosteroids (ICSs) as the controller therapy in patients with moderate or severe asthma who had previously been taking ICSs. Objective: The aim of this meta-analysis is to thoroughly compare the efficacy and safety of MF versus other ICSs with equipotent daily doses in those patients. Methods: Relative databases were searched. Randomised controlled trials of more than or equal to weeks treatment duration comparing MF with other ICSs were reviewed. Results: Six trials with 5 randomised patients met the inclusion criteria. Significant differences favouring MF were found in all indices of pulmonary function. MF was superior compared to other ICSs in decreasing the frequency of rescue medication use and morning difficulty breathing score. There was no significant difference between MF and other ICSs therapy in morning wheezing score, cough score and percentage of patients with no nocturnal awakenings due to asthma. For the treatmentrelated adverse effects (AEs), treatment-related severe AEs, discontinuations due to AEs and some common symptom of AEs, MF was all similar to other ICSs in their incidence. From Department of Respiratory and Critical Care Medicine, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Tongji Medical College, Huazhong University of Science and Technology, 95 Jiefang Avenue, Wuhan, China Corresponding author: Jianping Zhao jpzhaotj@yahoo.com.cn Submitted date: 2/5/22 Accepted date: 7/8/22 Conclusions: In adult patients with moderate or severe asthma who had previously been taking ICSs, MF was superior to other ICSs with equipotent daily doses as controller monotherapy in improving pulmonary function and decreasing the frequency of rescue medication use, and was similar to other ICSs in the incidence of AEs. These results demonstrated the priority of MF in asthma therapy. (Asian Pac J Allergy Immunol 22;:26-5) Key words: bronchial asthma, therapy, mometasone furoate, inhaled corticosteroids, meta-analysis Introduction Current asthma treatment guidelines recommend inhaled corticosteroids (ICSs) as a first-line controller therapy for patients with persistent asthma. Mometasone furoate (MF) is a potent ICS available in clinical practice to treat asthma and is formulated for delivery by dry powder inhaler (DPI). Previous randomised controlled trials (RCTs) have shown that MF is effective for treating subjects with persistent asthma. 2-7 More importantly, it is well tolerated and effective in improving pulmonary function in subjects with moderate or severe asthma who had previously been taking ICSs. 2,,6 There were some comparative studies of MF versus other ICSs available in those patients, but the results were not very consistent. A meta-analysis of available RCTs was thus performed to assess the efficacy and safety of MF versus other ICSs with equipotent daily doses in patients with moderate or severe asthma who had previously been taking ICSs. Methods Identification and eligibility of relevant studies We searched MEDLINE, EMBASE and CINAHL databases for papers published until April 22 using the following medical subject headings, full text and key word terms: mometasone AND asthma*. In addition, a search of the Cochrane Central Register of Controlled Trials (CENTRAL) 26

2 Mometasone versus other inhaled steroids was performed using the above search strategy to identify any additional trials. There were no language restrictions. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Inclusion and exclusion criteria Included studies met the following criteria: (I) Target population: moderate or severe asthma consistent with American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria who had previously been taking ICSs as daily maintenance therapy for > days. (II) Intervention: studies comparing MF with other ICSs in approximately equipotent daily doses based on guideline GINA. (III) Length of treatment: studies of at least weeks in duration. (IV) Design: randomised (parallel group or cross-over) controlled trials. Major reasons for exclusion of studies were (I) Treatment duration less than days. (II) No relative results. Data extraction and quality assessment Two reviewers independently identified trials and reviewed the titles, abstracts and citations (Danlei Yang and Jianmiao Wang). Two reviewers independently assessed studies for inclusion based on the criteria for population, intervention, study design and treatment duration (Hansvin Bunjhoo and Weining Xiong). Data were also independently extracted by two reviewers (Yongjian Xu and Jianping Zhao). Primary outcomes were measures of pulmonary function, including mean change from baseline in forced expiratory volume in the first second (FEV ), forced vital capacity (FVC), forced mid-expiratory flow (FEF 25%-75% ), and morning peak expiratory flow (PEF). Secondary outcome measures were symptom indices, such as symptom scores, rescue-medication use, no nocturnal awakening and response to therapy; and adverse effects (AEs), such as serious AE, withdrawals due to AEs, and so on. The methodological quality of each trial was evaluated using the Cochrane approach and Jadad scale criteria. 8 Statistical analysis Fixed effect odds ratios (OR) for binary outcomes and weighted mean differences (WMD) for continuous outcomes with 95% confidence intervals (CI) were calculated for each trial. Trials were pooled using fixed effect OR or WMD as appropriate. Heterogeneity was tested using the Breslow-Day test with a P value <. considered statistically significant. A random effects model was used if heterogeneity was found. I 2 statistic was also calculated to efficiently test for the heterogeneity, with I 2 <25%, 25-75%, and >75% to represent low, moderate, and high degree of inconsistency, respectively. 9 Publication bias was examined in funnel plots and tested with Egger s weighted regression method. The meta-analysis was performed using Review Manager 5..2 (Cochrane Library Software, Oxford, UK) and STATA. (STATA Corporation, College Station, Texas, USA). Results 8 articles were identified. The detailed steps of our literature search are shown in Figure. Twelve trials were potentially appropriate, of which one trial was excluded due to treatment duration that lasted less than weeks, three trials were excluded because of patients with mild asthma and previously not using ICSs, 2- and two trials were excluded because the daily doses of MF and other ICSs were not equipotent. 5,6 Thus, a total of six randomised controlled trials met the inclusion criteria and were selected for analysis (5 randomised patients).,6, 7-2 Table shows the characteristics of the six included trials. Articles indentified using search terms (n = 8) Articles excluded based on title and abstract (n = 26) Articles identified for full-text review (n = 2) Articles excluded (n = 6) Not using corticosteroids previously (n = ) Dosed of corticosteroids were not equipotent (n = 2) treatment less than weeks (n = ) Articles included in meta-analysis (n = 6) Figure. Flow diagram of the literature search and trial selection process. 27

3 Asian Pac J Allergy Immunol 22;:26-5 Table. Characteristics of the included studies Study No. of Subjects Bernstein 5 Multicentre, doubleblind, randomised, double-dummy doseranging study Bousquet 69 Multicentre, 2 7 randomised, evaluatorblind, active-controlled study Chervinsky Multicentre, randomised, doubleblind, double-dummy, dose-ranging study Connor 68 Multicentre, 2 2 randomised, parallel group, double-blind evaluator-blind study Corren Multicentre, randomised, doubleblind, double-dummy, placebo, activecontrolled, parallel group, clinical study Nathan Multicentre, doubleblind, 2 double-dummy, placebo- controlled, randomised study Study Design Patients Interventions Duration, weeks Asthma for at least 6 months and Mometasone furoate 2µg 2 had been using an inhaled b.i.d. versus Beclomethasone glucocorticoid daily for at least dipropionate 68µg b.i.d. days Patients 2 years, with a history of asthma for at least 6 months and had been using an inhaled glucocorticoid daily for at least days 8 and 65 years, with a history of asthma for at least 6 months Patients 2 years, had a history of asthma for at least 6 months and who had been using an inhaled corticosteroid daily for at least days Patients 2 years, with a history of asthma for at least 6 months Patients 2 yeas, had a history of asthma for at least 6 months and who were maintained on prescribed inhaled glucocorticoids at least days. Mometasone furoate µg b.i.d. versus Budesonide µg b.i.d. Mometasone furoate 2µg b.i.d. versus Beclomethasone dipropionate 68µg b.i.d. Mometasone furoate µg b.i.d. versus Fluticasone propionate 25µg b.i.d. Mometasone furoate µg q.d. versus Budesonide µg q.d. Mometasone furoate 2µg b.i.d. versus Beclomethasone dipropionate 68µg b.i.d Two of the included trials compared MF with budesonide (BUD), 7,8 three compared MF with beclomethasone (BDP),,6,9 and the last one compared MF with fluticasone propionate (FP). 2 These trials scored five out of five for methodological quality, were of good quality, and most items had a high percentage across all studies. Pulmonary function as the outcome Changes from baseline in FEV (L) 25 patients from five studies were considered for this analysis (6 treated with MF, 65 treated with another ICS).,7-2 MF was superior to other ICS therapy in improving FEV in absolute value (Figure 2) (mean difference.2 [95% CI.7.7] L, p <.). No significant inter-study heterogeneity was found (I 2 = 26%). Changes from baseline in FVC (L) 25 patients from five studies were considered for this analysis (6 treated with MF, 65 treated with other ICS).,7-2 MF was superior to other ICS therapy in improving FVC (Figure 2) (mean difference. [95% CI..7] L, p =.9). No significant inter-study heterogeneity was found (I 2 =). Change from baseline in FEF 25%-75% (L/sec) 86 patients from four studies were considered for this analysis (22 treated with MF, 2 treated with other ICS).,8-2 MF was superior to other ICS therapy in improving FEF 25%-75% (Figure 2) (mean difference.9 [95% CI.9.28] L/sec, p =.). No significant inter-study heterogeneity was found (I 2 =7%). Changes from baseline in morning PEF (L/min) 25 patients from five studies were considered for this analysis (77 treated with MF, treated with other ICS).,7-2 MF was superior to other ICS therapy in improving morning PEF (Figure 2) (mean difference.96 [95% CI ] L/min, p <.). No significant inter-study heterogeneity was found (I 2 = 5%). Symptom index as the outcome Changes from baseline in morning wheezing scores 22 patients from two studies were considered for this analysis (59 treated with MF, 6 treated with other ICS).,8 MF was similar to other ICS therapy in improving morning wheezing scores (Figure ) (mean difference. [95% CI..28], (p =.5). No significant inter-study heterogeneity was found (I 2 = ). 28

4 (a) Changes from baseline in FEV (L) %.2% 2.2% 2.%.6%. [.2,.8].22 [.8,.6]. [-.8,.].6 [.5,.27]. [-.,.29] (95% CI) 6 Heterogeneity: Chi² = 5., df = (P =.25); I² = 26% Test for overall effect: Z =.66 (P <.) (b) Changes from baseline in FVC (L) (95% CI) 6 Heterogeneity: Chi² =.59, df = (P =.); I² = % Test for overall effect: Z =. (P =.9) (c) Change from baseline in FEF 25%-75% (L/sec) 65.2 [.7,.7] Mometasone versus other inhaled steroids %.2% 2.% 2.%.2%.9 [-.2,.2].26 [.,.2]. [-.,.7]. [-.,.2]. [-.6,.26] (95% CI) 22 Heterogeneity: Chi² =.6, df = (P =.); I² = 7% Test for overall effect: Z =.8 (P =.) 65. [.,.7] % 2.5%.% 6.6%.22 [.,.]. [-.6,.22].27 [.,.].2 [-.,.] (d) Changes from baseline in morning PEF (L/min) (95% CI) 6 Heterogeneity: Chi² = 7.25, df = (P =.2); I² = 5% Test for overall effect: Z =. (P <.) 2.9 [.9,.28] % 2.% 2.9%.% 9.% 2.56 [-.99, 27.] 2.6 [7.2, 5.] -2. [-5.9,.9] 9.2 [8.,.8] 8. [-2.96, 9.6] [7.6, 2.] Figure 2. Summary effects on changes in (a) FEV, (b) FVC, (c) FEF 25%-75% and (d) morning PEF of eligible studies comparing mometasone with other ICS. Changes from baseline in morning difficulty breathing scores 22 patients from two studies were considered for this analysis (59 treated with MF, 6 treated with other ICS)., 8 MF was superior to other ICS therapy in improving morning difficulty breathing scores (Figure ) (mean difference. [95% CI..26], p =.). No significant inter-study heterogeneity was found (I 2 = ). Changes from baseline in morning cough scores 22 patients from two studies were considered for this analysis (59 treated with MF, 6 treated with other ICS).,8 MF was similar to other ICS therapy in improving morning cough scores (Figure ) (mean difference. [95% CI -.7.], p =.). No significant inter-study heterogeneity was found (I 2 = ). 29

5 Asian Pac J Allergy Immunol 22;:26-5 (a) Changes from baseline in morning wheezing scores %.%. [.,.28].8 [-.9, 2.26] (95% CI) 59 Heterogeneity: Chi² =., df = (P =.97); I² = % Test for overall effect: Z = 2. (P =.5) 6. [.,.28] (b) Changes from baseline in morning difficulty breathing scores % 2.%. [-.,.27].5 [-.,.] (95% CI) 59 Heterogeneity: Chi² =.2, df = (P =.89); I² = % Test for overall effect: Z = 2.9 (P =.) 6. [.,.26] (c) Changes from baseline in morning cough scores % 22.%. [-.8,.]. [-.8,.2] (95% CI) 59 Heterogeneity: Chi² =., df = (P =.); I² = % Test for overall effect: Z =.6 (P =.) 6. [-.7,.] Favours experimental Favours control Figure. Summary effects on changes in (a) morning wheezing scores, (b) morning difficulty breathing scores and (c) morning cough scores of eligible studies comparing mometasone with other ICS. Patients with no nocturnal awakenings due to asthma (%) 6 patients from two studies were considered for this analysis ( treated with MF, 8 treated with other ICS). 8,9 MF was similar to other ICS therapy in decreasing nocturnal awakenings due to asthma (Figure ) (OR.2 [95% CI.6.65], p =.8). No significant inter-study heterogeneity was found (I 2 = ). Changes from baseline in rescue medication use (puffs/d) patients from three studies were considered for this analysis (28 treated with MF, 2 treated with other ICS)., 8, 9 MF was superior to other ICS therapy in decreasing rescue medication use (Figure ) (mean difference.56 [95% CI..] puffs/d, p =.2). No significant inter-study heterogeneity was found (I 2 = ). AEs as the outcome Treatment-related AEs 79 patients from three studies were considered for this analysis (58 treated with MF, 6 treated with other ICS). 6,8,2 MF was similar to other ICS therapy in the incidence of treatment-related AEs (Figure 5) (OR.6 [95% CI.7.52], p =.75). No significant inter-study heterogeneity was found (I 2 = ). Treatment-related severe AEs 5 patients from two studies were considered for this analysis ( treated with MF, treated with other ICS). 6, 8 MF was similar to other ICS

6 Mometasone versus other inhaled steroids (a) Patients with no nocturnal awakenings due to asthma (%) Mometasone Other ICS Odds Ratio Odds Ratio % 5.8% M-H, Fixed, 95% CI.2 [.6, 2.9].87 [.,.7] M-H, Fixed, 95% CI (95% CI) 8 events 7 Heterogeneity: Chi² =.5, df = (P =.5); I² = % Test for overall effect: Z =.8 (P =.9).2 [.6,.65] (b) Changes from baseline in rescue medication use (puffs/d) % 5.9% 7.8%. [-.,.5]. [.6,.] -. [-.9,.97] (95% CI) 28 Heterogeneity: Chi² =., df = 2 (P =.); I² = % Test for overall effect: Z = 2.9 (P =.2) 2.56 [.,.] Figure. Summary effects on changes in (a) Patients with no nocturnal awakenings due to asthma and (b) rescue medication use of eligible studies comparing mometasone with other ICS. therapy in the incidence of treatment-related severe AEs (Figure 5) (OR.52 [95% CI.5 5.], p =.). No significant inter-study heterogeneity was found (I 2 = ). Discontinuations because of AEs patients from five studies were considered for this analysis ( treated with MF, treated with other ICS).,6,7,9,2 MF was similar to other ICS therapy in the incidence of discontinuations because of AEs (Figure 5) (OR. [95% CI..5], p =.2). No significant inter-study heterogeneity was found (I 2 = ). Oral candidiasis 5 patients from six studies were considered for this analysis (6 treated with MF, 6 treated with other ICS)., 6, 7-2 MF was similar to other ICS therapy in the incidence of oral candidiasis (Figure 6) (OR. [95% CI ], p =.28). No significant inter-study heterogeneity was found (I 2 = ). Pharyngitis 7 patients from five studies were considered for this analysis (99 treated with MF, 86 treated with other ICS).,6,9 MF was similar to other ICS therapy in the incidence of pharyngitis (Figure 6) (OR.2 [95% CI.5 2.5], p =.). No significant inter-study heterogeneity was found (I 2 = 7%). Headache 7 patients from three studies were considered for this analysis (99 treated with MF, 86 treated with other ICS).,6,9 MF was similar to other ICS therapy in the incidence of headache (Figure 6) (OR. [95% CI. 2.6], p =.95). No significant inter-study heterogeneity was found (I 2 = ). Dysphonia 6 patients from four studies were considered for this analysis (89 treated with MF, 87 treated with other ICS).,6,7,9 MF was similar to other ICS therapy in the incidence of dysphonia (Figure 6) (OR.5 [95% CI.68.], p =.2). No significant inter-study heterogeneity was found (I 2 = ). Discussion To our knowledge, this is the first meta-analysis performed exclusively to explore the efficacy and safety of MF compared to other ICSs available with equipotent daily doses in adults with moderate to severe asthma. Current international or national guidelines, such as the Global Initiative for Asthma guidelines, recommend early intervention with regularly

7 Asian Pac J Allergy Immunol 22;:26-5 (a) Oral candidiasis % 2.%.8% 58.6%.8% 5.% 2. [.,.].29 [.29, 5.7] 7.69 [.5, 87.87]. [.5,.99] 7.5 [.5, 79.68] 2.9 [.5, 8.] (95% CI) 6 6 events 26 Heterogeneity: Chi² = 2.87, df = 5 (P =.72); I² = % Test for overall effect: Z =.8 (P =.28) (b) Pharyngitis (c) Headache (95% CI) 2 26 events 2 Heterogeneity: Chi² =.79, df = 2 (P =.5); I² = 7% Test for overall effect: Z =.28 (P =.). [.79, 2.26] %.%.% 2.9 [.66, 8.6].56 [.9,.67] 7.52 [.5, 79.5].2 [.5, 2.5] % 9.% 7.%. [.2, 5.8].2 [., 5.5].52 [.5, 5.7] (95% CI) 2 26 events 9 9 Heterogeneity: Chi² =.8, df = 2 (P =.79); I² = % Test for overall effect: Z =.6 (P =.95) (d) Dysphonia. [., 2.6] % 5.9% 27.7% 2.2%. [.6, 6.8] 2. [.7, 6.]. [.7,.5] 2. [.2, 9.] (95% CI) events 5 Heterogeneity: Chi² =.26, df = (P =.7); I² = % Test for overall effect: Z =. (P =.2).5 [.68,.] Figure 5. Summary effects on changes in (a) Treatment-related AEs, (b) Treatment-related severe AEs and (c) Discontinuations because of AEs of eligible studies comparing mometasone with other ICS. scheduled treatment with ICSs (referred to as controller therapy) for patients with asthma. However, if a change in ICS therapy is indicated at any point during the treatment course, it is yet to be determined whether MF is better than the other available ICSs. Thus, this meta-analysis was performed to compare the efficacy of different ICSs in improving lung function, symptoms and AEs. Patients treated with MF had significantly better final pulmonary function indices, such as change in the baseline of FEV, FVC, FEF 25%-75%, and morning PEF. The results showed a clear superiority of MF when compared to other ICSs, suggesting the advantage of using MF in improving pulmonary function. This can be explained firstly by the fact that MF is a highly potent steroid with the highest affinity in vitro for glucocorticoid receptor-binding assays when compared to other steroids, such as FP, BUD, dexamethasone and triamcinolone, and secondly because MF is a more potent stimulator of glucocorticoid receptor-mediated gene transcription. 2,22 Moreover, MF as a dry powder inhaler (DPI) produces a clinically 2

8 Mometasone versus other inhaled steroids (a) Treatment-related AEs Mometasone Other ICS Odds Ratio Odds Ratio % 6.8% 5.9% M-H, Fixed, 95% CI.29 [.59, 2.8].5 [.67,.65].8 [., 2.] M-H, Fixed, 95% CI (95% CI) 58 6 events 8 Heterogeneity: Chi² =., df = 2 (P =.75); I² = % Test for overall effect: Z =. (P =.75) (b) Treatment-related severe AEs.6 [.7,.52] %.5%. [.6, 6.8]. [., 6.95] (95% CI) 7 events 2 Heterogeneity: Chi² =.66, df = (P =.2); I² = % Test for overall effect: Z =. (P =.) (c) Discontinuations because of AEs.52 [.5, 5.] % 22.7%.% 7.9% Not estimable.2 [.2,.9].52 [.,.97]. [., 2.99] 2. [.2, 9.] (95% CI) events 7 22 Heterogeneity: Chi² = 2.9, df = (P =.8); I² = % Test for overall effect: Z =.8 (P =.2). [.,.5] Figure 6. Summary effects on changes in (a) Oral candidiasis, (b) Pharyngitis, (c) Headache and (d) Dysphonia of eligible studies comparing mometasone with other ICS. effective dose over a wide range of inhalation rates, and the uniformity of the delivered dose is substantially greater than previous metered dose inhalers or other DPIs. 2 According to the symptom-related indices, MF was superior to other ICSs in morning difficulty breathing score, and similar with regard to morning wheezing score, cough score and percentage of patients with no nocturnal awakenings due to asthma, but only two studies were involved in each comparison respectively.,8,9 Therefore these results should be cautiously regarded. Concerning decreasing the frequency of rescue medication use, MF was superior compared with other ICSs. As a whole, the results suggest that MF may improve some asthmatic symptoms and quality of life when compared to other ICSs. Regarding treatment-related AEs, treatmentrelated severe AEs and discontinuations because of AEs, there is no significant difference between MF and other ICSs. As for the four most common AEs, oral candidiasis, pharyngitis, headache and dysphonia, MF had a similar effect to other ICS therapies with regard to incidence. These results suggest that both treatments are equally safe and well tolerated. All trials included in this meta-analysis were of good quality, and combined with quite homogeneous clinical characteristics of the studied samples.

9 Asian Pac J Allergy Immunol 22;:26-5 Furthermore funnel plots for the primary endpoints showed no clear evidence of publication bias, and the test using Egger s method did not suggest publication bias for those dichotomous data (p value from.22 to.586). Selection bias was also avoided by a systematic search and independent evaluation of trial inclusion by two reviewers. All outcome measures across the trials were statistically homogeneous. However, a limitation of this metaanalysis should be addressed. Standard deviations of pulmonary function outcomes are very wide in some included studies. However, some detailed information, such as pulmonary function outcome of each patient, was unavailable in all the studies, which limited the further assessment of distribution of the data. Overall, this meta-analysis showed that, in adult patients with moderate or severe asthma who had previously been taking ICSs, MF was superior to other ICSs with equipotent daily doses as controller monotherapy in improving pulmonary function and decreasing the frequency of rescue medication use, and was similar to other ICSs in the incidence of AEs. These results demonstrated the priority of MF in asthma therapy. The comparisons between MF and each ICS need further studies in the future. References. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. Global Initiative for Asthma (GINA), National Heart, Lung, and Blood Institute, Bethesda, MD, 26. Available online at last accessed Noonan M, Karpel JP, Bensch GW, Ramsdell JW, Webb DR, Nolop KB, Lutsky BN. Comparison of once daily to twice-daily treatment with mometasone furoate dry powder inhaler. Ann Allergy Asthma Immunol. 2;86:6-.. 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