original article
T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n e
n engl j med 365;13 nejm.org september 29, 20111184
Changes in Forced Expiratory Volume  
in 1 Second over Time in COPD
J?rgen Vestbo, Dr.Med.Sc., Lisa D. Edwards, Ph.D., Paul D. Scanlon, M.D.,  
Julie C. Yates, B.S., Alvar Agusti, M.D., Ph.D., Per Bakke, Ph.D.,  
Peter M.A. Calverley, M.B., Ch.B., M.D., Bartolome Celli, M.D.,  
Harvey O. Coxson, Ph.D., Courtney Crim, M.D., David A. Lomas, M.D., Ph.D., 
William MacNee, M.B., Ch.B., M.D., Bruce E. Miller, Ph.D.,  
Edwin K. Silverman, M.D., Ph.D., Ruth Tal-Singer, Ph.D.,  
Emiel Wouters, M.D., Ph.D., and Stephen I. Rennard, M.D.,  
for the ECLIPSE Investigators*
From the Respiratory Section, Hvidovre 
Hospital, Hvidovre, and the University of 
Copenhagen, Copenhagen ? both in Den-
mark (J.V.); the Manchester Academic 
Health Sciences Centre, University of Man-
chester, Manchester ( J.V.), the University 
of Liverpool, Liverpool (P.M.A.C.), the Uni-
versity of Cambridge, Cambridge (D.A.L.), 
and the University of Edinburgh, Edinburgh 
(W.M.) ? all in the United Kingdom; 
GlaxoSmithKline, Research Triangle Park, 
NC (L.D.E., J.C.Y., C.C.), and King of Prus-
sia, PA (B.E.M., R.T.-S.); the Mayo Clinic, 
Rochester, MN (P.D.S.); the Thorax Insti-
tute, Hospital Clinic, Institut d?Inves ti-
gacions Bio m?diques August Pi i Sunyer, 
University of Barcelona, Barcelona, and 
CIBER Enfermedades Respiratorias, Palma, 
Mallorca ? both in Spain (A.A.); the Insti-
tute of Internal Medicine, University of Ber-
gen, Bergen, Norway (P.B.); Brigham and 
Women?s Hospital and Harvard Medical 
School ? both in Boston (B.C., E.K.S.); 
the University of British Columbia, Van-
couver, Canada (H.O.C.); the University 
of Maastricht, Maastricht, the Nether-
lands (E.W.); and the University of Ne-
braska Medical Center, Omaha (S.I.R.). 
Address reprint requests to Dr. Vestbo at 
the Respiratory Section 253, Hvidovre Hos-
pital, Kettegaard Alle 30, 2650 Hvidovre, 
Denmark, or at jvestbo@dadlnet.dk.
* Members of the Evaluation of COPD 
Longitudinally to Identify Predictive Sur-
rogate Endpoints (ECLIPSE) steering and 
scientific committees and the study in-
vestigators are listed in the Supplemen-
tary Appendix, available at NEJM.org.
This article (10.1056/NEJMoa1105482) was 
published on September 26, 2011, at NEJM 
.org.
N Engl J Med 2011;365:1184-92.
Copyright ? 2011 Massachusetts Medical Society.
A bs tr ac t
Background
A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated 
rate of decline in forced expiratory volume in 1 second (FEV1), but data on the vari-
ability and determinants of this change in patients who have established disease 
are scarce.
Methods
We analyzed the changes in FEV1 after administration of a bronchodilator over a 
3-year period in 2163 patients. A random-coefficient model was used to evaluate 
possible predictors of both FEV1 levels and their changes over time.
Results
The mean (?SE) rate of change in FEV1 was a decline of 33?2 ml per year, with sig-
nificant variation among the patients studied. The between-patient standard devia-
tion for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of 
patients had an estimated decline in FEV1 of more than 40 ml per year, 31% had a 
decline of 21 to 40 ml per year, 23% had a change in FEV1 that ranged from a de-
crease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase 
of more than 20 ml per year. The mean rate of decline in FEV1 was 21?4 ml per year 
greater in current smokers than in current nonsmokers, 13?4 ml per year greater 
in patients with emphysema than in those without emphysema, and 17?4 ml per 
year greater in patients with bronchodilator reversibility than in those without 
reversibility.
Conclusions
The rate of change in FEV1 among patients with COPD is highly variable, with 
increased rates of decline among current smokers, patients with bronchodilator 
reversibility, and patients with emphysema. (Funded by GlaxoSmithKline; ECLIPSE 
 ClinicalTrials.gov number, NCT00292552.)
The New England Journal of Medicine 
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Changes in FEV1 over Time in COPD
n engl j med 365;13 nejm.org september 29, 2011 1185
Since the seminal studY by Fletcher et al. in the 1970s,1,2 it has been widely ac-cepted that chronic obstructive pulmonary 
disease (COPD) is characterized by an accelerated 
decline in forced expiratory volume in 1 second 
(FEV1). However, surprisingly few longitudinal 
studies of patient cohorts have provided detailed 
data regarding the rate of decline in FEV1,3-8 and 
none of these studies have related changes in FEV1 
to specific subgroups of patients with COPD or to 
levels of systemic biomarkers. We used data from 
a large, observational, 3-year study that included 
detailed assessments of patients with COPD to 
examine the variability of changes in FEV1 and to 
explore whether these changes differed among pa-
tient subgroups and whether certain biomarkers 
could predict changes in FEV1.
Me thods
Study Design and Patients
Our analysis was based on data collected in the 
Evaluation of COPD Longitudinally to Identify Pre-
dictive Surrogate Endpoints (ECLIPSE) observation-
al study.9,10 Patients with COPD who were between 
the ages of 40 and 75 years were enrolled in the 
study if they had a history of 10 or more pack-years 
of smoking, as well as an FEV1 that was less than 
80% of the predicted value and a ratio of FEV1 to 
forced vital capacity (FVC) of 0.7 or less; both mea-
surements were made after use of a bronchodilator. 
Respiratory symptoms, smoking history, occupa-
tional exposure, and coexisting medical conditions 
were documented at study entry with the use of a 
modified version of the American Thoracic Society?
Division of Lung Disease (ATS-DLD) questionnaire.
The study was conducted according to the Dec-
laration of Helsinki and Good Clinical Practice 
guidelines. All patients provided written informed 
consent, and the study was approved by the rele-
vant ethics and review boards. The study was con-
ducted in accordance with the protocol, available 
with the full text of this article at NEJM.org.
Study Assessments
After the baseline visit, patients returned to their 
study centers on seven occasions for follow-up as-
sessments: at 3 months and at 6 months and then 
every 6 months for 3 years. At each visit, the patient 
reported the number of COPD exacerbations since 
the last visit. Exacerbations were defined as wors-
ening of COPD symptoms that required treatment 
with antibiotics or systemic glucocorticoids, alone 
or in combination, or hospitalization, as reported 
in more detail previously.11 At each visit, the sever-
ity of COPD was graded according to the stages 
of disease as defined by the Global Initiative for 
Chronic Obstructive Lung Disease (GOLD).3
At baseline and at each subsequent visit, pa-
tients underwent spirometry (Viasys MasterScope) 
before and 15 minutes after inhaling 400 ?g of 
salbutamol from a metered-dose inhaler with the 
use of a Volumatic spacer (GlaxoSmithKline). Com-
puted tomographic (CT) scanning of the chest was 
performed at baseline to evaluate the severity and 
distribution of emphysema. Quantitative assess-
ment of lung volumes and estimation of the per-
centage of lung CT voxels below a threshold of 
?950 Hounsfield units was performed with the use 
of Pulmonary Workstation software, version 2.0 
(VIDA Diagnostics).12
Subgroups and Biomarkers
Subgroups were based on status with respect to 
emphysema and chronic bronchitis, bronchodila-
tor reversibility, and cardiovascular disease. Em-
physema was defined as more than 10% of lung 
volume with a density of ?950 Hounsfield units or 
less during a maximal inspiratory breath hold. 
Chronic bronchitis was defined as the presence of 
phlegm for periods of 3 months or more for at least 
2 years and was assessed on the basis of responses 
to relevant ATS-DLD questions. Patients were clas-
sified as having either emphysema or chronic bron-
chitis, both entities, or neither entity. Bronchodila-
tor reversibility was defined as an increase in FEV1 
that was 12% above the baseline value and at least 
200 ml after inhalation of 400 ?g of albuterol. 
Patients were classified as having cardiovascular 
disease if they reported ?heart trouble,? hyperten-
sion, heart failure, or ischemic heart disease on the 
ATS-DLD questionnaire.
Serum and plasma samples for biomarker mea-
surements were obtained at baseline and stored at 
?80?C until they were analyzed. Relationships be-
tween changes in FEV1 and circulating levels of 
C-reactive protein, interleukin-8, interleukin-6, 
fibrinogen, tumor necrosis factor alpha, surfac-
tant protein D, and Clara cell secretory protein 
16 (CC-16) were also measured. Details of the as-
says are described in the Supplementary Appen-
dix, available at NEJM.org.
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T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n e
n engl j med 365;13 nejm.org september 29, 20111186
Statistical Analysis
Random-coefficient models with both a random 
intercept and a random slope were constructed to 
determine the effect of patient characteristics on 
post-bronchodilator FEV1 at baseline and its rate of 
change over the 3-year study period. Quadratic and 
piecewise models with fixed and random join 
points (i.e., the points at which lines with different 
slopes meet) did not provide substantially better 
fit than did the linear model. The random slope 
was based on time of FEV1 assessment. The final 
predictors of baseline FEV1 (i.e., at the time of en-
rollment) and its rate of change were determined 
with the use of a series of models that were built up 
by means of stepwise selection of baseline clinical 
characteristics, phenotypes of interest, and bio-
markers measured at study entry, as well as each 
covariate?s interaction with time. Effect estimates 
were adjusted for age, sex, height, and weight at 
study entry; current smoking status and smoking 
history (pack-years) at study entry; and number of 
exacerbations during the year before entry. For non-
significant terms in the models, effect estimates 
were the model coefficients just before removal 
from the model. The empirical Bayes estimate of 
the rate of change in FEV1 was calculated for each 
patient and summarized in the form of a histogram 
(Fig. 1). Comparisons of patient characteristics 
were carried out by means of analyses of variance, 
Kruskal?Wallis tests, or chi-square tests, as appro-
priate; t-tests based on the appropriate linear com-
binations of the random effects and their standard 
errors were used to compare the rates of change in 
FEV1. P values of less than 0.05 were considered to 
indicate statistical significance. No adjustments 
were made for multiple testing. All analyses were 
conducted with the use of SAS software, version 
9.1 (SAS Institute). Additional details about mod-
el selection can be found in the Supplementary 
Appendix.
R esult s
Patient Characteristics
A total of 2164 patients were recruited for the study, 
1 of whom was subsequently excluded because of 
inadequate FEV1 measurements for analyses. Of the 
remaining 2163 patients, 1447 had eight FEV1 as-
sessments, 198 had seven, 95 had six, 99 had five, 
96 had four, 81 had three, 67 had two, and 80 had 
only one. The baseline characteristics of the pa-
tients are reported in Table 1, categorized accord-
ing to the number of FEV1 assessments available for 
evaluation. Patients with fewer measurements ap-
peared to have more severe disease. Lung function 
at baseline was associated with age, sex, anthropo-
metric measures, smoking history, and exacerba-
tion history (Table 2). Table 1 in the Supplemen-
tary Appendix shows baseline characteristics of the 
patients according to geographic region.
Rate of Change in FEV1
The mean rate of change in FEV1 was a decline of 
33?2 ml per year, with significant variation in the 
levels of change (Fig. 1). The between-subjects stan-
dard deviation for the decline in FEV1 was 59 ml per 
year. Slightly more than one in three participants 
(38%) had an estimated rate of decline in FEV1 of 
more than 40 ml per year over the 3-year period; 
in 31%, FEV1 declined by 21 to 40 ml per year, in 
23% the change in FEV1 ranged from a decline of 
20 ml per year to an increase of 20 ml per year, and 
in 8%, FEV1 increased by more than 20 ml per year. 
Patients with moderate disease (GOLD stage 2) had 
a mean rate of decline in FEV1 of 35?1 ml per year, 
as compared with declines of 33?1 ml per year in 
patients with severe disease (GOLD stage 3) and 
25?2 ml per year in patients with very severe dis-
ease (GOLD stage 4) (P=0.17 for stage 2 vs. stage 3, 
P<0.001 for stage 2 vs. stage 4, P=0.009 for stage 
3 vs. stage 4).
The rate of change was not associated with the 
number of FEV1 measurements. The mean rate of 
decline for patients with seven or eight assess-
ments was 32?1 ml per year, as compared with 
37?2 ml per year for those contributing four, five, 
or six measurements and 31?3 ml per year for 
those with one, two, or three measurements. Al-
though 10% of the patients died and 13% with-
drew from the study, the mean rates of change did 
not differ significantly among those who died, 
those who withdrew, and those who completed the 
study (Table 2 in the Supplementary Appendix). 
We did not see an increasing rate of decline with 
an increase in age or cumulative tobacco expo-
sure, expressed as pack-years of smoking. Al-
though men had higher levels of post-bronchodi-
lator FEV1 at baseline, the rate of change was 
similar for men and women. The rate of decline in 
FEV1 was affected by smoking status, with a de-
cline of 21?4 ml per year more among current 
smokers than among former smokers. FEV1 at 
baseline was lower in patients who reported more 
exacerbations in the year before study entry, but 
The New England Journal of Medicine 
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Changes in FEV1 over Time in COPD
n engl j med 365;13 nejm.org september 29, 2011 1187
the number of prior exacerbations had no effect 
on the subsequent rate of change. Exacerbations 
during follow-up, however, were associated with 
an excess decline in FEV1, with a mean loss of 
2?0.5 ml per year per exacerbation (Table 2).
Analysis of Subgroups
Patients with chronic bronchitis did not have a 
more rapid rate of decline in FEV1 but did have a 
lower mean FEV1 (43?20 ml per year) at baseline 
than did patients without chronic bronchitis. Pa-
tients with bronchodilator reversibility at baseline 
had a mean FEV1 that was 220?22 ml per year high-
er than did patients without reversibility at baseline, 
and their FEV1 declined by an additional 17?4 ml 
per year. The presence or absence of self-reported 
cardiovascular disease affected neither FEV1 at 
baseline nor its rate of change. In the subset of pa-
tients for whom CT data were available (1807 pa-
tients), the mean FEV1 at baseline was 327?21 ml 
lower in those with clinically significant emphyse-
ma (>10% low-attenuation areas) than in those with 
little or no emphysema, and FEV1 declined by an 
additional 13?4 ml per year.
Analysis of Biomarkers
We analyzed data for the subset of patients for 
whom data on all biomarker values were available 
(1793 patients); the results of these analyses were 
not corrected for multiple testing. Several of the 
biomarkers we examined were associated with FEV1 
at baseline (Table 3). This association was most 
pronounced for fibrinogen, for which the differ-
ence in FEV1 associated with an increase of 1 SD 
was similar to the difference in FEV1 between cur-
rent and former smokers. Only CC-16 levels were 
significantly associated with the rate of change in 
FEV1, with an additional decline of 4?2 ml per year 
for each decrease of 1 SD in the level of CC-16. The 
association between the CC-16 level and the rate of 
decline in FEV1 was not modified by age, sex, GOLD 
stage, current smoking status or smoking history, 
or patient subgroup. Neither surfactant protein D 
nor any of the biomarkers believed to reflect sys-
temic inflammation were related to a change in 
FEV1 over time (Table 3).
Discussion
In this observational study of patients with COPD, 
we found that the rate of decline in FEV1 over a 
3-year period was highly variable. Although COPD 
is considered to be a progressive disease, only 38% 
of patients had an estimated rate of decline in FEV1 
of more than 40 ml per year. Current smoking was 
most strongly associated with the rate of decline in 
FEV1. In addition, patients with emphysema (as de-
fined on the basis of CT scanning) and patients 
with bronchodilator reversibility both had an ex-
cess loss of FEV1 over the 3-year study period, as 
compared with the study participants who did not 
have these conditions. None of the biomarkers were 
strongly associated with a decline in FEV1; however, 
the baseline level of CC-16 was associated with the 
rate of decline and may possibly serve as a biomark-
er of disease progression, if this finding can be 
replicated in other populations.
The relatively modest declines in lung function 
observed in the current study are not substantially 
different from those reported in the Understand-
ing Potential Long-Term Impacts on Function with 
Tiotropium (UPLIFT) trial (ClinicalTrials.gov num-
ber, NCT00144339), in which the mean rate of 
decline in FEV1 over a period of 4 years was 41 ml 
per year.8 In addition, when assessed according to 
the severity of airflow limitation, the rate of de-
cline appears to be inversely related to the GOLD 
stage; this observation is consistent with the 
findings in both the UPLIFT study and the To-
Pa
tie
nt
s 
(%
)
32
24
28
20
16
8
4
12
0
?300 ?200 ?100 0 100 200 300
Change in FEV1 (ml/yr)
Figure 1. Distribution of Estimated Annual Rates of Change in Forced 
Expiratory Volume in 1 Second (FEV
1
) over a 3-Year Period in Patients 
with Chronic Obstructive Pulmonary Disease.
Empirical Bayes estimates of the change in FEV
1
 were calculated for each 
patient with the use of the random-coefficient model and are summarized 
in the form of a histogram. Each bar represents a change in FEV
1
 of 20 ml 
per year.
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T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n e
n engl j med 365;13 nejm.org september 29, 20111188
wards a Revolution in COPD Health (TORCH) 
study (ClinicalTrials.gov number, NCT00268216).7
Our study had several limitations. First, it in-
cluded only patients with moderate, severe, or very 
severe COPD and thus cannot identify factors of 
importance that are associated with rates of de-
cline in early-stage COPD. Epidemiologic studies 
have identified the presence of breathlessness13 
and bronchial hyperreactivity14 as indicators of 
progressive loss of lung function, but recruitment 
for these studies and for ECLIPSE differed so much 
that a direct comparison is impossible.
Second, all the patients in our study received 
treatment for their COPD, which was managed by 
their usual physicians. Although none of the 
drugs available for the treatment of COPD have 
been shown unequivocally to reduce the decline in 
FEV1,3 a secondary analysis in the TORCH study 
indicated that declines in FEV1 may be reduced 
with regular treatment,15 and similar indications 
were evident in subgroup analyses in the UPLIFT 
trial.16 Our study was purely observational, and 
we chose not to include treatment in our analy-
ses, since the effects of treatment on the rate of 
decline in FEV1 are likely to be confounded as a 
result of bias by indication and other biases that 
are characteristic of observational pharmacoepi-
demiologic studies. Moreover, the diagnosis and 
management of COPD in the patients in our study 
were carried out at specialist centers, and our re-
sults may not extend beyond this patient popula-
tion for a variety of reasons, including the clini-
cally determined care they received. An estimated 
15% of the patients assessed in our study had 
Table 1. Characteristics of the Patients According to Number of Measurements of Forced Expiratory Volume 
in 1 Second (FEV1).*
Characteristic
All Patients
(N = 2163) No. of Assessments P Value?
7 or 8 
(N = 1645)
4 to 6 
(N = 290)
1 to 3 
(N = 228)
Age (yr) 63?7 63?7 65?7 64?8 0.001
Female sex (%) 35 35 33 34 0.80
Smoking status
Current smoker (%) 36 34 40 44 0.006
Smoking history (pack-yr) 49?27 48?27 53?29 51?27 0.004
Body-mass index? 27?6 27?6 26?6 26?6 0.46
FEV1 after bronchodilator use
Value (liters) 1.35?0.52 1.39?0.52 1.20?0.52 1.21?0.50 <0.001
Percent of predicted value 48?16 50?16 44?16 44?15 <0.001
Exacerbations (no.)
In yr before study 0.8?1.2 0.8?1.1 1.0?1.4 0.9?1.3 0.001
First yr of study 1.2?1.5 1.1?1.4 1.7?2.0 0.9?1.4 <0.001
Phenotype (%)
Emphysema 67 66 70 71 0.24
Chronic bronchitis 35 34 38 39 0.12
Emphysema and chronic bronchitis 22 21 23 24 0.56
Neither emphysema nor chronic bronchitis 23 24 17 16 0.002
COPD and CVD 56 54 60 59 0.09
Treatment (%)
Inhaled glucocorticoids 72 71 73 73 0.66
Long-acting beta-agonists 68 68 70 67 0.62
Tiotropium 46 46 49 42 0.22
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Changes in FEV1 over Time in COPD
n engl j med 365;13 nejm.org september 29, 2011 1189
improved lung function over the 3-year study pe-
riod. Whether this represents an expected statis-
tical distribution or a true response to treatment 
is unknown. However, the possibility that some 
patients with COPD might have improvement over 
time was noted by Fletcher et al.2
Patients who continued to smoke were at in-
creased risk for marked progression, as compared 
with former smokers, and this remained true ir-
respective of the GOLD stage. In contrast, cumu-
lative exposure did not affect future decline. This 
finding points to smoking cessation as the most 
important tool in secondary and tertiary preven-
tion for patients at all stages of COPD.1 Exacerba-
tions had an effect on the rate of decline in FEV1, 
but this effect was very modest, as compared with 
the effect of smoking. The effect of exacerbations 
was also similar to that found in the Lung Health 
Study17 but was smaller than the effects in other 
studies18,19; however, because studies differ consid-
erably in design and inclusion criteria, direct com-
parisons are difficult. In our study, the associa-
tion between bronchodilator reversibility and the 
rate of decline in FEV1 is more difficult to interpret. 
Reversibility is known to be an unstable phenom-
enon20 that does not predict mortality when post-
Table 1. (Continued.)
Characteristic
All Patients
(N = 2163) No. of Assessments P Value?
7 or 8 
(N = 1645)
4 to 6 
(N = 290)
1 to 3 
(N = 228)
Biomarkers
C-reactive protein (?g/ml) 0.07
Mean 3.2 3.1 3.2 4.3
Interquartile range 1.5?7.3 1.6?6.8 1.5?7.9 1.3?11.7
Interleukin-6 (pg/ml) <0.001
Mean 1.5 1.4 1.9 2.5
Interquartile range 0.8?3.1 0.7?2.7 0.9?3.9 1.1?4.8
Interleukin-8 (pg/ml) 0.015
Mean 7.1 6.9 7.8 7.8
Interquartile range 3.4?13.2 3.3?12.4 3.6?17.3 3.5?15.2
Fibrinogen (mg/dl) 0.007
Mean 449 444 465 456
Interquartile range 389?518 388?512 394?535 391?541
TNF-? (pg/ml) 0.40
Mean 2.4 2.4 2.4 2.4
Interquartile range 2.4?11.7 2.4?15.2 2.4?7.2 2.4?2.4
CC-16 (ng/ml) 0.26
Mean 5.0 5.0 5.3 4.7
Interquartile range 3.5?7.0 3.4?6.9 3.7?7.5 3.5?7.0
Surfactant protein D (ng/ml) <0.001
Mean 120 117 124 139
Interquartile range 84?172 84?165 83?188 93?206
* Plus?minus values are means ?SD. CC-16 denotes Clara cell protein 16, COPD chronic obstructive pulmonary disease, 
CVD cardiovascular disease, and TNF-? tumor necrosis factor alpha.
? P values are for the overall comparison of the three subject groups (determined by the number of assessments) and 
are based on analyses of variance, Kruskal?Wallis tests, and Cochran?Mantel?Haenszel tests, as appropriate.
? The body-mass index is the weight in kilograms divided by the square of the height in meters.
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T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n e
n engl j med 365;13 nejm.org september 29, 20111190
bronchodilator FEV1 is taken into account.21 Fur-
thermore, analyses of the larger Lung Health Study, 
which involved patients who had milder disease 
than the patients in our study, and the smaller In-
haled Steroids in Obstructive Lung Disease in Eu-
rope (ISOLDE) study, which involved patients with 
more severe disease, did not show an association 
between reversibility and rate of decline.20,22 Our 
definition of reversibility, which included both a 
relative and an absolute criterion, may have led 
to the association we observed ? a possibility 
that should be examined in replication studies.
We studied a number of biomarkers and found 
that only one, CC-16, was associated with the rate 
Table 2. Effects of Patient Characteristics on Baseline Forced Expiratory Volume in 1 Second (FEV1) and on Annual Rate 
of Change in FEV1.*
Characteristic
Effect on Baseline 
FEV1 P Value
Effect on Annual Rate 
of Change in FEV1 P Value
ml ml/yr
Age (per yr) ?10?1.4 <0.001 0?0.3 0.21
Female sex ?55?26.0 0.04 3?3.8 0.42
Height (per cm) 19?1.5 <0.001
Weight (per kg) 5?0.6 <0.001
Smoking status
Current smoker (yes vs. no) 102?20.7 <0.001 ?21?3.8 <0.001
Smoking history (per pack-yr) ?1?0.4 0.02 0?0.1 0.20
Prior exacerbations
?3 vs. 0 ?259?34.3 <0.001 ?3?6.7 0.67
?3 vs. 1 ?107?37.1 0.004 2?7.2 0.83
?3 vs. 2 ?47?41.6 0.25 ?5?8.1 0.57
Exacerbations during follow-up (per exacerbation) ?2?0.5 <0.001
Bronchodilator reversibility (yes vs. no) 220?22.4 <0.001 ?17?4.2 <0.001
Emphysema (yes vs. no) ?327?21.2 <0.001 ?13?4.2 0.002
Chronic bronchitis (yes vs. no) ?43?20.2 0.033 ?2?3.8 0.67
Cardiovascular disease (yes vs. no) 11?19.7 0.57 1?3.6 0.77
* Plus?minus values are means ?SE.
Table 3. Effects of Biomarkers on Forced Expiratory Volume in 1 Second (FEV1).*
Biomarker?
Effect on Baseline 
FEV1 P Value?
Effect on Annual Rate  
of Change in FEV1 P Value?
ml ml/yr
Fibrinogen ?93?10.6 <0.001 ?1?2.1 0.63
Interleukin-6 0?10.0 >0.99 1?2.3 0.52
Interleukin-8 20?9.9 0.04 ?2?2.0 0.36
TNF-? 1?9.9 0.89 0?1.8 0.84
C-reactive protein ?23?10.3 0.037 4?2.1 0.07
CC-16 33?10.8 0.002 4?2.2 0.04
Surfactant protein D 0?10.3 0.96 ?3?2.1 0.18
* Plus?minus values are means ?SE. 
? Effects are per increase of 1 SD in the values of the individual biomarkers (i.e., a change of 1 SD in the level of the bio-
marker resulted in a specific effect on FEV1). CC-16 denotes Clara cell protein 16, and TNF-? tumor necrosis factor alpha.
? P values were not corrected for multiple testing.
The New England Journal of Medicine 
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Changes in FEV1 over Time in COPD
n engl j med 365;13 nejm.org september 29, 2011 1191
of decline in FEV1. This association was weak, and 
whether it is biologically meaningful has yet to 
be determined. Without confirmation, it does not 
seem appropriate to speculate on the potential 
significance of this finding. The list of poten-
tially valuable biomarkers is long23 and growing. 
Other markers will undoubtedly be tested in 
other studies.
In conclusion, our data show that COPD is 
not invariably progressive. In more than half the 
patients in our study, the rate of decline in FEV1 
over a period of 3 years was no greater than that 
which has been observed in people without lung 
disease. This finding could indicate that COPD 
may ?burn out? or at least stabilize for periods 
of 3 years or more, which would be good news 
for patients and could influence a variety of 
management decisions that depend on progno-
sis. The continuation of smoking is strongly as-
sociated with an increased rate of decline in 
FEV1, a finding that underscores the importance 
of smoking cessation for patients with this con-
dition. Since our findings challenge the concept 
that progressive loss of lung function is inevi-
table in COPD, they should spark interest in re-
vising our view of the course of this condition.
Supported by grants from GlaxoSmithKline (to Drs. Vestbo, 
Scanlon, Agusti, Bakke, Calverley, Celli, Coxson, Lomas, MacNee, 
Silverman, Wouters, and Rennard).
Dr. Vestbo reports receiving consulting fees from AstraZeneca, 
Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Ny-
comed, and Pfizer, speaking fees from AstraZeneca, Boehringer 
Ingelheim, GlaxoSmithKline, Novartis, and Nycomed, and grants 
on behalf of his institution from GlaxoSmithKline; Dr. Scanlon, 
receiving travel support from Boehringer Ingelheim and Novar-
tis and receiving grants from Boehringer Ingelheim, Forest 
Laboratories, GlaxoSmithKline, Pfizer, and Novartis on behalf 
of his institution; Dr. Agusti, receiving fees for serving on the 
boards of Almirall, AstraZeneca, Boehringer Ingelheim, Esteve, 
GlaxoSmithKline, Novartis, Nycomed, and Roche, speaking 
fees from Almirall, AstraZeneca, Boehringer Ingelheim, Esteve, 
GlaxoSmithKline, and Nycomed, payment for the development 
of educational presentations from Nycomed, and receiving grants 
from Almirall, GlaxoSmithKline, and Nycomed on behalf of his 
institution; Dr. Bakke, receiving speaking fees from AstraZeneca, 
GlaxoSmithKline, and Pfizer; Dr. Calverley, receiving fees for 
serving on the boards of GlaxoSmithKline, Boehringer Ingel-
heim, and Nycomed, consulting fees from Merck and Novartis, 
payment for providing expert testimony for Forest, speaking fees 
from AstraZeneca and GlaxoSmithKline, travel support from 
Boehringer Ingelheim, and receiving speaking fees from Novar-
tis and Pfizer on behalf of his institution; Dr. Celli, receiving 
consulting fees from Aeris, Almirall, AstraZeneca, Boehringer 
Ingelheim, Novartis, and Rox Medical; Dr. Coxson, receiving 
consulting fees from GlaxoSmithKline and Spiration, speaking 
fees from AstraZeneca, travel support from AstraZeneca and 
Spiration, and receiving grants from GlaxoSmithKline and Spira-
tion on behalf of his institution; Dr. Lomas, receiving fees for 
serving on the board of GlaxoSmithKline, consulting fees from 
GlaxoSmithKline, speaking fees from GlaxoSmithKline, travel 
support from Boehringer Ingelheim and GlaxoSmithKline, and 
receiving grants from GlaxoSmithKline on behalf of his institu-
tion; Dr. MacNee, receiving travel support from AstraZeneca, 
Boehringer Ingelheim, GlaxoSmithKline, and Pfizer, and he and 
his institution receiving consulting fees from Pfizer and fees for 
membership on the boards of Pfizer and GlaxoSmithKline; Dr. 
Rennard, receiving fees for membership on the boards of Almi-
rall, Novartis, Nycomed, and Pfizer, consulting fees from Able 
Associates, Adelphi Research, APT Pharma/Britnall, Aradigm, 
AstraZeneca, Boehringer Ingelheim, Chiesi, CommonHealth, 
Consult Complete, COPDforum, Datamonitor, Decision Resourc-
es, Defined Health, Dey, Dunn Group, Easton Associates, Equi-
nox, Forest, Gerson, GlaxoSmithKline, InfoMed, KOL Connec-
tion, M. Pankove, MedaCorp, MDRx Financial, Mpex, Novartis, 
Nycomed, Oriel Therapeutics, Otsuka, Pennside, Parma Ventures, 
Pearl, Pharmaxis, Price Waterhouse, Propagate, Pulmatrix, Reckner 
Associates, Recruiting Resources, Roche, Sankyo, Schlesinger 
Medical, Scimed, Sudler and Hennessey, TargeGen, Theravance, 
United BioSource, Uptake Medical, and VantagePoint Manage-
ment, speaking fees from AstraZeneca, Convergent Health Solu-
tions for Reviews and Trends in COPD, COPD Foundation, Cre-
ative Educational Concepts, Dey, France Foundation, Information 
TV, Network for Continuing Education (CHARM), Novartis 
(Horsham), Nycomed, Otsuka, and Pfizer, travel support from 
Almirall, AstraZeneca, Boehringer Ingelheim, California Aller-
gy Society, Creative Educational Concept, France Foundation, 
GlaxoSmithKline, Information TV, Network for Continuing Edu-
cation, Novartis, Nycomed, and Pfizer, and receiving grants from 
AstraZeneca, Biomarck, Boehringer Ingelheim, Centocor, Mpex, 
Nabi, Novartis, Nycomed, and Otsuka on behalf of his institu-
tion; Dr. Silverman, receiving consulting fees from AstraZeneca 
and GlaxoSmithKline, speaking fees from AstraZeneca and 
GlaxoSmithKline, and receiving grants from GlaxoSmithKline 
on behalf of his institution; and Dr. Wouters, receiving fees for 
membership on the board of Nycomed, speaking fees from 
AstraZeneca, GlaxoSmithKline, and Novartis, and grants from 
AstraZeneca and GlaxoSmithKline. Drs. Crim, Edwards, Miller, 
Tal-Singer, and Yates report being employees of and owning 
stock in GlaxoSmithKline. No other potential conflict of interest 
relevant to this article was reported.
Disclosure forms provided by the authors are available with 
the full text of this article at NEJM.org.
We thank all the study participants for their willingness to 
advance medical science in the field of COPD, Drs. Nestor M?ller 
and Paola Nasute Fauerbach for their radiologic expertise in the 
assessment of emphysema, and Tara Candido, Sebastian Cogs-
well, Heather Davis, Nima Farzaneh, Lukas Holy, Natasha 
Krowchuk, Helena Lee, Evan Phillips, Claudine Storness-Bliss, 
Nerissa Tai, Anh-Toan Tran, Nghia Tran, Eugene Wang, and To-
monori Yokogawa for technical assistance with the CT analysis 
and data management.
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