Do you want to buy antibiotics online without prescription? http://buyantibiotics24h.com/ - This is pharmacy online for you!
Assessment of progression of COPD: report of a workshop
held in Leuven, 11–12 March 2004M Decramer, R Gosselink, M Rutten-Van Mo¨lken, J Buffels, O Van Schayck, P-A Gevenois,
R Pellegrino, E Derom, W De Backer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thorax 2005;60:335–342. doi: 10.1136/thx.2004.028712
Recently performed long term trials have enhanced the
as the population at the end of the trial is no
insight into the assessment of progression of COPD. The
longer representative of the population at thebeginning. Furthermore, drop out in the major
present review focuses on the initial assessment of COPD in COPD trials is not completely random, but is atgeneral practice and the assessment of disease
random or informative, with the worst patients
progression. Several variables may be used to assess this
dropping out earlier than the better ones.19 Dropout is also greater in the placebo group than in
progression, all of which are associated with significant
the active treatment group, and patients drop-
methodological problems. Finding the appropriate mix of
ping out from the active treatment group are
outcome measures to capture all aspects of disease
usually better than those dropping out of theplacebo group. The combination of these factors
progression is a significant challenge.
poses an important methodological problem and
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
calls for more sophisticated statistical models.
The purpose of the present review is to address
the challenges of assessing the natural course of
During the last decade insight into the COPD from the perspective of what is known
natural course of chronic obstructive pul-
from the large long term trials conducted to date.
We will first address the current view on the
siderably. This insight largely stems from four
assessment of incipient COPD and then consider
large scale and long term studies on the effects of
the assessment of the progression of COPD.
inhaled corticosteroids,1–4 large scale 1 year stu-dies with tiotropium,5 6 and with the combina-tion of long acting b
corticosteroids.7 8 These studies have unravelled
a number of methodological problems associated
It is clear that COPD cannot be diagnosed on the
with large scale long term studies and have
basis of symptoms alone. In general, symptoms
enhanced insight into the phenotype. In addi-
tion, other studies have enhanced our knowledge
Although a large fraction of patients with
of how to diagnose the disease in the early
COPD have symptoms of cough, sputum and/or
stages.9–11 The diagnosis of COPD has also been
dyspnoea, the diagnosis requires demonstration
modified to a significant extent by the recent
of not fully reversible airflow obstruction and,
GOLD guidelines.12 Although, classically, COPD
has been defined as a disease associated with
COPD has been defined in different ways. The
largely irreversible airflow obstruction, it has
European Respiratory Society (ERS) definition
become increasingly clear that up to 40% of
states that COPD is characterised by airflow
patients with COPD show significant reversibil-
obstruction that is irreversible.20 The more recent
ity, particularly in terms of vital capacity or
GOLD guidelines12 define COPD as a disease with
inspiratory capacity.13–15 It therefore appears
airflow obstruction that is not fully reversible.
more appropriate to define COPD as ‘‘not fully
The latter is presently considered as the most
reversible airflow obstruction’’ rather than ‘‘irre-
adequate. Airflow obstruction should always be
versible airflow obstruction’’, as in the GOLD
documented with spirometric tests showing a
decrease in the FEV1/FVC ratio below the 5thpercentile21 or below 70%.12 Whether this latter
progression of COPD besides the classical annual
definition of airflow obstruction is also adequate
. . . . . . . . . . . . . . . . . . . . . . .
for an elderly population remains a matter of
decline in forced expiratory volume in 1 second
debate.10 In a few patients, however, airflow
(FEV1) have become available.16–18 These new
obstruction may occur with a decrease in FEV
methods may facilitate future long term studies
a similar extent to vital capacity (VC) so that
although this is not yet certain. Moreover,
their ratio remains normal.21 Under these condi-
significant methodological problems with long
tions, a normal total lung capacity (TLC) is the
term studies have become apparent. Firstly, in
most long term studies drop out is important,
ranging from 25% to 53% over 3 years. This not
Abbreviations: COPD, chronic obstructive pulmonary
only causes important problems regarding the
FVC, forced vital capacity; MCID, minimal clinically
important difference; 6MWD, 6 minute walking distance;
between treatment groups, but also creates a
QoL, quality of life; DVO2max, change in maximal oxygen
. . . . . . . . . . . . . . . . . . . . . . .
significant problem for the analysis of the results
consumption; DWmax, change in maximal work load
Decramer, Gosselink, Rutten-Van Mo¨lken, et al
only parameter capable of differentiating obstruction from
Table 1 Annual decline in FEV1 in ml/year versus mean
restriction. Moreover, a large fraction of patients do not
(SD) FEV1 in ml: the accuracy of the mean FEV1
report or clearly underreport symptoms.22 Most patients in
the earlier stages of GOLD I and II are likely to be treated ingeneral practice rather than in hospital.
Is the GP able to establish this diagnosis? We found no
clearcut answer to this question in the literature. While there
is little doubt about the role of spirometric testing in the GP
surgery in detecting COPD, there is little evidence that it is
sufficiently accurate for diagnostic and staging purposes.
One study in Australia showed that GPs performed poorly in
spirometric testing even after instruction.23 Indeed, only 35%
of the tracings generated by GPs who attended an intro-
ductory workshop on spirometry reached the American
Thoracic Society (ATS) acceptability criteria; for those whodid not attend the workshop, only 16% of the tracings theygenerated reached these acceptability criteria. The majorproblem appeared to be failure to reach the end of test
need to range from at least 200–800 for 80% power and a
criteria. This was in line with other studies performed in
significance level of 5%, which are minimal requirements.
general practice.24 25 More recent studies, however, have
The standard deviations given pertain to at least 3 years
shown a substantially better performance by GPs.9 26 The
follow up and four measurements per year, which appears to
latter study reported an equal amount of non-reproducible
tests (16–18%) in general practice as in a regular pulmonary
Secondly, due to the limits of the accuracy and precision by
function laboratory. This may be due in part to the
which FEV1 can be measured, a follow up of at least 3 years is
involvement of practice assistants trained with a 5 hour
required to estimate the decline in FEV1. Indeed, if we
course in spirometric testing. More research is needed on the
assume a mean FEV1 of 1.60 l, then—given an accuracy of
role of these practice assistants in improving the performance
5%—the minimal volume that can be measured accurately
of spirometric tests in general practice.
would be 80 ml. Table 1 shows the annual decline and the
A recent study advocated the use of peak flow rate
mean (SD) FEV1 measured in the major studies. As can be
measurements in the diagnosis of COPD.27 This study showed
seen, the annual decline is clearly below the accuracy of the
that a peak flow rate of less than 80% had a sensitivity of 91%
mean FEV1 measurement in these trials. Given an annual
and a specificity of 82% in detecting COPD. This sensitivity
decline of 30–60 ml/year, clearly more than 2 years is needed
was even greater for patients with moderate to severe disease.
to have differences that exceed the accuracy limits of
However, with a positive predictive value of 30%, peak flow
spirometry. Because of this long term follow up, drop out
measurement is clearly insufficient for diagnostic purposes.
of patients will be important, ranging from 25% to 50%.
In addition, the study was a retrospective subgroup analysis
Table 2 shows the drop out rates in the placebo and active
which may limit its value. A complete flow-volume loop is an
treatment groups in recently published major studies.
important diagnostic element in the diagnosis of COPD
Because of the high requirements for accuracy and precision,
because incipient obstruction is primarily localised in the
concerted efforts were made in most trials to reduce
small airways and does not markedly affect the peak
variability of spirometric testing as much as possible. A
expiratory flow rate (see above).28 One study suggested that
number of measures were used to this end—for example,
patients with mild to moderate COPD may be reluctant to be
limiting the number of centres;31 training sessions for
referred to a pulmonologist. In this study GPs performed
pulmonary function technicians;1 3 33 use of an identical
3209 spirometric tests in patients at risk and found 723 new
spirometer in all centres;1 3 measurements always at the
cases of probable COPD (23%). Only 278 of these subjects
same time of the day to avoid diurnal variation;1 33 measure-
(39%) agreed to consult a pulmonologist.29 Whether this is a
ments after administration of a standardised dose of
generalised problem remains to be studied.
Thirdly, the drop out rate in long term studies is usually
ASSESSMENT OF DISEASE PROGRESSION OF COPD
large (table 2) and is not completely at random.19 Indeed, the
worst patients drop out first so that the population at the end
of the trial is very different from the intention to treat
assessing the progression of COPD for several decades.30 In
population. Since baseline characteristics of future drop outs
normal subjects the annual decline amounts to 20–30 ml/
are usually different from those who complete the study, it is
year compared with an average of 60 ml/year in patients with
possible to correct for this differential drop out by using
COPD.31 In the 1990s several randomised controlled studies
mixed effect models taking the baseline characteristics as
on the effects of inhaled steroids were conducted with the
covariates. If, however, this drop out is informative,19 34 then
correction is not really possible. Informative drop out is
largely building on the design of the Lung Health Study I.31 In
defined as drop out that is not predictable from other
these studies the annual decline ranged from 42 ml to 69 ml
measurements observed but depends on the unobserved
measurements—that is, those measurements that would
The problems with measuring the annual decline in FEV
have been observed if the patient would not have dropped out
are essentially threefold. Firstly, the variability in the annual
from the study. Since in most studies conducted so far drop
decline is large which has been known ever since the first
out is greater in the placebo group than in the active
publication.30 In the published studies the SD of the decline
treatment group (table 2), it is also important to use all
ranges from 58 ml/year in the Lung Health Study4 to over
available data from those completing the study and from
75 ml/year in ISOLDE3 and to 100 ml in EUROSCOP.1 Given
drop outs in the analysis and to use a mode of analysis that
that published studies assume arbitrarily that a difference in
takes this factor into account. When this is taken into
annual decline of 20 ml/year1–3 would be clinically significant,
account, the above calculated sample size would need to
the sample size of the patients completing the study would
range between 1000 and 1500 patients at least. This means
Table 2 Drop out rate (%) in the active and placebo groups in major COPD studies
that, for most long term studies, the sample size is just at or
(47) m/year compared with a decline of 21 (31) m/year in
below this limit (table 2). It should be noted that such a
those who survived. This study also showed that the 6MWD
study would then still only be minimally powered for the
and its decline appeared to be an independent and possibly a
primary outcome variable. If subgroup analysis is under-
better predictor of survival than FEV1.37
taken, substantially more patients would be needed.
Data obtained from trials designed to assess the effects of
Although in the last decades measurement of the decline in
pulmonary rehabilitation programmes or lung volume
FEV1 has been the standard measure of disease progression
reduction surgery in COPD confirm that the decline in
of COPD, there is little supportive evidence to show that it is
exercise tolerance is a fact and may be even more pronounced
the best measure. Given the limitations associated with the
than was previously thought. These are summarised in
pathophysiology of airflow obstruction outlined recently,13–15
table 3. The data presented in long term studies should be
it may reflect more loss of elastic recoil and loss of
interpreted with caution. Indeed, the ‘‘survival of the fittest’’
interdependence between airway and lung parenchyma than
generally tends to underestimate the decline, since patients
airway obstruction. Relatively few data are available on
exhibiting lower initial values or a more rapid decline tend to
decline in VC, inspiratory capacity (IC), or transfer factor.
die at an earlier time point (drop out not completely atrandom, see above). This might eventually result in an
overestimation of ‘‘mean’’ exercise tolerance after 1 or
The use of CT scans to assess the progression of COPD has
been limited to date.18 In the study by Dirksen et al18 the
In two studies substantial decreases in walking distance
variance in the progression of COPD estimated by CT
occurred over 12 months38 and 18 months39 in the patients
scanning was considerably smaller than with the decline in
with COPD who were not randomised to participate in a
FEV1. This is promising as it would allow studies on the
rehabilitation programme. Interestingly, exercise tolerance of
progression of COPD to be performed with considerably fewer
rehabilitated patients did not deteriorate in these studies.
patients. We await the confirmation of these results by
Surprisingly, exercise tolerance over 24 months did remain
stable in the control group of a third long term follow up
study.40 The reason for this discrepancy is unclear but mighthave been caused by differences in the degree of severity of
Over the past decade the decline in FEV1 as a function of time
COPD or a less liberal use of oral corticosteroids.
has been used as a marker for the natural history of COPD
Pulmonary rehabilitation does, however, not always
and as an outcome measurement to document the efficacy of
‘‘protect’’ against progressive decline in exercise tolerance.
therapeutic interventions such as smoking cessation (see
Indeed, a substantial decline has been reported in patients
above). Although COPD is, by definition, characterised byairflow obstruction, it is now increasingly regarded as a
after rehabilitation in two recently published studies. First,
systemic disease.35 The hormonal, metabolic, and musculo-
control patients included in the NETT trial, who followed a 6–
skeletal implications of the systemic effects of COPD
10 week rehabilitation program but did not undergo surgery,
involving oxidative stress, inflammatory mediators, cyto-
exhibited a substantial decline in FEV1 and in maximal work
kines, and endocrine hormones result in loss of body weight,
load over the 24 month follow up period.41 Decreases up to
osteoporosis, skeletal muscle dysfunction and wasting. One
20 Watts or more were observed in 57%, 59%, and 90% of the
of the markers of the systemic effects of COPD is the decrease
patients 6, 12, and 24 months after the end of the
in exercise capacity which results from an interaction
rehabilitation programme, respectively. These findings are
between decline in pulmonary function and some of the
in line with those of Ries et al42 who investigated the effects of
extrapulmonary effects of COPD such as cardiovascular
a maintenance treatment on the long term effects of an
impairment, skeletal muscle weakness, and alteration in
8 week pulmonary rehabilitation programme in COPD in a
body composition. It is increasingly clear that some markers
controlled study. A significant decline over time was observed
may have important effects on prognosis.36
in both groups. In the control group 6MWD fell by 44 m and
The decline in exercise tolerance over years has only
maximal oxygen consumption by 130 ml/min over the
recently been systematically assessed in patients with
24 month follow up period, whereas FEV1 decreased by only
COPD.37 In this study, 198 patients with COPD and 41 age
70 ml over the same period.42 It thus appears that decline in
matched controls were followed for 2 years. The 6 minute
exercise tolerance is not infrequently encountered in patients
walking distance (6MWD) decreased in the COPD group
with severe COPD (table 3), and that only rehabilitation
from 238 (107) m to 218 (112) m. In patients who died
programmes exceeding 3 months in duration are able to
within 2 years the mean decline in 6MWD averaged 40
prevent this decline to a certain extent.
Decramer, Gosselink, Rutten-Van Mo¨lken, et al
Table 3 Decline in exercise tolerance in patients with COPD
FEV1, initial FEV1 in litres or percentage predicted; follow up, duration of period over which exercise tolerance was assessed; D 6MWD, change in 6 minutewalking distance in metres over the respective follow up period; D shuttle test, change in shuttle distance in metres over the respective follow up period; DWmaxand DVO2max, change in maximal work load and oxygen consumption over the respective follow up period.
this increased frequency might be associated with an
It is well established that health status and health related
accelerated decline in quality of life.52 The centrality of
quality of life—terms which will be used interchangeably
exacerbations in the patients’ lives is illustrated in a
here—do not correlate strongly with lung function para-
qualitative study in which patients told a number of near
meters like FEV1.43–45 This would suggest that the same
death stories that described severe exacerbations as life
physiological limitation may affect quality of life of COPD
changing.53 COPD patients with higher exacerbation rates are
patients differently, and it justifies the use of quality of life
reported to have a poorer quality of life than those with lower
outcomes in addition to clinical outcomes. Although the
exacerbation rates.54 The impact of an exacerbation on quality
degree of association is not strong, there is a clear association
of life may be considerably longer than just a temporary
between the two outcomes when a wider range of FEV1 %
impairment of quality of life. In a study that evaluated the
predicted is considered.46 Quality of life has also been shown
time course of recovery of health status after an exacerbation
to be related to exercise performance,16 healthcare utilisa-
treated with antibiotics, it was shown that SGRQ scores
continued to improve up to 26 weeks after the initial
Cross sectional studies have shown that quality of life
exacerbation that marked the end of the observation period.17
deteriorates as lung function declines. In the early stages of
The greatest improvement was seen during the first 4 weeks,
COPD the decline in lung function might go unnoticed and
but improvements during the second and third month were
might not affect quality of life. In a cross sectional study in
still above the 4 units considered to be clinically relevant.
COPD patients aged .64 years the progression of COPD from
When patients had a further exacerbation within the
GOLD stages 0 to III did not correspond to a statistically
6 months after the initial exacerbation, health status did
significant difference in health status.46 However, an FEV1 of
not improve much. These results are in line with those of
50% predicted or less seemed to mark a threshold below
Seemungal et al55 who reported that, 91 days after the onset
which the St George Respiratory Questionnaire (SGRQ) total
of an exacerbation, peak expiratory flow rates and symptoms
and impact score became clearly impaired.46 This association
had not fully recovered in about 7% and 5% of exacerbations,
between GOLD stage and SGRQ score was found after
correction for differences in age, sex, living conditions, waste/
In 1 year or shorter term trials quality of life after
hip ratio, occiput wall distance, and number of co-morbid-
treatment often improved, even in the placebo group.7 8
ities, all variables that are related to quality of life. However,
This makes reduction in the declining quality of life a useless
the variability in health status scores within a GOLD stage
end point in these short term trials. A more relevant outcome
in short term trials might be the proportion of patients
The ISOLDE study was the first prospective study to show
reaching improvement beyond the minimal clinically impor-
that COPD related quality of life deteriorated linearly over a
tant difference (MCID).56 The concept of MCID was
3 year period.17 As a result, reducing the decline in quality of
introduced to improve the potential use of information
life might become an informative end point in future longterm trials. The ISOLDE study showed that the SGRQ total
provided by quality of life instruments.56 This is important
score worsened by 3.2 units per year in the placebo group
in order to distinguish statistically significant effects from
compared with 2.0 units per year in the fluticasone
clinically relevant effects, because small but clinically
propionate group—a statistically significant reduction in the
irrelevant effects can be statistically significant when the
rate of deterioration of 37%. However, in the BRONCUS trial,
sample size is sufficiently large. Further work on the
which included less severe COPD patients, the SGRQ total
interpretability of scores and changes in scores is necessary.
score worsened only by approximately 1.3–1.5 units a year in
This includes further work on the association between the
both the placebo and active treatment group during the last
MCID and the severity of COPD. It also includes a stronger
2 years of the trial after an initial improvement in the first
foundation for the interpretation of the MCID using external
year.33 51 The difference between the two trials is perhaps
reference measures of clinically relevant change such as the
related to the fact that lung function was optimised with a
occurrence of exacerbations or the use of healthcare services
course of oral prednisolone before the patients were
like hospital admissions. The proportion of patients improv-
randomised into the ISOLDE trial, which was not the case
ing by at least the MCID has become an increasingly used end
before the start of the BRONCUS trial. Whether the decline in
point in addition to the mean change in scores, because it can
quality of life accelerates when lung function worsens is not
easily be related to costs in order to report the cost
yet clear. In the ISOLDE trial a weak but significant
effectiveness ratio (‘‘costs per additional patient with
improved quality of life’’).57–60 In addition to the proportion
quality of life was only found for the SGRQ impact score.17
of improved patients, it is important to report the proportion
It has recently been shown that a reduction in the decline
showing deterioration greater than or equal to the MCID.
in quality of life might be causally related to a reduction in
Because of the natural decline in quality of life, the
the number of exacerbations.52 As COPD worsens the
proportion of patients reaching at least the MCID is not a
frequency and severity of exacerbations might increase, and
useful end point in long term studies.
Most long term clinical drug trials and many methodolo-
necessary when initial outpatient treatment has failed.
gical studies on quality of life in COPD have used the SGRQ.
Failure rates of 12–21% have been reported.75 78 The Spanish
In addition to this questionnaire, several other reliable and
study by Miravittles et al78 estimated the costs associated with
valid disease specific quality of life measures such as the
treatment failure to be eight times higher than the average
Chronic Respiratory Disease Questionnaire (CRQ) and the
cost of a successfully treated exacerbation. Estimates of the
costs of exacerbations vary from $US160 in a German study
(QoLRIQ) have proved to be sensitive to changes in quality
to $US797 in a Dutch study (price level 2002)*.76–81 Costs rise
of life that result from treatments including pharmacother-
with the severity of the exacerbation,77 80 81 with the Dutch
apy.61–63 The CRQ is a little different in that its original version
study reporting that the mean costs of severe exacerbations
includes an individualised dyspnoea domain. This means
were seven times the costs of moderate exacerbations and 47
that, at baseline, patients identify five important daily
activities and report their degree of dyspnoea on these same
It is obvious that the potential for cost savings is largest for
five activities at baseline and during follow up visits. This was
treatments that slow down disease progression, prevent
done to improve the instrument’s responsiveness. Since then,
exacerbations, and treat exacerbations effectively. From an
there has been an ongoing debate about the lack of
economic perspective, it is most efficient to target the new
standardisation, the limited comparability of CRQ scores,
and increasingly expensive treatments to the group of COPD
and the difficulty in eliciting activities that patients perform
patients who are at increased risk of being admitted to
regularly to allow evaluation at repeated measurements. In a
hospital for an exacerbation. It is therefore necessary to
head-to-head comparison of the individualised and standar-
identify the risk factors of hospitalisation. A large number of
dised approach it was recently shown that the individualised
potential risk factors for exacerbations and hospital admis-
approach was more responsive to change, which has
sions have been identified in the literature including:
important consequences for reducing the required samplesize.64 Moreover, while the SGRQ is the most widely used
scale for health quality of life, it is still doubtful whether its
N number, type and severity of co-morbidities;
complexity allows incorporation in daily practice. If decline in
health status is to be assessed as an outcome measure in
N history of high healthcare resource use;
routine care for COPD, there is a need for a simple but reliable
Especially when designing long term studies with many
repeated measurements of quality of life, it is important to
N being a smoker and number of pack-years;
note that several mechanisms that have been addressed by
the term ‘‘response shift’’ might prevent instruments from
detecting an objective deterioration or improvement in
quality of life.65 Patients may recalibrate the measurement
degree of dyspnoea and other symptoms of COPD;
continuum or scale back their reference point against which
N impaired health status/quality of life;
their current health is compared. Hence, the quality of life
scale no longer has the same psychological anchors as before.
Patients may change their opinion about the relativeimportance of the aspects of quality of life or may redefine
These predictors are not mutually exclusive but may be
or reconceptualise quality of life. All these processes are
phenomena of normal adaptive self-regulation that might
Table 4 gives an overview of the cost of improving one
seriously affect changes in self-reported quality of life scores
additional patient’s quality of life as reported in some
economic evaluations. Even though the studies use differentquality of life instruments, a table like this might provide a
Increase in healthcare utilisation and costs
general impression of the relative cost effectiveness of these
In a review paper on the economic aspects of COPD the
medical care costs per COPD patient in 2000 were reported to
Prospective economic evaluations usually present the
vary from $US930 in Sweden to $US2631 in the UK.66 It has
proportion of patients using a particular type of healthcare
been estimated that the annual costs per COPD patient are
service and the mean healthcare utilisation and costs per
approximately three times the costs of asthma.67 68 Several
patient per year. Statistical tests of the differences between
cross sectional studies have shown a strong association
treatments in the use and costs of separate types of
between the increase in healthcare resource utilisation and
healthcare services should be interpreted with care as
the progression of COPD.69–72 Costs are disproportionately
substitution effects are common. A treatment that reduces
distributed. A relatively small proportion of severely ill
the number of hospital days may increase the number of
patients with COPD are responsible for a substantial share
physician visits. Showing that an intervention reduces the
of the total healthcare costs of COPD patients.67 73 74 COPD
use of healthcare services, especially hospital admissions,
patients with co-morbidities are particularly costly and the
requires large sample sizes as the mean annual number of
Confronting COPD Study has estimated that patients with
admissions is low in patients with stable COPD at study entry
co-morbidities account for 30–57% of the COPD population.72
(between 0.11 and 0.24 per patient per year).51 61
Hospital admissions and medications are the two major cost
In addition to testing whether differences in costs are
drivers,66–74 but which of the two ranks first depends on the
statistically significant, the aim of every economic evaluation
severity of COPD and the country or region under considera-
is to obtain an unbiased estimate of the magnitude of this
difference. This is particularly challenging because of the
Unscheduled care is the major portion of the direct medical
combined occurrence of a few characteristics that are typical
costs. Exacerbations are a key driver of the costs ofunscheduled care. In severe COPD, exacerbations are more
* Costs were converted to 2002 $US using harmonised indices of
frequent75 and the severity of the exacerbation itself is also
consumer prices published by EUROSTAT to correct for inflation and
related to the underlying severity of the disease.76 77
purchasing power parities as published by OECD to convert national
Admission to hospital for a COPD exacerbation may become
Decramer, Gosselink, Rutten-Van Mo¨lken, et al
Table 4 Costs per additional patient with relevant improvement in quality of life
Costs per additionalpatient with improved
(44% MDI/56% DPI)60Salmeterol v placebo59
v placebo58Detection+early treatment with
fluticasone v placebo58Rehabilitation (2 months inpatient
MCID, minimal clinically important difference; MDI, metered dose inhaler; DPI, dry powder inhaler; QoL, quality oflife; SGRQ, St George’s Respiratory Questionnaire; CRQ, Chronic Respiratory Questionnaire.61–64
for cost data.82 Firstly, the variable of interest in cost analysis
data to the local setting should be pre-specified in the
is the cumulative cost over a certain time period whereas
statistical analysis plan of an economic evaluation.
clinical and quality of life data are often measured at several
An alternative or, even better, an addition to the empirical
points in time. Secondly, costs tend to vary widely over time
economic evaluations is modelling the cost effectiveness.
within one patient. A patient who is being hospitalised during
Models can be populated with different country-specific
time interval t will have very high costs over this interval
treatment patterns and costs and they can be used to
while costs over t21 and t+1 can be very low. Thirdly,
extrapolate trial results to a longer time horizon and include
resource use data are usually characterised by severe
quality adjusted survival. In particular, stochastic models that
skewness of the underlying frequency distribution—that is,
address the uncertainty surrounding model based cost
a few patients will have very high costs and the majority of
patients will have limited costs. The most costly patients areusually the most severely ill patients who are most likely to
drop out from a clinical trial, especially from a placebo
Recently conducted long term trials have contributed sub-
control group. In statistical terminology, drop out is not
stantially to our insight into the progression of COPD. The
‘‘completely at random’’ but either ‘‘at random’’ or ‘‘infor-
main methods used are annual decline in FEV
mative’’.19 82 It is important to stress that these types of drop
functional and exercise capacity, decline in health status, and
out complicate both the clinical analyses and the economic
use of healthcare resources. Each of these variables is
analyses. Instead of ignoring the problem and not reporting
associated with significant problems that are largely related
the nature of the drop out or the methods that have been
to selective drop out occurring in long term studies. This puts
used to estimate the costs of drop outs, there are now so-
a particular burden on the statistical analysis and may
called principled methods of imputation available that
require the use of more sophisticated models of analysis.
outperform the naı¨ve methods such as complete caseanalysis, linear extrapolation, last value carried forward,
and others. ‘‘Outperforming’’ means that they produce a less
The authors acknowledge the expert secretarial assistance of Mrs C
biased estimate of the mean costs and a more accurate
Ausseloos, Mrs E Lahousse, and Mrs A Vandeborne.
estimate of the uncertainty around the mean.83 One of theseprincipled methods—multiple imputation using propensity
. . . . . . . . . . . . . . . . . . . . .
scores—has recently been applied in the cost effectiveness
study of tiotropium versus ipratropium.60 In a separate paper
M Decramer, R Gosselink, Respiratory Division, University Hospital,
on the same study, the impact of different imputation
Katholieke Universiteit Leuven, 3000 Leuven, Belgium
methods on the cost estimates was shown.84
M Rutten-Van Mo¨lken, Institute for Medical Technology Assessment,
In multinational economic evaluations the challenge of
Erasmus Medical Centre Rotterdam, The Netherlands
estimating cost effectiveness is even greater as it is far more
J Buffels, Department of General Practice, Katholieke UniversiteitLeuven, 3000 Leuven, Belgium
difficult to transfer costs between countries than to transfer
O V Schayck, Department of General Practice, University of Maastricht,
clinical data. The pure biological effect of a drug can be
expected to be the same, irrespective of the country, but
P-A Gevenois, Department of Radiology, Erasme University Hospital,
resource use and cost data are setting specific. They depend
on local treatment patterns, which may be influenced by
R Pellegrino, Centro di Fisiopatologia Respiratoria e dello Studio della
culture and traditions, the structure of the healthcare system,
Dispnea, Azienda Ospedaliera S Croce e Carle, 12100 Cuneo, Italy
financial and other incentives.85 Differences in absolute prices
E Derom, Department of Respiratory Diseases, University of Ghent,
and, more importantly, relative prices may cause the cost
effectiveness of a treatment to differ from country to country.
W D Backer, Department of Pulmonary Disease, University of Antwerp,
As a consequence, simply pooling data from different
countries without any adaptation of the data to the local
This workshop was supported by GlaxoSmithKline-Belgium.
setting or any testing of whether the effect of the treatmenton resource utilisation is the same across countries is
theoretically not sound. However, it is often unavoidable as
1 Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled
the trials usually lack statistical power to do separate
budesonide in persons with mild chronic obstructive pulmonary disease who
analyses per country and the adaptation of the resource use
continue smoking. N Engl J Med 1999;340:1948–53.
2 Vestbo J, Sørensen T, Lange P, et al. Long-term effect of inhaled budesonide in
33 Decramer M, Dekhuijzen PNR, Troosters T, et al. and the BRONCUS trial
mild and moderate chronic obstructive pulmonary disease: a randomised
committee. The bronchitis randomised on NAC cost-utility study (BRONCUS):
controlled trial. Lancet 1999;353:1819–23.
hypothesis and design, Eur Respir J 2001;17:329–36.
3 Burge PS, Calverley PMA, Jones PW, on behalf of the ISOLDE study
34 Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis.
investigators, et al. Randomised, double blind, placebo controlled study of
fluticasone propionate in patients with moderate to severe chronic obstructive
35 Andreassen H, Vestbo J. Chronic obstructive pulmonary disease as a systemic
pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–303.
disease: an epidemiological perspective. Eur Respir J 2003;46(Suppl.):2s–4s.
4 The Lung Health Study Research Group. Effect of inhaled triamcinolone on the
36 Marquis K, Debigare R, Lacasse Y, et al. Mid thigh muscle cross-sectional
decline in pulmonary function in chronic obstructive pulmonary disease.
area is a better predictor of mortality than body mass index in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
5 Vincken W, van Noord JA, Greefhorst APM, et al. Improved health outcomes
in patients with COPD during 1 year’s treatment with tiotropium. Eur Respir J
37 Pinto-Plata VM, Cote C, Cabral H, et al. The 6-min walk distance: change
over time and value as a predictor of survival in severe COPD. Eur Respir J
6 Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily
titropium in chronic obstructive pulmonary disease. Eur Respir J
38 Bestall JC, Paul EA, Garrod R, et al. Longitudinal trends in exercise capacity
and health status after pulmonary rehabilitation in patients with COPD. Respir
7 Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/
formoterol in the management of chronic obstructive pulmonary disease. Eur
39 Troosters T, Gosselink R, Decramer M. Long-term effects of outpatient
rehabilitation of COPD. A randomized trial. Am J Med 2000;109:207–12.
8 Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone
40 Gu¨ell R, Casan P, Belda J, et al. Long-term effects of outpatient rehabilitation
in the treatment of chronic obstructive pulmonary disease: a randomised
of COPD: a randomized trial. Chest 2000;117:976–83.
controlled trial. Lancet 2003;361:449–56.
41 National Emphysema Treatment Trials Research Group. A randomized trial
9 Buffels J, De Gryse J, Heyrman J, et al. Office spirometry significantly
comparing lung volume reduction surgery with medical therapy for severe
improves early detection of COPD in general practice. The DIDASCO study.
emphysema. N Engl J Med 2003;348:2059–73.
42 Ries AL, Kaplan RM, Myers R, et al. Maintenance after pulmonary
10 Lundba¨ck B, Lindberg A, Lindstro¨m M, et al. Not 15% but 50% of smokers
rehabilitation in chronic lung disease: a randomized trial. Am J Respir Crit
develop COPD? Report from the Obstructive Lung Disease in Northern
Sweden studies. Respir Med 2002;97:115–22.
43 Ferrer M, Alonso J, Prieto L, et al. Validity and reliability of the St George’s
11 Zielinski J, Bednarek M, et al. Early detection in a high-risk population using
Respiratory Questionnaire after adaptation to a different language and
spirometric screening, Chest 2001;119:731–6.
culture: the Spanish example. Eur Respir J 1996;9:1160–6.
12 Pauwels R, Buist A, Calverley P, on behalf of the GOLD Scientific Committee,
44 Hajiro T, Nishimura K, Tsukino M, et al. Comparison of discriminative
et al. Global strategy for the diagnosis, management, and prevention of
properties among disease-specific questionnaires for measuring health-
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
related quality of life in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1998;158:1185–9.
13 O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung
45 Rutten-van Mo¨lken MPMH, Roos B, Van Noord JA. An empirical comparison
hyperinflation and endurance during exercise in chronic obstructive
of the St Georges Respiratory Questionnaire and the Chronic Respiratory
pulmonary disease. Am J Respir Crit Care Med 1998;158:1557–65.
Questionnaire in a clinical trial setting. Thorax 1999;54:995–1003.
14 Pellegrino R, Rodarte JR, Brusasco V. Assessing the reversibility of airway
46 Antonelli-Inc C, Imperiale V, Bellia F, et al. Do GOLD stages of COPD severity
obstruction. Chest 1998;114:1607–12.
really correspond to differences in health status? Eur Respir J 2003;22:444–9.
15 Newton MF, O’Donnell DE, Forkert L. Response of lung volumes to inhaled
47 Van den Boom G, Rutten-van Mo¨lken MPMH, Tirimanna PRS, et al.
salbutamol in a large population of patients with severe hyperinflation. Chest
Association between health-related quality of life and consultation for
respiratory symptoms: results from the DIMCA programme. Eur Respir J
16 Jones PW, Quirk F, Baveystock CM, et al. A self-complete measure of health
status for chronic airflow limitation. The St George’s Respiratory
48 Alemayehu B, Aubert RE, Feifer RA, et al. Comparative analysis of two
Questionnaire. Am Rev Respir Dis 1992;145:1321–7.
quality-of-life instruments for patients with chronic obstructive pumonary
17 Spencer S, Jones PW and the GLOBE Study Group. Time course of recovery of
disease. Value Health 2002;5:436–41.
health status following an infective exacerbation of chronic bronchitis. Thorax
49 Fan V, Curtis JR, MacDowell M, et al. Using quality of life to predict
hospitalizations and death in chronic obstructive lung disease. Chest
18 Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha1-
antitrypsin augmentation therapy. Am J Respir Crit Care Med
50 Domingo-Salvany A, Lamarca R, Ferrer M, et al. Health-related quality of life
and mortality in male patients with chronic obstructive pulmonary disease.
19 Little RJA, Rubin DA. Statistical analysis with missing data. New York: John
Am J Respir Crit Care Med 2002;166:680–5.
51 Decramer M, Rutten-van Mo¨lken MPMH, Dekhuijzen PNR, et al. Effects of N-
20 Siafakas NMP, Vermeire NB, Pride P, et al. Optimal assessment and
acetyl-cysteine on outcomes in COPD. The Bronchitis Randomized on NAC
management of chronic obstructive pulmonary disease (COPD). The European
Cost-Utility Study (BRONCUS). Lancet 2005 (in press).
Respiratory Society Task Force. Eur Respir J 1995;8:1398–420.
52 Spencer S, Calverley PMA, Burge PS, et al. Impact of preventing
21 Quanjer PH, Tammeling GJ, Cotes JE, et al. Lung volumes and forced
exacerbations on deterioration of health status in COPD. Eur Respir J
ventilatory flows. Report Working Party Standardization of Lung Function
Tests, European Community for Steel and Coal. Official Statement of the
53 Bailey Ph. Death stories: acute exacerbations of chronic obstructive
European Respiratory Society. Eur Respir J 1993;6:5–40.
pulmonary disease. Qual Health Res 2001;11:322–38.
22 Rennard S, Decramer M, Calverley PMA, et al. Impact of COPD in North
54 Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on
America and Europe in 2000: subjects’ perspective of the Confronting COPD
quality of life in patients with chronic obstructive pulmonary disease.
International Survey. Eur Respir J 2002;20:799–805.
Am J Respir Crit Care Med 1998;157:1418–22.
23 Eaton T, Withy S, Garrett JE, et al. Spirometry in primary care practice: the
55 Seemungal TAR, Donaldson GC, Bhowmik A, et al. Time course and recovery
importance of quality assurance and the impact of spirometry workshops.
of exacerbations in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2000;161:1608–13.
24 Mulder HH, vander Molen T, Postma DS, et al. Measuring FEV1 in general
56 Hays RD, Wolley JM. The concept of clinically meaningful difference in health-
related quality-of-life research. How meaningful is it? PharmacoEconomics
25 Ponsioen BP, Hop WCJ, Vermue NA, et al. Characteristics of adults with
persistent cough in general practice. Primary Care Respir J 2000;11:68–9.
57 Goldstein RS, Gort EH, Guyatt GH, et al. Economic analysis of respiratory
26 Shermer TR, Jacobs JE, Chavannes NH, et al. Validity of spirometric testing in
rehabilitation. Chest 1997;112:370–9.
a general practice population of patients with chronic obstructive pulmonary
58 Van den Boom G, Rutten-van Mo¨lken MP, Molema J, et al. The cost
disease (COPD). Thorax 2003;58:861–6.
effectiveness of early treatment with fluticasone propionate 250 micrograms
27 Jackson H, Hubbard R. Detecting chronic obstructive pulmonary disease using
twice a day in subjects with obstructive airway disease: results of the DIMCA
peak flow rate: cross sectional survey. BMJ 2003;327:653.
program. Am J Respir Crit Care Med 2001;164:1057–66.
28 Macklem PT, Thurlbeck WM, Fraser RG. Chronic obstructive disease of small
59 Jones PW, Wilson K, Sondhi S. Cost-effectiveness of salmeterol in patients
airways. Ann Intern Med 1971:167–77.
with chronic obstructive pulmonary disease: an economic evaluation. Respir
29 de Miguel Diez J, Izquierdo Alonso JL, Molina Paris J, et al. Reliability of
chronic obstructive pulmonary disease diagnosis by primary care physicians
60 Oostenbrink JB, Rutten-van Mo¨lken MPMH, Al MJ, et al. One-year cost-
and pneumologists in Spain. Predictive factors. Arch Bronconeumol
effectiveness of tiotropium versus ipratropium to treat chronic obstructive
pulmonary disease. Eur Respir J 2004;23:241–9.
30 Burrows B, Earle RH. Course and prognosis of chronic obstructive lung
61 Jones OW, Bosh TK. Quality of life changes in COPD patients treated with
disease. N Engl J Med 1969;280:397–404.
salmeterol. Am J Respir Crit Care Med 1997;155:1283–9.
31 Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and
62 Mahon JL, Laupacis A, Donner A, et al. Randomised study of n of 1 trials
the use of anticholinergic bronchodilator on the rate of decline of FEV1. The
versus standard practice. BMJ 1996;312:1069–74.
Lung Health Study. JAMA 1994;272:1497–505.
63 Van Stel HF, Maillee AR, Colland VT, et al. Interpretation of change and
32 Dirksen A, Holstein-Rathlou NH, Madsen F, et al. Long-range correlations of
longitudinal validity of the quality of life for respiratory illness questionnaire
serial FEV1 measurements in emphysematous patients and normal subjects.
(QoLRIQ) in inpatient pulmonary rehabilitation. Qual Life Res
Decramer, Gosselink, Rutten-Van Mo¨lken, et al
64 Schunemann HJ, Griffith L, Jaeschke R, et al. A comparison of the original
76 Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations.
Chronic Respiratory Questionnaire with a standardized version. Chest
77 Andersson F, Borg S, Jansson SA, et al. The costs of exacerbations in chronic
65 Carver CS, Scheier MF. Scaling back goals and recalibration of the affect
obstructive pulmonary disease (COPD). Respir Med 2002;96:700–8.
system are processes in normal adaptive self-regulation: understanding
78 Miravitles M, Murio C, Guerro T, et al. Pharmacoeconomic evaluation of
‘response shift’ phenomena. Soc Sci Med 2000;50:1715–22.
acute exacerbatios of chronic bronchitis and COPD. Chest
66 Ruchlin HS, Dasbach EJ. An economic overview of chronic obstructive
pulmonary disease. PharmacoEconomics 2001;19:623–42.
79 Pechevis M, Fagnani F, Brin S, et al. Infections respiratoires re´cidivantes du
67 Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest
sujet atteint de bronchite chronique obstructive: prise en charge me´dicale et
couˆts. Rev Mal Resp 1996;13:507–12.
68 Rutten-van Mo¨lken MPMH, Postma MJ, Jore MA, et al. Current and future
80 Rychlik R, Pfeil T, Daniel D, et al. Socioeconomic relevance of acute
health care impact of asthma and COPD in The Netherlands. Respir Med
exacerbations of chronic bronchitis in the Federal Republic of Germany.
A prospective cost of illness study. Dtsch Med Wochenschr
69 Hilleman DE, Dewan N, Malesker M, et al. Pharmacoeconomic evaluation of
chronic obstructive pulmonary disease. Chest 2000;118:1278–85.
81 Oostenbrink JB, Rutten-van Mo¨lken MPMH. Resource use and risk factors of
70 Jansson SA, Andersson F, Borg S, et al. Costs of COPD in Sweden according
high cost exacerbations. Respir Med 2004;98:883–91.
to disease severity. Chest 2002;122:1994–2002.
82 Rubin D, Schenker N. Multiple imputation in healthcare databases: an
71 Miravitlles M, Murio C, Guerrero T, on behalf of the DAFNE Study Group, et
overview and some applications. Stat Med 1991;10:595–8.
al. Costs of chronic bronchitis and COPD. A 1-year follow-up study. Chest
83 Oostenbrink JB, Al MJ. The analysis of incomplete cost data due to dropout.
72 Wouters EFM. Economic analysis of the Confronting COPD survey: an
84 Oostenbrink JB, Al MJ, Rutten-van Mo¨lken MPMH. Methods to analyse cost
overview of results. Respir Med 2003;97(Suppl C):S3–14.
data ofpatients who withdraw in a clinical trial setting. PharmacoEconomics
73 Grasso ME, Weller WE, Shaffer TJ, et al. Capitation, managed care, and
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
85 Drummond M, Pang F. Transferability of economic evaluation results.
In: Drummond M, McGuire A, eds. Economic evaluation in health care.
74 Strassels SA, Smith DH, Sullivan SD, et al. The costs of treating COPD in the
Merging theory with practice. Oxford: Oxford University Press,
United States. Chest 2001;119:344–52.
75 Dewan NA, Fafique S, Kanwar B, et al. Acute exacerbations of COPD: factors
86 Briggs AH. Handling uncertainty in cost-effectiveness models.
associated with poor treatment outcome. Chest 2000;117:662–71.
10th European Forum on Quality Improvement in Health Care13–15 April 2005, ExCel Conference Centre, LondonFor further information on how to register please go to:http://www.quality.bmjpg.com
Scientific publications by Dr. Leif LaaksonenJ.P. Desclaux, L. Laaksonen and P. Pyykkö: Finite-difference Dirac-Fock calculations of electric dipole polarizabilities for (ns)1 and (ns)2 atoms. J. Phys. B: At. Mol. Phys.14 (1981) 419. R.G. Egdell, M. Hotokka, L. Laaksonen, P. Pyykkö and J.G. Snijders: Photoelectron spectra and their relativistic interpretation for gaseous bismuth trihalides.
GATES CACTUS & SUCCULENT SOCIETY Cactaceae Azetekium, Epithelantha, Geohintonia, Pelecyphora Ferocactus, Hamatocactus, Leuchtenbergia Eriosyce,under 5” (incl. Neoporteria, Neochilenea) Eriosyce, over 5” (incl. Neoporteria, Neochilenea) Parodia- hooked spines (incl. Notocactus) Parodia- w/o hooked spines (incl. Notocactus) Collections, 5 to 12 plants (triple points) CRASSU