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doi:10.1378/chest.06-1696
(Chest. 2007; 131:682-689)
© 2007 American College of Chest Physicians
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A Pooled Analysis of FEV1 Decline in COPD Patients Randomized to Inhaled Corticosteroids or Placebo*

Joan B. Soriano, MD, PhD; Don D. Sin, MD, FCCP; Xuekui Zhang, MSc; Pat G. Camp, MSc; Julie A. Anderson, MD; Nick R. Anthonisen, MD; A. Sonia Buist, MD; P. Sherwood Burge, MD; Peter M. Calverley, MD; John E. Connett, PhD; Stefan Petersson, PhD; Dirkje S. Postma, MD; Wojciech Szafranski, MD and Jørgen Vestbo, MD

* From the Program of Epidemiology and Clinical Research (Dr. Soriano), Fundació Caubet-CIMERA Illes Balears, International Centre for Advanced Respiratory Medicine, Bunyola, Mallorca, Illes Balears, Spain; James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research (Dr. Sin, Mr. Zhang, and Ms. Camp), St. Paul’s Hospital, Vancouver, BC, Canada; the Department of Statistics (Dr. Anderson), GlaxoSmihKline R&D, Greenford, Middlesex, UK; the Department of Medicine (Dr. Anthonisen), University of Manitoba, Winnipeg, MB, Canada; the Department of Medicine (Dr. Buist), Oregon Health and Science University, Portland, OR; the Department of Respiratory Medicine (Dr. Burge), Heartlands Hospital NHS Trust, Birmingham, UK; the Department of Medicine (Dr. Calverley), University Hospital Aintree, Liverpool, UK; the Division of Biostatistics (Dr. Connett), School of Public Health, University of Minnesota, Minneapolis, MN; the Department of Statistics (Dr. Petersson), AstraZeneca R&D, Lund, Sweden; the Department of Pulmonology (Dr. Postma), University of Groningen, the Netherlands; the Department of Lung Diseases (Dr. Szafranski), Voivodeship Specialist Hospital, Radom, Poland; and North West Lung Centre (Dr. Vestbo), South Manchester University Hospital NHS Trust, Wythenshawe Hospital, Manchester, UK.

Correspondence to: Joan B. Soriano, MD, PhD, Head, Program of Epidemiology and Clinical Research, Fundació Caubet-CIMERA Illes Balears, International Centre for Advanced Respiratory Medicine, Recinte Hospital Joan March, Carretera Soller Km 12; 07110 Bunyola, Mallorca, Spain; e-mail: jbsoriano{at}caubet-cimera.es

Abstract

Background: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV1.

Methods: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting ≥ 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV1 decline in COPD patients, and whether this relationship is modified by gender and smoking.

Results: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (± SE) relative increase in FEV1 of 2.42 ± 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV1 decline (–0.01 ± 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV1 during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV1 with ICS therapy than did male ex-smokers.

Conclusions: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV1 among those who completed these randomized clinical trials.

Key Words: COPD • corticosteroids • FEV1 • natural history • pooled analysis

COPD represents an increasing burden throughout the world and is considered to be a major global epidemic.1 It affects 5 to 15% of all adults in industrialized countries, its prevalence increases steeply with age, and it caused 2.7 million deaths worldwide in 2000.23 Current international guidelines such as the Global Initiative for Chronic Obstructive Lung Disease and the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines45 define COPD as a modifiable and treatable disease. However, the natural history of COPD, which is characterized by an accelerated rate of lung function decline in terms of FEV1, has been convincingly modified only by smoking cessation.6

Both the Global Initiative for Chronic Obstructive Lung Disease4 and the ATS/ERS guidelines5 consider COPD as an inflammatory disease with pulmonary and systemic components. Inhaled corticosteroids (ICSs) are widely used in the treatment of COPD, at all stages of the disease, although guidelines recommend that they be restricted to individ- uals with an FEV1 of < 50% predicted who have frequent exacerbations because of their efficacy in improving symptoms and quality of life and in reducing exacerbations of COPD.45 However, there is ongoing controversy over whether ICS therapy modifies the natural history of COPD.78 Previous metaanalyses91011 based on the published results of randomized controlled trials (RCTs) of ICS therapy vs placebo in COPD were methodologically heterogeneous and produced inconclusive results. A relatively new tool, pooled analysis, which collects individual patient-level data and analyzes trials as a single, new trial, has advantages over classical metaanalyses as it avoids many of the methodological pitfalls related to classic metaanalytic techniques that rely exclusively on published data.12

By pooling seven long-term RCTs, we recently reported13 that ICS therapy was associated with a 27% lower all-cause mortality rate in COPD patients, and that this survival effect may be modulated by gender, smoking status, and postbronchodilator FEV1. The current study is aimed at quantifying whether the regular use of ICSs vs placebo improves FEV1 decline in COPD patients, and whether this relationship is modified by gender and smoking. Additionally, we aimed to determine whether short-term changes in lung function with ICS therapy vs placebo (ie, improvement in FEV1 within the first 6 months of therapy) can predict survival in COPD patients.

Materials and Methods

The methods of the Inhaled Steroids Effect Evaluation in COPD study13 have been reported. Briefly, we pooled data from all seven RCTs in which stable patients with COPD were randomly assigned to receive ICSs or placebo for at least 12 months. These trials included the Lung Health Study (LHS)-2,14 the Copenhagen City Lung Study (CCLS),15 Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE),16 ERS Study on COPD (EUROSCOP),17 the Trial of Inhaled Steroids and Long Acting ß2-Agonists,18 and the trials by Szafranski et al19 and Calverley et al20 (Table 1 ). All trials and centers were authorized by their corresponding institutional review boards, and all participants signed a written informed consent form, as per the international standards that were valid during the conduct of these trials.


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  		Table 1. Characteristics of Individual Trials at the Time of Randomization*

 
Anonymized data collected from the seven RCTs were sent from each trial site to the central Inhaled Steroids Effect Evaluation study coordinating center, where they were merged together for analytic purposes. As previously discussed,13 each trial used slightly different methods, from recruitment and selection criteria to design, and excluded asthma patients somewhat differently. All trials pooled in this metaanalysis randomized COPD patients who were in the stable phase, and were considered by the investigator to be able to survive for at least the duration of the trial, producing, therefore, valid spirometry data. All metaanalyses included female participants in varying percentages (Szafranski et al19, 14.5%; CCLS15, 38.5%), and age inclusion criteria was ≥ 40 years. All trials included current smokers and ex-smokers, except for the LHS-2,14 where current smoking was an inclusion criterion. COPD severity ranged from the mildest, in EUROSCOP,17 to the most severe, in the 1-year trials of Szafranski et al19 and Calverley et al.20 All trials collected spirometry data every 6 months after randomization, around a period free of exacerbation, and performed spirometry and recorded the findings with methods and machines that met the standards of the ATS or ERS guidelines that were available at the time of the conduct of each trial.21

As the principal aim of this analysis was to determine the effects of ICS therapy on the rate of decline in FEV1, we included only those participants who had three or more measurements of FEV1 over time. All FEV1 values (postbronchodilator) were converted into percent predicted values according to the reference equations of Hankinson et al,22 and FEV1 values for all time points were standardized as percentages of the baseline value. A mixed-effects model that takes into account the nested structure of the data (patients nested within individual trials) and the longitudinal structure of the FEV1 measurements was used to analyze the FEV1 data (PROC MIXED function, SAS, version 9.1; SAS Institute; Cary, NC). This model takes into account variances of FEV1 measurements within individuals as well as between individuals. All estimates were adjusted for baseline values of age, body mass index (BMI), gender, current smoking status, and ICS therapy vs placebo. The effects of gender-ICS and smoking-ICS interactions on FEV1 changes were considered in the analysis. There was insufficient statistical power to consider three-way interactions. Data from study dropouts and those persons lost to follow-up were censored (which is defined as a participant not contributing data beyond the last known visit) at the time of the last known visit. There was no extrapolation of any data in this report. As a stratified analysis, we determined the effect of ICS therapy on FEV1 decline in trials that followed the patients for at least 3 years (ie, EUROSCOP, ISOLDE, CCLS, and LHS-2) to eliminate the potential confounding influence of short-term trials. Finally, to determine whether short-term changes in FEV1 related to ICS therapy predicted the long-term mortality of COPD patients, we used a Cox proportional hazards model adjusted by sex, current smoking status, and treatment (PROC PHREG function, SAS, version 9.1; SAS Institute).

Results

Demographic and Clinical Characteristics
There were 3,911 COPD participants randomized to receive ICSs or placebo who had three of more measurements of FEV1. Of these, 29.2% were women (Table 1). Within all COPD participants analyzed in this pooled analysis, men were older, more frequently obese, and more likely to be current smokers than were women (p < 0.05) [Table 2 ]. Regarding COPD severity measured by FEV1, men had on average a higher FEV1 in absolute terms, but a lower FEV1 in terms of percent predicted than women (p < 0.05).


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  		Table 2. Demographic and Clinical Characteristics of Participants at Baseline by Gender

 
Treatment Effect (ICS vs Placebo in FEV1 Decline Data)
In the first 6 months after randomization, ICS use was associated with a significant increase in FEV1 relative to placebo therapy (mean [± SE] additional increase in FEV1 over 6 months, 2.42 ± 0.19%; p < 0.01 [ICS vs placebo use]) [Fig 1 ]. This relative increase in the percent predicted FEV1 can be quantified in absolute terms as 42 mL in men and 29 mL in women over 6 months. The relative increase in FEV1 related to ICS therapy in the first 6 months was apparent in both male and female participants, as well as in participants who were smokers and ex-smokers (Table 3 ). However, from 6 to 36 months, there was no significant difference between placebo and ICS therapy in FEV1 decline (–0.01 ± 0.09%; p = 0.86).


Figure 1
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  		Figure 1. Relative change in FEV1 from baseline in COPD patients randomized to receive ICSs or placebo. The horizontal axis represents months (total number of participants at each visit). {blacksquare} = participants who were randomized to receive ICSs; {square} = participants who were randomized to receive placebo; bars = SE.

 

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  		Table 3. Effects of ICS on FEV1 Changes in the First 6 Months From Baseline Values, by Gender and Smoking Status*

 
Of interest, the treatment effect of ICSs vs placebo in FEV1 decline data displayed a significant interaction with gender and smoking. The gender-treatment interaction and the smoking-treatment interaction were both significant in the first 6 months (Fig 2 ). Continued smoking attenuated the increase in FEV1 related to ICS therapy in both men and women (Table 3). So, during the first 6 months of treatment, female ex-smokers who were receiving ICS therapy had a 6.5% increase in FEV1 (or 65 mL) vs placebo, but corresponding figures for female current smokers were a 0.9% increase in FEV1 (or 20 mL) vs placebo. Similarly, during the first 6 months of treatment, male ex-smokers who were receiving ICS therapy had a 3.4% increase in FEV1 (or 45 mL) vs placebo, but corresponding figures for male current smokers were a 2.4% increase in FEV1 (or 37 mL) vs placebo (all p < 0.05).


Figure 2
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  		Figure 2. Relative change in FEV1 from baseline in COPD patients who were randomized, by gender and treatment group. Top, A: ex-smokers. Bottom, B: current smokers. {blacktriangleup} = female ICS participants; • = male ICS participants; {circ} = male placebo participants; {triangleup} = female placebo participants; bars = SE.

 
Additionally, within the first 6 months, female ex-smokers had a larger increase in FEV1 with ICS therapy than did male ex-smokers who received ICS therapy (women receiving ICSs, 4.7% increase in FEV1; men receiving ICSs, 1.5% increase in FEV1) [Table 4 ], although differences in the absolute values of FEV1 were minor. Stratified analysis for gender or smoking status showed no significant differences between ICS and placebo therapy on the rate of decline in FEV1 after the first 6 months in women and men or in smokers and ex-smokers (Table 4). Actually, both percent predicted and absolute values were virtually identical in each one of the subgroups of gender and smoking in the ICS group from 6 to 36 months to those in the placebo group from 0 to 36 months.


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  		Table 4. Effects of Inhaled Corticosteroids on FEV1Change From Baseline Values Throughout the Entire Follow-up Period by Gender and Smoking Status

 
Stratified Analysis of Trials That Had at Least 3 Years of Follow-up
As with the main analysis, in the 2,845 participants in EUROSCOP, ISOLDE, CCLS, and LHS-2, ICS therapy in the first 6 months was associated with a significant mean improvement in FEV1 relative to placebo therapy in both current smokers (1.39 ± 0.14%; p < 0.001) and ex-smokers (3.97 ± 0.41%; p < 0.001). From 6 to 36 months of follow-up, however, ICS therapy did not have any significant impact on FEV1 decline over time. In current smokers, there was a mean change of 0.02 ± 0.09% (p = 0.787) in FEV1 over this time period in those receiving ICS therapy relative to placebo therapy; while in ex-smokers, the mean difference between ICS therapy and placebo was 0.16 ± 0.23% (p = 0.493).

Survival Analysis
The possibility that the initial increase in FEV1 with ICS therapy over the first 6 months was a predictor of survival was explored (Table 5 ). Baseline FEV1 (in liters) was inversely associated with mortality in both men and women. Among current smokers, men had a higher mortality rate than did women. Additionally, in ex-smokers there was a small trend toward improved survival in those participants who had a larger increase in FEV1 from baseline values compared to those with reduced changes with ICS therapy, but it did not reach statistical significance (p = 0.081).


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  		Table 5. The Relationship of FEV1 Changes Related to ICS Therapy in the First 6 Months and All-Cause Mortality During the Subsequent Follow-up Period*

 
Discussion

The most important finding of the present study, which was conducted with primary individual-based data and was adjusted by major demographic and clinical characteristics, was that ICS therapy in COPD patients did not affect the rate of decline in FEV1 among those who completed these randomized clinical trials. ICS therapy only produced significant but small improvements in FEV1 over the first 6 months of therapy, an effect that was most pronounced in female ex-smokers. Beyond this time frame, however, ICS therapy had no significant effect on the rate of decline in FEV1. In ex-smokers, there was a modest (but not statistically significant) relationship between the initial improvement in FEV1 and survival, which, while it is not definitive due to the limited sample size, raises the hypothesis that short-term improvements in FEV1 related to ICS therapy may confer long-term benefits for COPD patients. A larger study is needed to confirm this initial observation.

Previous metaanalyses on this topic,91011 because they relied largely on published data, could not differentiate the short-term effects from the long-term effects of ICS therapy. Moreover, they could not determine the potential modifying effects of gender and smoking status on FEV1 changes related to ICS therapy. Additionally, because we had access to individualized data, we were able to adjust for salient confounding variables, namely, baseline age, BMI, gender, and current smoking status, and take into account intraindividual as well as interindividual variation in FEV1 measurements over time.

The short-term improvements in FEV1 with ICS therapy are consistent with the antiinflammatory effects of ICSs in COPD patients.23 So far, ICSs have been suggested to reduce the percentage of neutrophils in BAL fluid and the number of bronchial mast cells,24 but without an effect on the number of bronchial CD8+ lymphocytes and macrophages or the number of sputum neutrophils.252627 In individuals receiving ICS therapy, the bronchial epithelium, which is a major source of proinflammatory cytokines in the lungs, produces less interleukin (IL)-6 and IL-8 than the bronchial epithelium of patients not receiving ICS therapy.28 Interestingly, airway IL-6 levels have been associated with an increased frequency of exacerbations29 and with an accelerated decline in lung function in COPD patients.30

Why ex-smokers would experience larger benefits from ICS therapy than current smokers is uncertain. A similar finding has been reported also in asthma patients, both in short-term and long-term studies313233 assessing the effects of ICSs on lung function decline. Some investigators34 have postulated that cigarette smoking induces a predominant neutrophilic response in the airways that is generally poorly responsive to corticosteroid therapy. Other investigators35 have suggested that smoking down-regulates histone deacetylase activity in alveolar macrophages. Since this is a critical molecule in mediating the antiinflammatory effects of corticosteroids, the airway inflammation in active smokers may be expected to be less responsive to therapy with corticosteroids than the inflammation in ex-smokers. Additionally, cigarette smoking may induce drug-metabolizing enzymes, which may accelerate the breakdown of ICSs and their clearance from the lungs.36 Whatever the mechanism, the findings from the present study suggest that ICSs work best in COPD patients who abstain from smoking.

Our findings also suggest that female COPD patients, especially when they quit smoking, have larger benefits from ICS therapy than do male COPD patients. The reason underlying this observation is not entirely clear and requires further exploration in the future. Although there is ongoing controversy, adult women appear to have increased susceptibility to COPD when they smoke compared to men.3738 When they stop smoking, women gain more lung function than do men who stop smoking,39 and in women methacholine reactivity is more strongly related to FEV1 decline than in men.38 ICSs attenuate airway reactivity to methacholine,14 raising the possibility that ICSs may be able to amplify the beneficial effects of smoking cessation on airway responsiveness and inflammation. Future studies will be needed to validate this hypothesis.

Consistent with previous research,91011 the magnitude of the changes in respiratory function with ICS therapy reported here is considered to be small, and some statistically significant differences in group averages might be of little clinical relevance at the individual patient level. Redelmeier et al40 quantified that a change in FEV1 of approximately 4%, which is equivalent to an absolute increase or decrease of 112 mL, was a minimum for a patient with severe COPD to detect a decrease or increase in perceived dyspnea. None of the comparisons here achieved this threshold. Therefore, any beneficial effect of ICS therapy in COPD patients might be due to mechanisms that are unrelated to respiratory function.

There are certain limitations to the present study. We pooled data from all existing RCTs, and selection biases at recruitment within each of the seven RCTs cannot be ruled out (ie, more women came from the LHS-2, the RCT with the longest duration).14 All statistical techniques used here are simplistic, in the sense that they create means of individual and group values and they assume a rather linear FEV1 decline. It might appear attractive to differentiate slow vs rapid decliners in the response to ICS therapy, but, based on individual mean values, some (most) apparently fast decliners were actually driven by fewer data points with different RCT durations, making analysis and interpretation difficult. Further, lung function decline might prove to be nonlinear, and the effects of recurrent exacerbations, which may produce FEV1 drops of 7 to 10 mL per exacerbation, need to be considered.41 As mentioned earlier, we censored all participants who were lost to follow-up or had died at their last visit and excluded participants who did not have more than two serial FEV1 measurements. This selection of participants with three or more time points will likely imply bias, but the alternative option was considered to be inappropriate. Data from ISOLDE42 indicate that censored participants are generally sicker and experience a faster decline in lung function than those who complete clinical trials, and that they are more likely to be in the placebo group than in the active-treatment group. As such, it is likely that we underestimated the true effects of ICS therapy on FEV1, especially after 6 months when the rate of number of dropouts from the study significantly increased. Since compliance rates decrease significantly over time,43 this may have further diluted the effects of ICS therapy on FEV1 decline and may have substantially reduced the power of the study to capture treatment benefits in terms of the decline in FEV1.44 Thus, the FEV1 data beyond 1 year should be interpreted cautiously. Finally, we did not have measures of smoking history beyond baseline status as current smoker or ex-smoker; therefore, we could not determine whether differences in switchers, the number of pack-years of smoking or treatment groups could have influenced our findings.

In summary, the present study indicates that ICS therapy slightly improves lung function within the first 6 months of therapy but has no material effect on the rate of decline in lung function thereafter among those patients who completed these randomized clinical trials. The initial improvement in lung function related to ICS therapy is most pronounced in female participants and in those participants who have quit smoking.

Acknowledgements

We dedicate this article to the fond memory of our loving friend and colleague, Professor Romain Pauwels.

Footnotes

Abbreviations: ATS = American Thoracic Society; BMI = body mass index; CCLS = Copenhagen City Lung Study; ERS = European Respiratory Society; EUROSCOP = European Respiratory Society Study on Chronic Obstructive Pulmonary Disease; ICS = inhaled corticosteroid; IL = interleukin; ISOLDE = Inhaled Steroids in Obstructive Lung Disease in Europe; LHS = Lung Health Study; RCT = randomized controlled trial

Interdisciplinary Capacity Enhancement: Bridging Excellence in Respiratory Disease and Gender Studies (ICEBERGS), which is supported by funding from Canadian Institutes of Health Research (IGH/ICRH), the Canadian Lung Association, and the Heart and Stroke Foundation of Canada (http://www.icebergs.ubc.ca).

Dr. Soriano was an employee of GlaxoSmithKline, a manufacturer of respiratory drugs, up to 2005. Dr. Sin has received honoraria for speaking engagements from AstraZeneca and GlaxoSmithKline, and has received consultancy fees and research funding from GlaxoSmithKline. Dr. Anderson is currently an employee of GlaxoSmithKline, a manufacturer of respiratory drugs. Dr. Anthonisen and Dr. Buist are members of a respiratory advisory board for GlaxoSmithKline. Dr. Calverley has received honoraria for speaking engagements and research funding from AstraZeneca and GlaxoSmithKline. Dr. Petersson is currently an employee of AstraZeneca, a manufacturer of respiratory drugs. Dr. Postma has received honoraria for speaking engagements and research funding from AstraZeneca and GlaxoSmithKline. Dr. Vestbo has received honoraria for speaking engagements and research funding from AstraZeneca and GlaxoSmithKline. Drs. Zhang, Camp, Burge, Connett, and Szafranski 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.

Received for publication September 12, 2006. Accepted for publication October 2, 2006.

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Related Editorial

Inhaled Steroids and Outcomes in COPD: Progressing Beyond FEV1
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E. R. Sutherland
Inhaled Steroids and Outcomes in COPD: Progressing Beyond FEV1
Chest, March 1, 2007; 131(3): 648 - 649.
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