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Original Research: COPD |

The Efficacy and Safety of Combination Salmeterol (50 μg)/Fluticasone Propionate (500 μg) Inhalation Twice Daily Via Accuhaler in Chinese Patients With COPD* FREE TO VIEW

Jin-Ping Zheng, MD, FCCP; Lan Yang, MD; Ya Mei Wu, MD; Ping Chen, MD, FCCP; Zhong Guang Wen, MD; Wen-Jie Huang, MD; Yi Shi, MD; Chang-Zheng Wang, MD; Shao-Guang Huang, MD; Tie-ying Sun, MD; Guang-Fa Wang, MD; Sheng-Dao Xiong, MD; Nan-Shan Zhong, MD, FCCP
Author and Funding Information

*From the Guangzhou Institute of Respiratory Disease (Drs. Zheng and Zhong), First Affiliated Hospital of Guangzhou Medical College, Guangzhou, People’s Republic of China; First Affiliated Hospital (Dr. Yang), Xi’An Jiao Tong University, Xi’An, People’s Republic of China; First Affiliated Hospital (Dr. Wu), Chongqing Medical University, Chongqing, People’s Republic of China; Shenyang People’s Liberation Army General Hospital (Dr. Chen), Shenyang, People’s Republic of China; Beijing People’s Liberation Army 304 Hospital (Dr. Wen), Beijing, People’s Republic of China; Nanjing People’s Liberation Army General Hospital (Dr. Shi), Nanjing, People’s Republic of China; Xinqiao Hospital (Dr. C.-Z. Wang), Chongqin, People’s Republic of China; Ruijing Hospital (Dr. S.-G. Huang), Shanghai, People’s Republic of China; Beijing Hospital (Dr. Sun), Beijing, People’s Republic of China; First Affiliated Hospital of Beijing University (Dr. G.-F. Wang), Beijing, People’s Republic of China; Tongji Hospital (Dr. Xiong), Wuhan, People’s Republic of China; and Guangzhou People’s Liberation Army General Hospital (Dr. W.-J. Huang), Guangzhou, People’s Republic of China.

Correspondence to: N. S. Zhong, MD, FCCP, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical College, Guangzhou 510120, People’s Republic of China; e-mail: nanshan@vip.163.com



Chest. 2007;132(6):1756-1763. doi:10.1378/chest.06-3009
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Background: Few studies of the efficacy and safety of therapy with combinations of salmeterol/fluticasone propionate (SFCs) have been conducted in Chinese patients with COPD, and the benefits of combination therapy in nonsmoking patients with COPD are, to our knowledge, not known.

Study objectives: The aims were to establish the efficacy and tolerability of the therapy with SFC (salmeterol, 50 μg/fluticasone, 500 μg, twice daily) in the management of Chinese COPD patients and to investigate the effectiveness of SFC in nonsmokers with COPD.

Methods and patients: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Changes in prebronchodilator and postbronchodilator FEV1, quality of life determined by the St. George Respiratory Questionnaire (SGRQ) scores, relief bronchodilator use, nighttime awakenings, and frequency of exacerbations of COPD were measured in patients randomized to receive SFC (n = 297) or placebo (n = 148). Never-smokers, former smokers, and current smokers accounted for 11.7%, 66.7%, and 21.6%, respectively, of the study population.

Results: After 24 weeks, the mean changes in prebronchodilator and postbronchodilator FEV1 were 180 mL (95% confidence interval [CI], approximately 91 to 268; p < 0.001) and 65 mL (95% CI, approximately 14 to 115; p = 0.012), respectively, greater for the SFC group than that for the placebo group. The differences in response to treatment were significant (all p < 0.0001) in former or current smokers but not in never-smokers (p > 0.05). The mean improvement in the total SGRQ score for the SFC group was 5.74 (p < 0.01) greater than that for the placebo group. SFC significantly reduced the frequency of nighttime awakenings and the use of relief bronchodilator. The adjusted ratio of exacerbations of COPD for the SFC group relative to the placebo group was 0.61 (95% CI, approximately 0.45 to 0.84; p < 0.01). There were no significant differences between the SFC and placebo groups in safety measures.

Conclusions: SFC therapy achieved sustained improvement in lung function, quality of life, and control of symptoms, and was well tolerated in Chinese patients. Greater improvements in lung function were found only for COPD patients with a history of smoking.

Trial registration: http://ctr.gsk.co.uk/Summary/fluticasone_salmeterol/studylist.asp Identifier: No. SCO100540.

Figures in this Article

Over the past 2 decades, there has been a dramatic increase in tobacco consumption in China; approximately 67% of men and 4% of women > 15 years of age are currently smokers.1There are > 320 million Chinese smokers, representing about one third of all smokers worldwide. COPD, which predominantly develops in individuals with a significant smoking history, is a leading and rising cause of mortality worldwide.2In south China, the prevalence of COPD is reported to be 9.4% for those ≥ 40 years of age3and is expected to rise as the full impact of the increase in the numbers of Chinese smokers manifests itself. In 2002, the World Health Organization Global Burden of Disease Project4 ranked COPD as second in its list of the 20 leading causes of death in China.

COPD is characterized by inflammation and airflow obstruction56 with chronic progressive symptoms and impaired health status,7particularly in those persons who experience episodes of acute symptom exacerbation.8The use of combination therapy involving a long-acting β2-adrenoceptor agonist (LABA), such as salmeterol (SAL), and inhaled corticosteroid (ICS), such as fluticasone propionate (FP), to reduce airflow obstruction and improve health outcomes in COPD patients has been supported by a number of studies,12 including the 12-month Trial of Inhaled Steroids And Long-Acting β2-Adrenoceptor Agonists (TRISTAN).13 The complementary actions of the LABA and ICS components work together to produce clinical benefits. Therapy with a combination of SAL/FP (SFC) has been shown to reduce exacerbations and to improve lung function and health status to a significantly greater extent than those with either FP or SAL monotherapy. In addition, SFC has demonstrated an ability to restore responsiveness to relief medication in patients with COPD, in whom cigarette smoking was associated with a blunted vasodilator response to inhaled salbutamol.14

Although cigarette smoking is one of the most important risk factors for the development of COPD, it is not the only risk factor. Environmental toxic gases, air pollution, and indoor biomass fuel pollutants have also been reported to induce COPD.15 In most studies published in the last few years, only those persons with a history of heavy smoking (smoking index, > 20 pack-years910 or 10 pack-years13,16) were enrolled in the study. However, in the real world, some patients with COPD were never-smokers. Whether or not these never-smokers would benefit from SFC therapy is not known.

Few studies have examined ethnic differences in response to COPD treatment (eg, SFC therapy in Chinese COPD patients). Drug metabolism can be influenced by, among others things, genetic and environmental factors. For some drugs (eg, theophylline, warfarin, and corticosteroids), the mean response of Chinese patients is known to be substantially different from that of other ethnic groups. Differences in the frequency of β2-adrenergic receptor polymorphisms in black, white, and Chinese populations have been proposed to account for observed differences in β2-adrenergic responsiveness between ethnic groups.17Adherence to therapy with ICSs could also be associated with race-ethnicity and other factors.18 We therefore initiated the present study in order to investigate the efficacy and safety of SFC in Chinese patients with COPD, including never-smokers.

Patients

We recruited outpatients 40 to 79 years of age in whom COPD had been diagnosed, as defined by the European Respiratory Society19 and the Global Initiative for Chronic Obstructive Lung Disease,15 distributed evenly in 12 hospitals (Guangzhou Institute of Respiratory Disease, south China; First Affiliated Hospital, Xi’An Jiao Tong University, Xi’An, northwest China; First Affiliated Hospital, Chongqing Medical University, Chongqing, southwest China; Shenyang People’s Liberation Army General Hospital, Shenyang, northeast China; Beijing People’s Liberation Army 304 Hospital, Beijing, north China; and Guangzhou People’s Liberation Army General Hospital, Guangzhou, south China). Patients were recruited regardless of their smoking history. All patients had a baseline FEV1 after bronchodilation that was approximately 25 to 69% of predicted normal values, a postbronchodilation FEV1/FVC ratio of < 70%, and poor reversibility of airflow obstruction, defined as an increase of < 10% of the normal predicted FEV1 value 30 min to 2 h after the inhalation of 400 μg of salbutamol. Predicted FEV1 values were selected from the European Committee of Coal and Steel predictions,20and adjusted for people of Chinese ethnicity according to the recommendation of Zheng and Zhong.21

The specific study exclusion criteria were as follows: the presence of concurrent respiratory disorders other than COPD; a requirement for regular or long-term oxygen therapy (> 12 h/d); the use of oral corticosteroids or ICSs (beclomethasone dipropionate or equivalent, > 1,000 μg daily) or antibiotics in the 4 weeks before the 2-week run-in period; the use of β-blockers (except topical betaxolol for glaucoma and celiprolol for hypertension, provided the dosage did not exceed 200 mg/d); a moderate-to-severe COPD exacerbation or lower respiratory tract infection during the run-in period; and any significant medical condition or disease that would place the patient at risk or interfere with the study evaluation. This study was conducted in compliance with the protocol and principles of the Declaration of Helsinki (1996) and was approved by the State Food and Drug Administration of China and the local ethics committees at all sites. All participants provided written informed consent.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. There was a 2-week run-in period to the study; a 24-week treatment period with clinic visits at weeks 0, 2, 4, 8, 12, 16, 20, and 24; and a 2-week posttreatment follow-up period. During the run-in period, patients stopped taking ICSs and LABAs. Inhaled salbutamol was used as relief medication and regular COPD treatment (with no change in dose for 1 month prior to screening and during the study), including inhaled short-acting anticholinergics, methylxanthines, mucolytics, and sodium cromoglycate, nedocromil sodium, and antihistamine, was permitted throughout the study. If patients had clinically stable symptoms during the run-in period, they were randomized to receive therapy with SFC (FP, 500 μg; SAL, 50 μg) or placebo twice daily for 24 weeks via a dry-powder inhaler (ACCUHALER; GlaxoSmithKline R&D; Greenford, UK/DISKUS; GlaxoSmithKline; Research Triangle Park, NC). Randomization was stratified at week 0 by smoking status (ie, current, former, or never-smoker), which was recorded at each subsequent visit.

The primary efficacy end point was prebronchodilator FEV1 when patients had abstained from using all bronchodilators for at least 6 h, and from study medication for at least 12 h. Other efficacy end points included postbronchodilator FEV1 (recorded 30 min to 2 h after the inhalation of salbutamol, 400 μg), supplemental salbutamol use, nighttime awakenings, health status (assessed at weeks 0, 8, 16, and 24 by the St. George Respiratory Questionnaire [SGRQ]), and exacerbations of COPD (defined as a worsening of symptoms that required treatment with antibiotics or oral corticosteroids and/or hospitalization).

All lung function measurements were performed at the same time of day using the same spirometer; at each visit the highest of three technically acceptable measurements of FEV1 taken before and 30 min to 2 h after the inhalation of salbutamol, 400 μg, via a spacer (Volumatic; GlaxoSmithKline R&D) were recorded. Patients daily recorded the use of salbutamol for relief of symptoms, the number of nighttime awakenings due to COPD symptoms, and any changes in medication.

In terms of the safety assessment, participants were questioned about the occurrence of adverse events at each clinic visit. Hematology, urinalysis, biochemistry, and 12-lead ECG measurements were made at weeks 0 and 24; vital signs and oropharyngeal examination results were recorded at each visit.

Statistical Analysis

Based on the results of the TRISTAN study,13 we estimated that 348 evaluable patients would be needed in order to detect a 100-mL difference in FEV1 between treatment groups at the 5% significance level with 90% power. We therefore planned a study enrollment of 500 patients in order to randomize 420 (SFC group, 280 patients; placebo group, 140 patients). Predose and postdose FEV1 and changes from baseline and SGRQ scores were analyzed using repeated-measures analysis of covariance. Covariates used for analyses were age, sex, smoking status, baseline value, and study center. Interactions of treatment with all covariates were tested for predose and postdose FEV1. FEV1 values at the end of the study were analyzed by the last-observation-carried-forward method. For nighttime awakenings and the use of a relief bronchodilator, median data were analyzed for each time interval and were compared between treatment groups using the van Elteren extension to the Wilcoxon rank sum test. The rate of COPD exacerbations was calculated using maximum likelihood-based analysis, assuming a negative binomial distribution with time on treatment as an offset variable and adjusting for the effects of age, sex, smoking status, baseline FEV1, and study center.

Study Population

Of the 510 patients screened in this study, 445 were randomized and treated (SFC group, 297 patients; placebo group, 148 patients). A total of 52 patients (12% from the SFC group; 11% from the placebo group) were dropped from the study. The reasons for discontinuation from the SFC and placebo groups were adverse events (SFC group, 3.7%; placebo group, 2.7%), not meeting inclusion criteria (SFC group, 2.0%; placebo group, 2.0%), consent withdrawn (SFC group, 1.7%; placebo group, 0.7%), lost to follow-up (SFC group, 2.0%; placebo group, 0.7%), protocol violations (SFC group, 0.7%; placebo group, 2.7%), lack of efficacy (SFC group, 0.7%; placebo group, 2.0%), exacerbation of COPD (SFC group, 0.3%; placebo group, 0.0%), and other reasons (SFC group, 1.0%; placebo group, 0.0%). Demographic and disease characteristics at screening are provided in Table 1 . There was no statistically significant difference between the two groups with regard to baseline smoking status and lung function, duration of COPD, vital signs, and laboratory test results. Although 11% of patients in the SFC arm and 14% in the placebo arm were never-smokers, the remainder of the patients had a significant smoking history with a median of 30 to 35 pack-years. Treatment compliance over the 24-week study period was high and comparable across the treatment groups (SFC group, 96%; placebo group, 95%).

Lung Function
Prebronchodilator FEV1:

A significantly greater increase in the mean (± SD) prebronchodilator FEV1 was observed at the end of the study (1,240 ± 606 mL) compared with baseline (1,063 ± 377 mL; p < 0.001) in the SFC group, but not in the placebo group (1,022 ± 383 vs 1,030 ± 366 mL, respectively; p > 0.05). Significantly greater increases in predose FEV1 were observed throughout the study during treatment with SFC compared to placebo (Fig 1 ). After adjusting for the effects of center, age, sex, baseline smoking status, and FEV1, the mean change in FEV1 from baseline was higher in the SFC group than in the placebo group (difference, 180 mL; 95% confidence interval [CI], approximately 91 to 268 mL; p < 0.0001) after 24 weeks of treatment.

Adjusted changes in prebronchodilator FEV1 between baseline and 24 weeks of treatment according to smoking status are shown in Table 2 . Prebronchodilator FEV1 increased significantly in all nonsmoking, ex-smoking, and smoking subgroups treated with SFC; however, no significant changes were found in the placebo group. The differences in response to treatment between the SFC and placebo groups were significant (all p < 0.01) in COPD patients with a history of smoking (ie, former and current smokers) but did not reach significance (p = 0.3592) in never-smokers.

2-h Postbronchodilator FEV1:

The mean baseline postbronchodilator FEV1 values were 1,218 ± 379 and 1,178 ± 384 mL, respectively, in the SFC and placebo groups (the difference was not statistically significant). After 24 weeks of treatment, the mean elevation in postdose FEV1 from baseline was 99 mL in the SFC group and 28 mL in the placebo group (p < 0.01). Significantly greater increases in postdose FEV1 were observed throughout the study during treatment with SFC compared to placebo (Fig 2 ). After adjusting for the effects of center, age, sex, baseline smoking status, and FEV1, the mean change in postdose FEV1 from baseline was 65 mL higher (95% CI, approximately 14 to 115 mL; p = 0.012) in the SFC group than in the placebo group after 24 weeks of treatment.

Use of Relief Medication and Symptom-Free Days

Significant reductions in the overall salbutamol use (ie, the number of inhalations per day per patient) were observed during treatment with SFC compared to placebo. Salbutamol use decreased in the SFC group as the study progressed (median total daily use for each 4-week interval from baseline to 24 weeks, 40, 37, 32.5, 35.5, 32, and 30 puffs, respectively) but did not change significantly in the placebo group (median total daily use was 60, 62, 62.5, 68, 65, and 63 puffs, respectively) [Fig 3 ].

The number of nighttime awakenings requiring salbutamol use was lower for the SFC group than for the placebo group. The percentage of days free from nighttime awakenings was consistently higher in the SFC group than in the placebo group (p < 0.05).

Health Status

The baseline mean overall SGRQ scores were 44.8 for the SFC group and 44.5 for the placebo group. These scores decreased (ie, improved) for both groups over the 24-week study period; however, at the end of the study, the mean change in total score was 5.74 U (95% CI, approximately 2.79 to 8.69; p = 0.0001) greater for the SFC group (Fig 4 ). There was a statistically and clinically significant improvement in the overall quality of life of patients in the SFC group relative to the control group. Among patients with more severe disease (postdose FEV1, < 50% predicted), even greater improvements in the overall SGRQ scores for the SFC group relative to the control group of 4.043, 5.192, and 6.847 U, respectively (all p < 0.05), were recorded at 8, 16, and 24 weeks. However, there was no significant difference in the SGRQ scores at 24 weeks between the SFC and control groups in patients with moderate disease (ie, postdose FEV1, ≥ 50% predicted). In addition, an analysis of the symptom score component of the SGRQ showed that, after 24 weeks of treatment, the mean change in symptom score from baseline was 9.67 U (95% CI, approximately 5.55 to 13.79 U) greater in the treatment group than that in the control group. For the activity and impact components, the mean changes from baseline were 4.83 and 5.23 U, respectively, greater for the treatment group at the end of the study. All of the differences were clinically and statistically significant.

Other Efficacy Measures

The annual rates for exacerbations of COPD needing to be treated with antibiotics, systemic corticosteroids, or hospitalization, and the total occurrence rates were 0.68, 0.16, 0.10, and 0.81, respectively, for the SFC group, and 1.15, 0.48, 0.13, and 1.35, respectively, for the placebo group. Exacerbations requiring antibiotic treatment were the most common for both groups. The total risk of exacerbations was reduced by 39% for the SFC group compared with the placebo group (rate ratio, 0.61; 95% CI, approximately 0.45 to 0.84; p = 0.0021). The average number of exacerbations of COPD per year for those with an FEV1 of > 50% predicted were 1.03 (95% CI, approximately 0.79 to 1.33) in the SFC group and 1.61 (95% CI, approximately 1.18 to 2.21) in the placebo group; the rate ratio of SFC to placebo was 0.64 (95% CI, approximately 0.42 to 0.96). For those with an FEV1 of < 50% predicted, the average number of exacerbations of COPD per year was 0.49 (95% CI, approximately 0.33 to 0.74) in the SFC group and 0.91 (95% CI, approximately 0.58 to 1.44) in the placebo group; the rate ratio was 0.54 (95% CI, approximately 0.29 to 0.99).

Safety

A total of 246 patients (SFC group, 56%; placebo group, 55%) experienced at least one adverse event during the study (Table 3 ). The nature and incidence of adverse events were similar across the SFC and placebo groups, including 1% of persons in both groups who experienced oropharyngeal candidiasis. The incidence of at least one drug-related adverse event was 11% in the SFC group and 7% in the placebo group. Adverse events resulted in withdrawal from the study in 4% of patients (SFC group) and 3% of patients (placebo group). Three patients experienced tetter in each group, but no skin bruising was reported in this study.

Two patients in the SFC group died during the study, one due to acute exacerbations of COPD and chronic renal failure, and the other due to combined cholestatic jaundice, abdominal carcinoma, and asphyxia (bile inhalation). Neither death was considered by the investigators to be related to the study drug. The incidence of serious adverse events was low (placebo group, 7%; SFC group, 8%). No significant differences were found in ECG abnormalities between the SFC and placebo groups. No treatment-related effects on vital signs or cardiac rate were observed.

In agreement with the results of previous studies,910,13,2223 we found that, compared with placebo, SFC significantly improved lung function and relieved clinical symptoms in our cohort of Chinese patients. SFC effectively and promptly increased predose and postdose FEV1. After 24 weeks of treatment, the mean changes in predose and postdose FEV1 were 180 and 65 mL, respectively, higher in the SFC group compared to the placebo group. Prebronchodilator FEV1 increased by about 16% in the SFC group, though poor reversibility of airflow obstruction had been found in these COPD patients before the study. This indicates that regular treatment with ICSs and LABAs can indeed improve lung function, but to a lesser extent than is observed in asthma patients, in whom postdose FEV1 can improve by > 200 mL. Hanania et al,10 also have reported a similar improvement in predose FEV1 (16.6% over baseline) in the SFC group. As demonstrated previously, the nature and incidence of adverse events were similar for the SFC and placebo groups in our study.

In our study, 52 of the participants (11.7%) were never-smokers. As shown in Table 2, prebronchodilator FEV1 increased significantly in all patients treated with SFC regardless of smoking status, but not in persons treated with placebo. However, the differences in prebronchodilator FEV1 response between the SFC and placebo groups were not significant in never-smokers. This might indicate that SFC therapy is more effective in smokers. Because the number of never-smokers was small, a further study with a larger sample size is needed to address these effects.

The number of nighttime awakenings was lower in the SFC group, and the percentage of days without nighttime awakenings was higher in the SFC group than in the placebo group. We found, as have previous studies,9,13 that SFC effectively reduced the use of relief bronchodilators compared to placebo.

In addition, SFC improved patients’ overall health-related quality of life and well being. After 24 weeks of treatment, clinically and statistically significant improvements over placebo were achieved for the SGRQ total score as well as all the domain scores. Moreover, this effect was more pronounced among patients in the SFC group with more severe COPD (postdose FEV1, < 50% predicted), who had an improvement in total mean SGRQ score at 24 weeks of 6.85 U (95% CI, approximately 3.06 to 10.64), which was both statistically and clinically significant. In contrast, there was no significant difference in improvement in SGRQ scores between the two treatment groups at 24 weeks for patients with moderate COPD (postdose FEV1, ≥ 50% predicted).

The degree of improvement was more significant than that reported in the TRISTAN trial13 (SGRQ total score improved by 2.2 U) and the Towards a Revolution in COPD Health16 (SGRQ total score improved by 3.1 U), which compared therapy with SFC to that with placebo. Most of the participants in the TRISTAN and Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes studies were white.

In our 24-week study, acute exacerbation was observed as a secondary outcome. The risk of exacerbation was reduced by 39% in the SFC group. Very similarly, a 39% reduction in exacerbation risk was also seen in the TRISTAN study,13 except that study was conducted over 1 year. Other 24-week studies of exacerbation risk have been reported, such as those of Collet et al24and Niewoehner et al25; however, optimally, the study period should be ≥ 1 year. Our data also showed that more frequent exacerbations of COPD were found in patients with severe obstruction, and that SFC therapy reduced the exacerbation rate both in patients with an FEV1 of < 50% predicted and FEV1% of ≥ 50% predicted; however, the reduction in exacerbation rate was greater in the former group (SFC/placebo rate ratio, 0.54) compared to the latter (SFC/placebo rate ratio, 0.64).

The absolute changes in lung function induced by SFC treatment, which were similar in our study to those observed by previous groups,9,13 happened rapidly, being noticeable after only 2 weeks of treatment. These changes could be sufficient to allow improvement in exercise tolerance, and to reduce the perceived severity of an exacerbation and hence the number of episodes reported. It is also likely that the broad-spectrum antiinflammatory activity of the SFC therapy had a role in significantly reducing the rate of exacerbations.26

The efficacy of half-year SFC therapy in the management of Chinese COPD patients seems to be remarkable. One explanation might be that the majority of patients were steroid naïve and had not previously received any regular treatment or participated in a clinical trial. Ethnic differences in response to SFC therapy might also be a contributing factor. For instance, Zhou et al27showed that low-dose administration of theophylline significantly reduced the time to first exacerbation, and improved SGRQ total, activity, and impact scores in Chinese patients with COPD, which has not been reported in white patients. Significant differences in theophylline pharmacokinetics constants were demonstrated between American and Chinese children with asthma28; therefore, recommended doses of aminophylline were approximately 4 to 7 mg/kg/d lower in Chinese children who were approximately 9 to 16 years of age.

As in other studies conducted using the same SFC regimen,9,13 we found that the nature and incidence of adverse events were similar across the SFC and placebo groups. However, higher dosages of corticosteroids are always a safety concern. Chen and colleagues29 reported that, for persons with mild asthma, the inhalation of beclomethasone dipropionate, 400 μg/d for a year, which was generally considered safe in whites, tended to reduce height growth and serum cortisol level after adrenocorticotropic hormone stimulation was reduced significantly compared with low-dose beclomethasone dipropionate inhalation (200 μg/d) as well as steroid-naïve patients. A lower FP dosage (250 μg) may retain the benefits of improving pulmonary function and quality of life while relieving symptoms of COPD.10 Further studies are necessary to confirm the efficacy of the lower dose of ICSs in Chinese patients.

We conclude that SFC therapy composed of an ICS and a LABA (ie, SAL, 500 μg/FP, 50 μg) was effective in Chinese patients with COPD by increasing predose and postdose FEV1, reducing the number of nighttime awakenings and the use of relief bronchodilator, improving quality of life, and decreasing the rate of exacerbations of COPD. The combination therapy was also well tolerated in these patients. A greater improvement in lung function was found in COPD patients with a history of smoking, but a larger sample size is needed to further investigate these results.

Abbreviations: CI = confidence interval; FP = fluticasone propionate; ICS = inhaled corticosteroid; LABA = long-acting β2-adrenoceptor agonist; SAL = salmeterol; SFC = combination of salmeterol/fluticasone propionate; SGRQ = St. George Respiratory Questionnaire; TRISTAN = Trial of Inhaled Steroids and Long-Acting β2-Adrenoceptor Agonists

All authors contributed equally to this article.

The study was funded by GlaxoSmithKline China.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Table Graphic Jump Location
Table 1. Demographics and Characteristics at Screening*
* 

Values are given as No. (%), unless otherwise indicated. BMI = body mass index.

Figure Jump LinkFigure 1. Improvement in predose FEV1 from baseline with SFC therapy compared to placebo (n = 445).Grahic Jump Location
Table Graphic Jump Location
Table 2. Changes in Prebronchodilator FEV1 Between Baseline and 24 Weeks After Beginning Treatment According to Smoking Status*
* 

Values are given as the mean ± SD, unless otherwise indicated.

 

p < 0.01 compared with baseline.

Figure Jump LinkFigure 2. Improvement in postdose FEV1 from baseline with SFC therapy compared to placebo (n = 445).Grahic Jump Location
Figure Jump LinkFigure 3. Median overall use of salbutamol as relief medication for patients in the SFC group compared to the placebo group.Grahic Jump Location
Figure Jump LinkFigure 4. Adjusted mean change in total SGRQ score from baseline for the SFC group vs the placebo group.Grahic Jump Location
Table Graphic Jump Location
Table 3. Incidence of Adverse Events ≥ 10%*
* 

Values are given as the No. (%). URTI = upper respiratory tract infection.

The authors thank the SCO100540 investigators, study site personnel, and the patients who participated in the study, as well as editorial assistance from Elsevier/Excerpta Medica.

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Xie, HG, Stein, CM, Kim, RB, et al Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.Pharmacogenetics1999;9,511-516. [PubMed]
 
Williams, LK, Joseph, CL, Peterson, EL, et al Race-ethnicity, crime, and other factors associated with adherence to inhaled corticosteroids.J Allergy Clin Immunol2007;119,168-175. [PubMed]
 
Siafakas, NM, Vermiere, P, Pride, NB, et al Optimal assessment and management of chronic obstructive pulmonary disease (COPD): European Respiratory Society consensus statement.Eur Respir J Suppl1993;16,5-40. [PubMed]
 
Quanjer, PH Standardized lung function testing: official statement of the European Respiratory Society.Eur Respir J Suppl1993;16,5-40. [PubMed]
 
Zheng, JP, Zhong, NS Normative values for pulmonary function testing in Chinese adults.Chin Med J (Engl)2002;115,50-54. [PubMed]
 
Dompeling, E, van Schayck, CP, van Grunsven, PM, et al Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids: a 4-year prospective study.Ann Intern Med1993;118,770-778. [PubMed]
 
Kerstjens, HA, Brand, PL, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease: Dutch Chronic Non-specific Lung Disease Study Group.N Engl J Med1992;327,1413-1419. [PubMed]
 
Collet, JP, Shapiro, P, Ernst, P, et al Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease: the PARI-IS Study Steering Committee and Research Group; Prevention of Acute Respiratory Infection by an Immunostimulant.Am J Respir Crit Care Med1997;156,1719-1724. [PubMed]
 
Niewoehner, DE, Lokhnygina, Y, Rice, K, et al Risk indexes for exacerbations and hospitalizations due to COPD.Chest2007;131,20-28. [PubMed]
 
Barnes, NC, Qiu, Y-S, Pavord, ID, et al Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease.Am J Respir Crit Care Med2006;173,736-743. [PubMed]
 
Zhou, Y, Wang, X, Zeng, X Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year.Respirology2006;11,603-610. [PubMed]
 
Zhong, NS Management of asthma in developing counties. Barnes, PJ Grunstein, MM Leff, ARet al eds.Asthma1997,1869-1881 Lippincott-Raven. Philadelphia, PA:
 
Chen, A, Chen, R, Zhong, N Systemic side effects of long-term treatment with low dose inhaled corticosteroids in children with asthma.Zhonghua Jie He He Hu Xi Za Zhi2001;24,740-743. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Improvement in predose FEV1 from baseline with SFC therapy compared to placebo (n = 445).Grahic Jump Location
Figure Jump LinkFigure 2. Improvement in postdose FEV1 from baseline with SFC therapy compared to placebo (n = 445).Grahic Jump Location
Figure Jump LinkFigure 3. Median overall use of salbutamol as relief medication for patients in the SFC group compared to the placebo group.Grahic Jump Location
Figure Jump LinkFigure 4. Adjusted mean change in total SGRQ score from baseline for the SFC group vs the placebo group.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Demographics and Characteristics at Screening*
* 

Values are given as No. (%), unless otherwise indicated. BMI = body mass index.

Table Graphic Jump Location
Table 2. Changes in Prebronchodilator FEV1 Between Baseline and 24 Weeks After Beginning Treatment According to Smoking Status*
* 

Values are given as the mean ± SD, unless otherwise indicated.

 

p < 0.01 compared with baseline.

Table Graphic Jump Location
Table 3. Incidence of Adverse Events ≥ 10%*
* 

Values are given as the No. (%). URTI = upper respiratory tract infection.

References

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Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial.Lancet2003;361,449-456. [PubMed]
 
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Calverley, MA, Anderson, JA, Celli, B, et al Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.N Engl J Med2007;356,775-789. [PubMed]
 
Xie, HG, Stein, CM, Kim, RB, et al Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.Pharmacogenetics1999;9,511-516. [PubMed]
 
Williams, LK, Joseph, CL, Peterson, EL, et al Race-ethnicity, crime, and other factors associated with adherence to inhaled corticosteroids.J Allergy Clin Immunol2007;119,168-175. [PubMed]
 
Siafakas, NM, Vermiere, P, Pride, NB, et al Optimal assessment and management of chronic obstructive pulmonary disease (COPD): European Respiratory Society consensus statement.Eur Respir J Suppl1993;16,5-40. [PubMed]
 
Quanjer, PH Standardized lung function testing: official statement of the European Respiratory Society.Eur Respir J Suppl1993;16,5-40. [PubMed]
 
Zheng, JP, Zhong, NS Normative values for pulmonary function testing in Chinese adults.Chin Med J (Engl)2002;115,50-54. [PubMed]
 
Dompeling, E, van Schayck, CP, van Grunsven, PM, et al Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids: a 4-year prospective study.Ann Intern Med1993;118,770-778. [PubMed]
 
Kerstjens, HA, Brand, PL, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease: Dutch Chronic Non-specific Lung Disease Study Group.N Engl J Med1992;327,1413-1419. [PubMed]
 
Collet, JP, Shapiro, P, Ernst, P, et al Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease: the PARI-IS Study Steering Committee and Research Group; Prevention of Acute Respiratory Infection by an Immunostimulant.Am J Respir Crit Care Med1997;156,1719-1724. [PubMed]
 
Niewoehner, DE, Lokhnygina, Y, Rice, K, et al Risk indexes for exacerbations and hospitalizations due to COPD.Chest2007;131,20-28. [PubMed]
 
Barnes, NC, Qiu, Y-S, Pavord, ID, et al Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease.Am J Respir Crit Care Med2006;173,736-743. [PubMed]
 
Zhou, Y, Wang, X, Zeng, X Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year.Respirology2006;11,603-610. [PubMed]
 
Zhong, NS Management of asthma in developing counties. Barnes, PJ Grunstein, MM Leff, ARet al eds.Asthma1997,1869-1881 Lippincott-Raven. Philadelphia, PA:
 
Chen, A, Chen, R, Zhong, N Systemic side effects of long-term treatment with low dose inhaled corticosteroids in children with asthma.Zhonghua Jie He He Hu Xi Za Zhi2001;24,740-743. [PubMed]
 
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