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.
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