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Introduction |
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 TOP Introduction Epidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Chronic obstructive pulmonary disease (COPD) threatens an emerging public health crisis. The two major drivers for this are the ageing of the world's population and the impressive, if deplorable, success of the multinational tobacco companies at forcing open world markets. Although the World Health Organization estimates that COPD is the sixth most common cause of death worldwide and that by 2020 it will be the third most common, COPD is also an orphan condition that overwhelmingly affects the poor and has been broadly ignored by scientists and by governments. Although the cost-effectiveness of smoking cessation, pulmonary rehabilitation, and long-term oxygen therapy in the later stages of the disease are all high, there is little active treatment that can currently be offered.
Recently, randomised controlled trials, specifically of inhaled corticosteroids (ICS) in patients with COPD have failed to show any modification of the decline in lung function associated with the disease. Analyses have, however, suggested that these drugs may reduce the number of exacerbations, which are related to quality of life. These findings remain controversial, since in some cases they are based on secondary analyses, have inevitably been carried out in selected populations, the results appear to be sensitive to the design of the trials and confidence intervals are often wide. More recently still, evidence has begun to emerge that the use of ICS and possibly long-acting β2-agonists may also reduce mortality as well as exacerbations in these patients. Exacerbations of COPD, particularly those leading to hospitalisation, are an important cost driver in the healthcare system and may account for three-quarters of the additional costs of a patient with COPD. With the lack of good alternative remedies, such an effect would clearly be important not only to patients but also to the health services.
Much of the new evidence comes, however, not from experimental studies, but from observational studies based on a variety of administrative databases. Although these databases have had an important part in the development of information about drug effects since the 1960s, interpretation of the data contained in them is less straightforward. Most recently, S. Suissa proposed a particular problem with some of the estimates of the effects of ICS on COPD from these sources, the so-called problem of "immortal time". This bias arises when time is allocated to the control (or treatment) group as "incident-free" even though no incident could have occurred during the period because of the definitions used in the study. It was suggested that some of the reports that ICS are effective in reducing mortality in patients with COPD can be accounted for by this bias. Combined with the surprisingly large effects that have been estimated using these methods, this bias has cast doubt on the robustness of these reports' findings.
The issues raised are not only relevant to the current debate on the effectiveness of ICS in COPD but affect a wide range of common problems in health policy. Use of databases is important, not simply as a substitute for randomised clinical trials that would be too large or expensive to undertake. They are also important for a broader understanding of the effectiveness of drug treatments. Very often, trials that are undertaken raise unrealistic hopes for effectiveness in the broader population, either because they are carried out in a highly restricted patient group or because use of the medication in practice is restricted by availability or by patient compliance. These issues need to be explored and one method of doing this is through the use of administrative databases. Robust interpretation of these data is therefore key to adequate policy-making.
The symposium reported here brought together a group of scientists who had experience in this field and many who had used different databases to explore the issue of the effectiveness of ICS and, in most instances, long-acting β2-agonists to improve the outcomes of patients with COPD. The result was not only an excellent review of what is known of the effectiveness of these drugs, but also an important review of the methods, problems, and potential pitfalls of the uses of administrative databases for pharmacoepidemiological research.
The idea for the symposium arose from a discussion between S. Suissa of McGill University, Montreal, Canada, and J.B. Soriano of GlaxoSmithKline, Greenford, UK, and was financially supported by GlaxoSmithKline. The proceedings will be of interest to those interested in the treatment of COPD and also to any interested in the appropriate use of administrative databases in pharmacoepidemiology.
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Epidemiology of COPD: overview and the US perspective |
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TOPIntroductionEpidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Summary
The burden of chronic obstructive pulmonary disease (COPD) is increasing in the USA. The prevalence of COPD is now almost equal in males and females. Although objectively measured, airflow limitation is now generally believed to provide the most accurate estimates of disease; international guidelines on the diagnosis and treatment of COPD do not agree on standards for objectively defined measures. Cigarette smoking continues to be the primary risk factor for COPD, however, work-related exposures may be an important contributor to the overall burden of COPD. Approximately 7% of the adult population in the USA has low lung function; 70% of these adults with low lung function have never had a diagnosis of any obstructive lung disease.
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and results in a substantial economic and social burden to society. In the USA, it is currently the fourth leading cause of death 1, and the World Health Organization (WHO) estimated that there were 2.74 million deaths worldwide from COPD in the year 2000 2. In 1993, the cost of COPD to the US economy was an estimated $23.9 billion, including $14.7 billion in direct medical costs and an additional $9.2 billion in indirect costs 1.
The global burden of COPD has also been increasing and is expected to continue to increase in the coming decades. According to the Global Burden of Disease Study, COPD, ranked twelfth worldwide in 1990 in terms of its impact on disability-adjusted life-yrs, is projected to rank fifth by the year 2020 3, 4. In the USA, death rates for COPD have climbed steadily over the past 40 yrs. While rates have begun to stabilise for males in recent years, they are, if anything, increasing for females 1. A similar pattern of increase is seen if trends in COPD-related healthcare utilisation, rather than mortality, are examined 5. What is even more striking is that these trends, at least in the USA, fly in the face of declining mortality from cardiovascular disease 2.
The two main reasons for these patterns are the increased consumption of cigarettes, especially in developing countries, and among females and the elderly. It has long been known that cigarette smoking is the primary risk factor for COPD 6. According to the third National Health and Nutrition Examination Survey (NHANES III) carried out in the USA between 1988–1994, current cigarette smokers are 3–5-times more likely than never-smokers to have airflow limitation and to report chronic respiratory symptoms 7, 8 (table 1
). The WHO estimates that there are now 1.1 billion smokers worldwide 9 and this figure is expected to increase to 1.6 billion by 2025 10.
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Prevalence of chronic obstructive pulmonary disease
The WHO Global Burden of Disease Study used data from a variety of published and unpublished sources to estimate the prevalence of COPD in various countries and regions throughout the world 3, 4. While the methodologies varied and some of the estimates are admittedly imprecise, a few general patterns emerged. First, the prevalence tended to be highest in countries where cigarette smoking is common, and the prevalence generally tends to be higher in males than in females. Recently, a different pattern has emerged in the USA with prevalence of COPD being almost equal in males and females 1, 5, 7. This likely reflects the increase in smoking among females that has occurred in the USA since World War II.
Estimates of the prevalence of COPD will depend on the definition and criteria used to define it 12. Estimates based on self-report of respiratory symptoms are very nonspecific and likely result in overestimates of disease, while estimates based on physician diagnosis will tend to lack sensitivity since mild disease is often undiagnosed. Objectively measured airflow limitation is now generally believed to provide the most accurate estimates of disease, but, even here there is a lack of consensus, since the American Thoracic Society, European Respiratory Society, and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definitions all differ. Celli et al. 13 recently compared a number of objectively defined measures and reported that prevalence estimates sometimes varied by as much as 100%. They recommended the GOLD clinical definition of a forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio <0.70 on the basis of its simplicity and accuracy 12. While it may be simple, its accuracy is still in question. Hardie et al. 14 recently reported on 71 asymptomatic, nonsmoking adults, selected as a random sample of adults of >70 yrs of age. Thirty-five per cent had a prebronchodilator ratio <0.70 and this increased to 50% among those of >80 yrs. One-third of those >80 yrs actually met GOLD stage II criteria despite having no history of smoking or any apparent symptoms.
Some of the best prevalence data for COPD come from the USA NHANES III study. This large probability sample of the US population included a subsample of >16,000 adults for whom pulmonary function tests, a complete medical history, and self-reported diagnostic data were available. COPD (defined as the presence of airflow limitation) was estimated to be present in 
24% of current smokers, 13% of exsmokers, and 7% of never-smokers (table 1
). These estimates were very similar for males and females 7, 8. The prevalence of physician-diagnosed COPD, defined as chronic bronchitis or emphysema, increases steadily in both males and females through the mid-to-late adult years and, in this latter age range, tends to be greater for males than for females (table 2).
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The NHANES III data can also be used to estimate the contribution of occupation to COPD 16. Using the GOLD stage II criterion of an FEV1/FVC ratio <0.70 and an FEV1 <80% of predicted, the fraction of COPD that may be attributable to work among individuals aged 30–75 yrs has been estimated as 19.2% overall and 31.2% among never-smokers.
Conclusion
Overall, the NHANES data suggest that 7% of the adult population in the USA have low lung function and that this is closely related to cigarette consumption and increasing age. These data also suggest that 70% of adults with low lung function have never had a diagnosis of any obstructive lung disease and that work-related exposures may be an important contributor to the overall burden of COPD.
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Epidemiology of COPD: a European perspective |
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TOPIntroductionEpidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Summary
Mortality rates from chronic obstructive pulmonary disease (COPD) vary across Europe. However, the continuing elevated prevalence rates of current smoking among males and the increasing trend observed in females in the last decades predicts an increase of COPD mortality in many countries in the coming years. The real prevalence of COPD within a given population may vary widely depending upon the tools used for its identification: reported respiratory symptoms, medical diagnosis and abnormal lung function. Even when the diagnosis is based on an objective tool like spirometry, largely variable prevalence rates are found within the same population. In view of the different criteria endorsed by different scientific societies, it is clear that further research is needed to reach a standardised criterion for airways obstruction. Patients underestimate their own morbidity and may therefore be undertreated. The cost of COPD, largely driven by exacerbations, is expected to increase considerably in the future, reflecting the previous smoking habits of an ageing population. The impressive prevalence in current smokers <45 yrs of age in most countries highlights the need to improve the quality of prevention; early detection and screening programmes may be useful in this population of smokers.
Introduction
Chronic obstructive pulmonary disease (COPD) is a very important cause of mortality and morbidity in Europe 17. Although COPD and asthma are considered different entities with respect to pathophysiological and cellular conditions 18, it is well recognised that chronic persistent asthma may have the feature of irreversible airflow obstruction, thus being encompassed within the term COPD, as clearly shown in the nonproportional Venn diagram published in the 1995 American Thoracic Society (ATS) guidelines 19. Further, many available statistics on COPD mortality and morbidity data are based upon the combination of chronic bronchitis, emphysema and asthma; codes 490–493 of the International Classification of Diseases, ninth revision (ICD-9) 20, or codes J40–47 of ICD-10 21. Sometimes, code 496 ICD-9 is also used to include within COPD the airflow obstruction not classified elsewhere.
Mortality
On a worldwide scale, according to the estimates by Murray and Lopez 22, if tobacco epidemics will not change their trends, in the interval 1990–2020, COPD will jump from the sixth to the third rank among the leading causes of death. At the European level, huge differences in the mortality rates have already been depicted in the Appendix "Epidemiology" of the European Respiratory Society (ERS) Consensus Statement on COPD 17. It has been reported that mortality rates for COPD vary more than five-fold among the European countries and that they increase greatly with age and are considerably lower in females 23. More recent data encompassing the period 1993–1997, provided by the World Health Organization 24, show a wide range in the mortality rates from >70 in Hungary to <10 in Greece (per 100,000 population of 35–74 yrs of age). Analogous figures for females range between 40 in Scotland to <5 in Greece.
The comparison of mortality rates among different countries depends upon the relative weight of relevant risk factors in the different populations, but it is also linked to technical factors such as the use of different reference populations for standardising the rates, and the use of different codes for reporting the same disease (e.g. code 491 ICD-9 is used more in south Europe, code 496 ICD-9 in the north).
Current trends in COPD in the UK 25 differ from those in many other countries, because in the past COPD was much more common than in other countries undergoing a smoking epidemic at the same time, and peak cigarette consumption in males and females occurred >25 yrs ago. Male mortality from COPD has been falling for 30 yrs, while female mortality has risen steadily during the same period. A strong socioeconomic gradient in morbidity and mortality persists.
In Italy, of 36,834 deaths that occurred in 1998 for respiratory diseases 26, approximately one-half have been caused by COPD (codes 490-493 ICD-9). The number of deaths stratified by sex, standardised mortality rates per 100,000 people (with the world population as reference), and male/female ratios for all respiratory diseases and COPD are reported in table 4.
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Among the factors that have been related to an increased risk of mortality (or of lower survival) for COPD in the general population, epidemiological data from Denmark have stressed the role of forced expiratory volume in one second (FEV1) and chronic mucus hypersecretion. For subjects with an FEV1 
40% at baseline, 5-yr survival after subsequent hospitalisation was only 28% 29. Within the framework of a 10–12-yr follow-up, chronic mucus hypersecretion was found to be a significant predictor (relative risk (RR) 3.5) of COPD-related death with pulmonary infection implicated 30.
Morbidity
Although COPD represents one of the main health issues of the present and the near future worldwide, some of its features are still undefined from a social and economic point of view. The real prevalence of COPD within a given population may vary widely depending upon the tools used for its identification: reported respiratory symptoms, medical diagnosis and abnormal lung function. Community surveys in countries of both northern and southern Europe 23 indicate that 4–6% of the adult population suffer from clinically relevant COPD. The prevalence increases greatly with age, however, two-thirds have only a mild reduction in lung function.
According to the Italian National Statistics Agency multipurpose survey on households, performed in 1999–2000, 4.4% of the Italian population (4.8% males, 3.9% females) suffered from chronic bronchitis and/or emphysema and/or respiratory failure. The highest rates have been found in the elderly >64 yrs of age (total 14.1%, males 18.3%, females 11.2%) 31.
Another source of routinely collected statistics is the hospital discharge standard form. Data pertaining to the year 2000 in Italy show that 20.6% of discharges for respiratory diseases are caused by Diagnosed Related Group 88 - COPD (126,927 cases). Total hospital days were 1,159,995 with an average length of stay of 9.4 days 32.
A dynamic multistate life table model was used to compute projections for the Netherlands 33. Changes in the size and composition of the population caused COPD prevalence to increase from 21 per 1,000 in 1994 to 33 per 1,000 in 2015 for males, and from 10 per 1,000 to 23 per 1,000 for females. Changes in smoking behaviour reduce the projected prevalence to 29 per 1,000 for males, but increase it to 25 per 1,000 for females. Total years of life lost increase by >60%, and disability-adjusted life-yrs lost increase by 75%. Costs rise 90%; smokers cause 90% of these costs. The model demonstrates the unavoidable increase in the burden of COPD, an increase that is larger for females than for males. The major causes of this increase are past smoking behaviour and the ageing of the population. According to the authors, changes in smoking behaviour will have only a small effect in the near future.
It is interesting to point out that among industrialised countries, Japan shows extremely low prevalence rates of COPD; in 1999, it was estimated that 212,000 people (139,000 males) were affected by COPD with a prevalence of 0.17% in the general population 28. One of the reasons that account for these values is the long delay in the uptake of tobacco smoking in Japan for cultural and socioeconomic reasons after the second World War.
The importance of sex, ageing and tobacco smoking in the development of COPD has been examined, in Italy, by Viegi et al. 34, using data collected, through questionnaire, in two longitudinal surveys carried out in the rural area of Po Delta (northern Italy) and in the urban area of Pisa-Cascina between 1980–1993. Data on prevalence rates of chronic bronchitis and emphysema (medical diagnosis) and of some respiratory symptoms, stratified by sex and smoking habit were obtained. The prevalence rate of chronic bronchitis was lower than that of chronic cough and phlegm, symptoms on which the diagnosis of chronic bronchitis is based 35. It confirms an underestimate of the frequency of such disease, when only medical diagnoses are considered 36.
The underestimate of COPD prevalence, possibly 25–50% and higher, has been found by several investigators 17, 37, 38. Two cross-sectional studies of respiratory symptoms and diseases in two population samples (5,700 subjects aged 35–36, 50–51 and 65–66 yrs) living in the same areas in northern Sweden were performed 6 yrs apart through a postal questionnaire 39. Lung function measurements were performed in stratified samples. Of the subjects diagnosed with chronic bronchitis, only 25% in 1986 and 23% in 1992 had been diagnosed prior to the study as having chronic bronchitis, emphysema or COPD. Chronic airflow limitation, defined as FEV1/forced vital capacity (FVC) <70% and FEV1 <80% of predicted value, was found in 171 subjects in 1986–1987 (12% of the examined subjects), and 166 subjects in 1993–1994 (11%). In 1986–1987, 26% of the subjects with chronic airflow limitation had been diagnosed as having chronic bronchitis or emphysema prior to the survey, while a diagnosis of asthma, chronic bronchitis or emphysema, or use of asthma medicines, was found in 58%. The corresponding figures in 1993–1994 were 31% and 63%, respectively.
Large differences in the prevalence of physician-diagnosed chronic bronchitis have been found in a postal survey conducted in 1996 in three countries 40: 10.6% in Tallinn, Estonia, 3.4% in Helsinki, Finland and 3.0% in Stockholm, Sweden. A representative sample of 14,076 French individuals of 
25 yrs completed a self-administered questionnaire 41. Prevalence rates of chronic bronchitis and of chronic cough and/or expectoration were 4.1% and 11.7%, respectively; in individuals with comorbidity, these figures were 10.4% and 24.4%, respectively. Smoking was associated with an increased frequency of chronic bronchitis. In subjects with chronic bronchitis, 44.6% had spirometry or peak expiratory flow measurements, 24% were diagnosed as having chronic bronchitis and 7.2% received care.
Even when the diagnosis is based on an objective tool like spirometry, largely variable prevalence rates are found within the same population in view of the different criteria endorsed by different scientific societies. For instance, Viegi et al. 42 have shown in adults of 25 yrs of age (n=1,727 in 1988–1991) that the prevalence rates of airflow obstruction range from 11% with the ERS criteria 17 to 18% with the "clinical" criteria (later labelled as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria Stage I) 43 to 40.4% with the 1986 ATS criterion 44. Corresponding figures for subjects aged 25–45 yrs and subjects of 46 yrs of age were as follows: ERS 10.8 and 12.2%, clinical 9.9 and 28.8%, and ATS 27 and 57%, respectively. When considering only moderate/severe obstruction, the rates were as follows: ERS 0.4 and 3.6%, clinical 0.3 and 4.4%, and ATS 0.5 and 5.2%, respectively. The trend was confirmed after stratifying for smoking habit and the presence/absence of respiratory symptoms/diseases. The highest specificity and predictive value for any respiratory symptom/disease was shown by the ERS, and the lowest was shown by the ATS criterion, while the reverse was true for sensitivity; overall accuracy was slightly lower for the ATS criterion. Multiple logistic regression models indicated a higher number of significant associations with known risk factors for airways obstruction according to clinical and ATS criteria than ERS criterion. The authors concluded that further research was needed to reach a standardised and epidemiologically consistent criterion for airways obstruction.
Probably, such a goal has not yet been achieved, even after the introduction of the GOLD criteria. Its ability to provide information of prognostic value in COPD patients has been questioned by Vestbo and Lange 45. Its applicability to the whole population regardless of age, has been criticised by Hardie et al. 14.
An interesting experience on early detection of COPD or asthma in a random sample from the general population aged 25–70 yrs has been carried out in 10 general practices located in the eastern part of the Netherlands within the framework of the Detection, Intervention, and Monitoring Programme of COPD and Asthma (DIMCA) 46. There was a two-stage protocol involving screening and a subsequent 2-yr monitoring of all subjects with positive results of screening. All known COPD and asthma patients were excluded. Of those eligible, 1,155 subjects (66%) participated in the screening stage, and 384 subjects (64% of those with positive screening results) participated in the monitoring stage. During the second stage, 252 subjects were detected with objective signs of COPD or asthma at an early stage. Smoking status as a screening criterion was neither sensitive nor specific. By extrapolation, 7.7% of the general population showed persistently reduced lung function or increased bronchial hyperresponsiveness (BHR). Another 12.5% of the general population showed a rapid decline in lung function (>80 mL·yr–1) in combination with signs of BHR, and a further 19.4% of the general population showed mild objective signs of COPD or asthma.
A promising approach in early detection of COPD in high-risk populations using spirometric screening also comes from a Polish experience 47 on 11,027 smokers of >39 yrs with a smoking history of >10 pack-yrs. Spirometric signs of airway obstruction were found in 24.3% of the screened subjects: mild 9.5%, moderate 9.6%, and severe obstruction 5.2%. In addition, the same research group 48 was able to demonstrate in a subgroup of screened smokers that, after a minimal antismoking intervention, those with abnormal lung function had a nearly doubled quitting rate at 1 yr compared with those with normal spirometry.
An assessment of the international variation in the prevalence of chronic bronchitis and its main risk factor, smoking, has been performed in 35 centres from 16 countries on 17,966 subjects (20–44 yrs of age), randomly selected from the general population, in the frame of the European Community Respiratory Health Survey 49. The median prevalence of chronic bronchitis was 2.6%, with wide variations across countries (0.7–9.7%). The prevalence of current smokers ranged 20.1–56.9%, with a median value of 40%. Current smoking was the major risk factor for chronic bronchitis, especially in males. Only 30% of the geographical variability in prevalence could be explained by differences in smoking habits, suggesting that other environmental and/or genetic factors may play an important role.
Recently, the first international survey estimating the burden of COPD in the general population was published 50. The Confronting COPD International Survey aimed to quantify morbidity and burden in COPD subjects in 2000. From a total of 201,921 households screened by random-digit dialling in the USA, Canada, France, Italy, Germany, the Netherlands, Spain and the UK, 3,265 subjects with a diagnosis of COPD, chronic bronchitis or emphysema, or with symptoms of chronic bronchitis, were identified. The mean age of the subjects was 63.3 yrs and 44.2% were female. Subjects with COPD in North America and Europe appeared to underestimate their morbidity, as shown by the high proportion of subjects with limitations to their basic daily life activities, frequent work loss (45.3% of COPD subjects <65 yrs of age reported work loss in the past year) and frequent use of health services (13.8% of subjects required emergency care in the last year), and thus may be undertreated. There was a significant disparity between subjects' perception of disease severity and the degree of severity indicated by an objective breathlessness scale. Of those with the most severe breathlessness (too breathless to leave the house), 35.8% described their condition as mild or moderate, as did 60.3% of those with the next most severe degree of breathlessness (breathless after walking a few minutes on level ground).
Some relevant issues in the natural history
The Danish research group of the Copenhagen City Heart Study has elucidated the relationship of mucus hypersecretion and COPD morbidity. Among males, chronic mucus hypersecretion was associated with an excess FEV1 decline of 22.8 mL·yr–1 (95% confidence interval (CI) 8.2–37.4) and with subsequent hospitalisation due to COPD after adjusting for age and smoking (RR 2.4, 95% CI 1.3–4.5) 51. Socioeconomic factors operating from early in life affect the adult risk of developing COPD independently of smoking in both females and males 52.
In a follow-up of 8,955 adults, elevated plasma fibrinogen was associated with reduced FEV1 and an increased risk of COPD hospitalisation rates 53. In a 21-yr follow-up on 9,187 adults, 
1-antitrypsin MZ heterozygotes had a slightly greater rate of decrease in FEV1 and were modestly over-represented among persons with airway obstruction and COPD. In the population at large, MZ heterozygosity may account for a fraction of COPD cases (2%), similar to the percentage of persons with COPD who have the severe but rare ZZ genotype 54. Among subjects with severe disease (FEV1/FVC <0.7) in a 14-yr follow-up of COPD patients, there was a significant risk ratio modification between effect of baseline body mass index (BMI) and weight change 55. In the normal-to-underweight (BMI <25), best survival was seen in those who gained weight, whereas for the overweight and obese (BMI 25), best survival was seen in stable weight. A high proportion of subjects with COPD experienced a significant weight loss, which was associated with increased mortality.
The Norwegian research group from Bergen tested the comparability of telephone and postal survey questionnaires for respiratory symptoms and risk factors 56. Furthermore, it demonstrated the use of biomarkers, like 1-antitrypsin and calprotectin, and lung function tests different from FEV1, like diffusing capacity 57. This group has provided a major contribution in understanding the role of occupational exposure on the development of COPD 58. In a 25-yr follow-up on 951 subjects from a random sample of 1,933 males aged 22–54 yrs, the decline in FEV1 was associated with age, body height and smoking. Accelerated decline in FEV1 was observed in subjects exposed to sulphur dioxide gas and metal fumes at work. The adjusted decline in FEV1 increased progressively in subjects exposed to increasing numbers of occupational agents.
Among the environmental risk factors, an increasing body of evidence is accumulating on air pollution, especially urban air pollution 59 whose acute increases (mainly the particulate matter) have been related to short-term health effects (i.e. mortality and hospital admissions) in patients suffering from COPD. Beyond the acute effect, chronic exposure to air pollution seems related to lung function impairment and development of COPD. The few cross-sectional studies performed have shown an increase of self-reported diagnosis of chronic bronchitis and emphysema, breathlessness, and mucus hypersecretion and lower levels of lung function in the more polluted areas. The only cohort study in adults showed a faster decline of lung function. The great importance for public health knowledge of air pollution is due to its ubiquitous nature that renders the whole general population at risk.
Costs
In the above-mentioned DIMCA study 46, the costs involved in detection (lung function assessments, organisation, transportation, and patient time) were calculated for three different scenarios, as follows: 1) the detection of subjects with persistently decreased lung function or an increased level of BHR during 6 months of monitoring; 2) scenario 1 plus the detection of subjects with a rapid decline in lung function with signs of BHR during 12 months of monitoring; and 3) scenario 2 plus the detection of subjects with a moderate increase in the decline in lung function or signs of BHR during 24 months of monitoring. The average costs per detected case varied from US $953 (scenario 1) to US $469 (scenario 3). Thus, detection of COPD or asthma at an early stage by means of a two-stage protocol seems feasible at relatively little expense in comparison with other mass screening programmes.
Further, in a prospective, randomised consent trial 60, the utilisation of healthcare resources and cost were ascertained in two groups: a screened group (n=416) and a control group (n=462). During an average follow-up of 3.6 yrs, there were no significant differences in healthcare resource utilisation and cost between the screened subjects and the controls. Resource utilisation before screening was not significantly different from resource utilisation after screening. Within the screened group, positive subjects with signs or symptoms of obstructive airway disease consulted their general practitioners 3.7-times more frequently for respiratory reasons than negative subjects. As expected, the total healthcare cost due to respiratory disease in screen-positive subjects was 6.4-times higher. Overall, there were no indications that screening for obstructive airway disease led to increased cost, above that of average care.
The burden of asthma and COPD on the general population is considerable in the Netherlands 61. The main cost element of asthma is medication, whereas hospitalisation accounts for the largest proportion of costs for COPD. Consequently, the annual cost per patient of managing COPD is almost three-times as high as that for asthma. Together, the two respiratory conditions cost the Dutch healthcare system US $346 million for direct medical costs in 1993, amounting to 1.3% of the total healthcare budget. The burden of COPD is expected to increase considerably in the future, reflecting the previous smoking habits of an ageing population.
Within the framework of the Italian National Healthcare System, a cost-of-illness analysis of three pathologies affecting the lower respiratory tract (community-acquired pneumonia (CAP), COPD and asthma) was conducted in a large region of north-east Italy, Triveneto, between 1999–2000 62. Patients of both sexes 14 yrs of age were randomly selected from 28 centres of pneumology. Consumption of medical resources used during the follow-up period was valued according to market prices and published official tariffs. A total number of 1,068 patients (596 males and 458 females) were selected: 42.5% were affected by asthma, 46.3% by COPD and 11.2% by CAP. Mean cost per patient per year for patients affected by asthma and COPD ranged 608–2,457 and from 1,500–3,912, respectively, depending on illness severity. The mean cost per episode of CAP was 1,586.
Exacerbations are the key drivers in the costs of COPD in Sweden 63. Among 202 subjects with COPD (defined according to the British Thoracic Society and ERS criteria), at least one exacerbation was reported by 61 subjects, who were then interviewed regarding resource use for these events. The average healthcare costs per exacerbation were Swedish krona (SEK) 120 (95% CI 39–246), SEK 354 (252–475), SEK 2,111 (1,673–2,612) and SEK 21,852 (14,436–29,825) for mild, mild/moderate, moderate and severe exacerbations, respectively. Exacerbations account for 35–45% of the total per capita healthcare costs for COPD.
Conclusion
Two comprehensive reviews summarising the European perspective on COPD epidemiology were published in 2001 64, 65. Chronic bronchitis is too infrequently diagnosed, investigated, and cared for. It is a substantial health problem even in young adults. The impressive prevalence in current smokers of <45 yrs of age in most countries highlights the need to improve the quality of prevention. Even if the current decline in the prevalence of smoking continues in Europe, in the near future there will be an increase in the prevalence of COPD (with the increase probably higher among females than males), largely due to the ageing of the population. Keeping these statistics in mind, decision-makers allocating funds to healthcare services need to consider that the prevention of moderate-to-severe exacerbations could be very cost-effective and improve quality of life. There is also a need for intervention studies that aim to avoid weight loss in normal-to-underweight COPD patients.
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The burden of illness and economic evaluation for COPD |
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TOPIntroductionEpidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Summary
This article reviews the important factors to consider in the design of economic evaluations or cost-effectiveness analyses (CEAs) of chronic obstructive pulmonary disease (COPD) treatments. The relevant costs associated with COPD can be divided into direct (direct medical and direct nonmedical) and indirect (programme and productivity) costs. The differences between the human-capital and friction-cost approaches to evaluate the impact of productivity loss are discussed. Since the primary cost-driver for COPD is hospital care for exacerbations, this may be the major outcome measure of interest in COPD economic evaluation studies. Robust CEA evaluations that take into account all of these factors will aid decision-makers in evaluating COPD therapies.
Introduction
Given the rising prevalence of chronic obstructive pulmonary disease (COPD) worldwide, it is urgent that its economic burden is understood and that more robust evaluations of healthcare interventions are designed to reduce its incidence and impact. Studies designed for making decisions and policy must apply robust methods and report results in a standardised fashion.
Economic evaluations are often known less precisely as cost-effectiveness analyses (CEAs). Although these terms have subtle differences, for purposes of this article, and to avoid confusion, "CEA" will refer to studies designed to evaluate the incremental impact of a particular COPD therapy or programme (usually new) versus the conventional approach. In recent years, standardised methods for conducting and reporting these studies have been embraced 66–70.
Capturing relevant costs related to chronic obstructive pulmonary disease and its treatment
Economic studies of COPD must include all relevant costs associated with the illness. Such costs should include not only the intervention of interest (e.g. inhaled bronchodilator therapy), but also all components associated with therapy, such as nebuliser equipment. Such costs can be divided into direct (direct medical and direct nonmedical) and indirect (programme and productivity) costs.
Programme costs refer to costs associated with building the infrastructure needed to deliver the technology. Many studies fail to take into account programme costs when evaluating interventions. For example, an evaluation of a new intensive smoking cessation clinic should include clinic costs (such as rent for office space and staff costs) amortised across the patient group as well as the cost of associated therapies such as nicotine patches or buspirone. Direct medical costs include all medical goods and services used to treat the illness. Usually, these costs are the easiest ones to identify and are thus part of most economic studies.
Direct nonmedical costs include items related to care not directly linked to the healthcare system. Comprehensive evaluations of nonmedical costs are needed for COPD. Such costs can include hired caregiver expenses, costs to the family, lost wages of family caregivers, expenses associated with modifications to living facilities, and transportation and parking costs for patients visiting their physicians. As these costs usually are not reimbursed by health insurance and are difficult to track, they are often excluded from economic studies. As a result, almost no information exists on the value of direct nonmedical costs in COPD. This may be an important oversight, particularly for developing countries. For example, transportation costs may be one of the largest expenses for those who have to travel from remote areas to receive care.
Productivity costs refer to the value of lost wages resulting from illness and from seeking treatment. They are particularly difficult to estimate and are usually excluded from economic evaluations. Nevertheless, productivity is reduced by sporadic absences, visits to healthcare providers and premature mortality. Even more so than direct nonmedical costs, this may be a particularly important omission where COPD is concerned, especially for burden-of-illness studies in developing countries. The value of permanent work loss is particularly important for diseases with high rates of premature mortality such as COPD. As productivity in COPD is potentially important, the two major approaches to valuing productivity, human-capital and friction-cost, are reviewed here in some detail.
Capital and friction-cost approaches to valuing productivity costs
The traditional approach to evaluating the impact of productivity loss caused by illness is the human-capital approach. This term derives from the observation that a person's earnings over a lifetime reflect an investment in that individual through education, on-the-job training, and work experience 71, 72. As these investments influence that individual's value to the economy, productivity loss usually is valued using market wage rates. For those not working for a wage (e.g. homemakers), wages are valued at those that replacement workers would earn for their specific services.
The friction-cost method differs from the human-capital approach in that it allows for the replacement of an absent worker by other workers or by those in the unemployed pool. The friction-cost method values productivity as the loss incurred during the time between a person's absence from work or termination of employment and the time at which another worker fills that position 73–75. The time required for worker replacement is called the "friction period."
Unfortunately for researchers, there is no general agreement on whether the human-capital or friction-cost method is more valid for measuring the productivity costs of illness 76–79. Further complicating the matter is that the estimate will vary greatly depending on which method is applied. For example, in a study of schizophrenia's impact on productivity, the human-capital and friction-cost methods resulted in an 85-fold difference in the estimate of productivity cost 80.
Time horizon
All downstream effects related to treatment for COPD should be included in cost studies. These costs should be tracked or modelled during the time that the intervention is expected to affect the individual or group. Often in the case of COPD, this time horizon equals a person's lifetime.
Key factors influencing cost
The call to "capture all costs" must be tempered by the reality of the study design's limitations and the budget available for conducting economic analyses. As there is no comparison group in burden-of-illness evaluations, comprehensiveness is more important for these studies than for CEAs of healthcare programmes. For CEAs, the intervention of interest is likely to have a large effect on some aspects of healthcare utilisation (e.g. hospital days), but little on other aspects. Since CEAs are an incremental form of analysis, it is only necessary to measure healthcare items that are expected to vary between the intervention and control groups. Of course, it is difficult to predict beforehand what will vary as a result of the intervention. Studies have shown that the primary "cost-driver" for COPD is hospital care for exacerbations, accounting for 70% of all direct medical costs in developed countries for this disease 81–86. Thus, if the intervention is expected to influence hospital care significantly, this may be the only item necessary to measure accurately. Other items with more subtle effects (e.g. office visits, medications) will probably require a more comprehensive analysis.
Methodological issues for cost-effectiveness studies
Cost-effectiveness studies are now common in medicine and have been applied to several therapies for COPD. Nevertheless, outside of smoking cessation programmes 87–93, few high quality CEAs exist for widely used COPD therapies 94. In fairness to researchers, few therapeutic breakthroughs for this disease have occurred, and many traditional therapies are perceived as only modestly effective (it could be argued that minimally effective therapies are not cost-effective and should not be applied). More recently, however, several therapies have begun development for persons with COPD 95. Ever tightening health budgets will force payers to scrutinise the value for expenditures of these new therapies more closely. In this context, it is an opportune time to review the important issues involved for conducting robust CEA evaluations of treatments.
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Pharmacotherapy of COPD |
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TOPIntroductionEpidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Summary
There are multiple goals to manage in chronic obstructive pulmonary disease (COPD) patients. The benefits of current pharmacological treatments for COPD are discussed here. The use of theophyllines remains somewhat controversial in the management of stable COPD, while the use of long-acting bronchodilators (such as salmeterol, formoterol, or tiotropium) alone or in combination with short-acting bronchodilators or theophylline are effective maintenance treatments for COPD. Treatment with inhaled corticosteroids (ICS) reduces symptoms and the frequency of exacerbations and improves the quality of life, but does not influence the long-term decline of forced expiratory volume in one second. However, combination therapy with ICS and long-acting β2-agonists improves lung function and symptoms and reduces rescue medication use and the frequency of moderate and/or severe COPD exacerbations. The Global Initiative for Chronic Obstrutive Lung Disease guidelines have recently been revised to recommend maintenance therapy with inhaled long-acting bronchodilators starting from moderate (stage II) COPD, and combination therapy with ICS starting from severe (stage III) COPD to prevent exacerbations.
Introduction
The main objectives of chronic obstructive pulmonary disease (COPD) management are the prevention of disease progression, the relief of symptoms, the improvement of exercise tolerance and health status, the prevention and treatment of exacerbations and/or complications, and the reduction of mortality and of side-effects from treatment 12.
The long-term therapy of moderate and severe COPD consists of pharmacological treatment, such as the regular use of bronchodilators, and of nonpharmacological treatment, such as rehabilitation and/or long-term oxygen in the presence of respiratory failure. The most recent COPD guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recognise, as part of the definition of the condition, that there is "an abnormal inflammatory response" in the lung to noxious gases or particles 12. This suggests the need for effective anti-inflammatory treatment in COPD. However, inhaled corticosteroids (ICS) have not been shown to have a consistent anti-inflammatory effect in patients with COPD, and thus, based on the results of clinical trials, treatment with ICS is recommended in some, but not all COPD patients, and, in particular, in patients with severe and very severe (stages III and IV, respectively) COPD and repeated exacerbations.
Bronchodilator medications, such as short-acting and long-acting β2-agonists, anticholinergics, and theophylline, are central to the symptomatic management of COPD. Long-acting inhaled β2-agonists, such as salmeterol and formoterol, have a duration of action of up to 12 h and significantly improve symptoms, exercise capacity, and health status in patients with COPD. The use of salmeterol (a long-acting β2-agonist) in COPD patients has been shown to significantly reduce dyspnoea and to improve forced expiratory volume in one second (FEV1) values after long-term treatment 96, 97, and to reduce dynamic hyperinflation 97. Formoterol, both a short- and long-acting β2-agonist, demonstrates better spirometric efficacy than either ipratropium 98 or theophylline alone 99, and its efficacy improves when administered in combination with ipratropium 100. A new long-acting once-daily anticholinergic agent, tiotropium, produces benefits of equivalent or greater size than salmeterol or formoterol 101, and is likely to be a useful addition to treatment for COPD. Thus, tiotropium has been shown to provide significant bronchodilation in terms of FEV1 response, and reduces dyspnoea and frequency of COPD exacerbations 102. Theophyllines remain somewhat controversial in the management of stable COPD. They have a slow onset of action and are used as a maintenance treatment rather than for rapid relief of symptoms.
Combination treatment with formoterol plus ipratropium provides better improvement of pulmonary function and a greater reduction in symptoms 103; similarly, combination treatment with salmeterol plus theophylline provides significantly greater improvements in pulmonary function, significantly greater reductions in symptoms, dyspnoea, and albuterol use, and significantly fewer COPD exacerbations 104. Taken together, these two studies suggest that combination therapy with long-acting bronchodilators with different mechanisms of action may, in fact, produce additive effects.
Whether ICS have an anti-inflammatory effect in patients with COPD remains controversial 105, 106. It is clear that these drugs do not modify the natural history of COPD, as measured by the rate of decline in FEV1 107–110. Data from studies on long-term effects of ICS provide evidence that regular treatment with ICS is only appropriate for symptomatic patients with severe to very severe COPD with an FEV1 <50% predicted (stage III: severe COPD, and stage IV: very severe COPD), and for repeated exacerbations requiring treatment with antibiotics or oral corticosteroids 111, 112. These studies have shown that long-term treatment with ICS reduces symptoms and the frequency of exacerbations and improves the quality of life 107–110, 112.
The recent randomised controlled trials examining the benefits of combining ICS and inhaled long-acting β2-agonists in the treatment of COPD have shown interesting results. The combination of fluticasone propionate and salmeterol improves lung function and symptoms, reduces the severity of dyspnoea and rescue bronchodilator use 111, 113, and reduces the frequency of moderate and/or severe COPD exacerbations 111. The combination of budesonide and formoterol reduces the mean number of severe exacerbations, improves FEV1 and peak expiratory flow values, and reduces all symptom scores and the use of rescue β2-agonists 114.
While ICS should be used only in patients with severe to very severe COPD, they are considered to be first choice maintenance treatment in mild, moderate and severe persistent asthma 115. Asthma may cause fixed airflow limitation and, thus, elderly asthmatics, in particular, may be misdiagnosed with COPD. The characteristics of asthmatics who develop fixed airflow limitation still fit the definition of asthma in terms of pathology 18, natural history 116, and response to treatment 117. These patients should be diagnosed and treated as asthmatics and not COPD patients. In this respect, it is recommended that asthma be excluded from the Venn diagram that is frequently used to illustrate the different components of COPD.
Conclusion
To conclude, on the basis of this evidence, the update of the GOLD guidelines on the management of COPD suggests regular treatment with inhaled long-acting bronchodilators (including tiotropium) and rehabilitation, starting from moderate (stage II) COPD. The evidence also suggests treatment with combined therapy with ICS starting from severe (stage III) COPD to prevent exacerbations.
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Possible sources of bias in observational studies of the effectiveness of inhaled corticosteroids in COPD |
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TOPIntroductionEpidemiology of COPD: overview...Epidemiology of COPD: a...The burden of illness...Pharmacotherapy of COPDPossible sources of bias...The Ontario and Alberta...The UK General Practice...The Saskatchewan ExperienceImmortal time bias in...The USA Lovelace Experience:...The USA PharMetrics Experience...The Integrated Primary Care...Use of routine databases...The TORCH study: towards...REFERENCES |
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Summary
The possible sources of bias that can arise from observational studies using computerised claims databases are discussed. The four classes of bias are selection (asthma versus chronic obstructive pulmonary disease) and confounding (indication, age, duration and severity of disease), choice of outcome (morbidity or mortality), timing of the drug exposure (i.e. cohort or case-control design), or time-related issues (incident or prevalent cohort and immortal time concerns).
Introduction
The observational studies conducted on the effectiveness of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) have all used computerised claims databases that have several limitations. The possible sources of bias that can arise from the use of these databases can be classified into four types.
Sources of bias
The first class of bias is selection and confounding. One challenge is to deal with the differential diagnosis of COPD and asthma, which is particularly crucial because the effectiveness of ICS has been very well established in asthma. Thus, as the inclusion of asthma patients may exaggerate the effectiveness of ICS, the study population must have clear criteria to identify COPD patients and exclude asthma patients. In particular, definitions and criteria based on a physician's reported diagnosis, drug treatment and age must be carefully combined to optimise the diagnosis of COPD. The study design used, namely, cohort or case-control approach may also engender some form of selection bias. Thus, the design must be carefully selected as must the source population and the base cohort. An important source of bias is confounding by indication. The disease severity and its markers must be identified and quantified to control for any imbalance between the users of ICS and the nonusers. In particular, the use of health services and the profile of use of other drugs for COPD must be examined and analysed to provide the proper statistical adjustment and elimination of confounding. Two additional confounding factors that must be taken into account are age and duration of COPD. Finally, the approach to account for these factors can either be by matching cases and controls on these factors, by restricting the study to subjects who have or do not have some of these factors, and of course, by statistical analysis using a multivariate regression model that will control for these differences simultaneously. An important point of discussion should be the timing of these markers of disease severity with respect to the outcome and the ICS exposure. For instance, should disease severity be evaluated at the start of disease or at the time of the outcome under study?
The second source of bias is related to the choice of the outcome, morbidity or mortality. Morbidity can be evaluated from exacerbations, outpatient or emergency room visits, as well as hospitalisation. An exacerbation can be identified in some databases by the use of drugs, such as the simultaneous treatment with oral corticosteroids and antibiotics, or indicated by a diagnostic code posed by a physician or during a hospitalisation. With respect to mortality, an issue raised by the studies conducted, to date, is the use of all-cause mortality as an outcome, as opposed to death due to COPD. Since medications would be expected to be more specific to the outcome of COPD death, studies that would focus on all-cause mortality may provide an underestimate of the effect since other causes may not be affected by the medication under study. Nevertheless, studies focusing on COPD mortality should address the validity of the cause of death in death certificates, as well as the issue of other causes and underlying cause, since these patients may have several conditions at the time of death.
The third source of bias is related to the exposure. An important point is the timing of the drug exposure, in particular, whether exposure is selected at cohort entry or at the time of the outcome under study. This question relates to the choice of design, cohort or case-control. In addition, whether the effects are acute or whether regular treatment is required to attain the effectiveness under study needs to be considered with respect to drug exposure. Drug exposure also affects the choice of the reference group and whether this group can include patients who do not currently use ICS but who used them previously, or patients who are restricted to other drugs or classes of drugs, such as bronchodilators. With these classifications and the question of timing of use, concern must then be placed upon issues of exposure misclassification. For instance, patients who are not using ICS should not be classified as users and vice versa. Finally, the exposure and its timing will also relate to the analysis of the data, and, particularly, whether exposure is fixed, such as for the intention-to-treat approach, or time-dependent, such as that used in nested case-control analysis.
The last source of bias is that arising from time-related sources. The cohorts under study may be incident (based on newly diagnosed patients) or prevalent (patients well into their disease) cohorts. It is determined by whether patients at time zero already have had COPD for some time or have already been exposed to the drug under study for some time. It may be preferable to use incident cohorts where new treatment or new disease defines time zero for the cohorts. If this is not possible, the duration of prior COPD or prior drug use should be examined and accounted for in the analysis. The choice of time zero is important and may be taken as the date of first COPD diagnosis, the date of the first hospitalisation for COPD, the date of any hospitalisation for COPD, or the first time an ICS or a referent drug was used. Finally, in all cohort studies that involve time-dependent exposure, immortal time should be identified and accounted for 118–120. Immortal time periods, defined by follow-up times during which patients cannot, by definition, incur the outcome, have to be identified and accounted for with a proper analysis. In addition, studies that improperly exclude immortal time or do not account for it in the proper exposure group should be identified and assessed with respect to bias.
Discussion
SORIANO: There is evidence that COPD patients who have an asthma component die more frequently than COPD patients without an atopy or hyperresponsiveness component. COPD patients with an asthmatic component are a subgroup of patients with more severe COPD. This subpopulation is easily 30–50% of individuals with COPD.
FABBRI: According to Burrows et al. 116, this is not true, i.e. smokers with COPD and asthma have a 10-yr survival (65%) that is in between smokers with COPD without asthma and asthmatics. In fact, nonsmoking asthmatics with fixed airflow limitation have a life expectancy similar to normal subjects.
VIEGI: In contrast to L. Fabbri's suggestion that the Venn diagram be removed, I believe that, rather than removing, we should understand these complex relationships better. Also, should we consider COPD just as a smoking-related disease? Fifteen per cent of COPD is work-related. What about the contribution of air pollution? We cannot anticipate the prevalence of COPD as only related to smoking.
ERNST: There are certainly patients with "pure" asthma or COPD. There are a number of patients, however, that fall somewhere in the middle. It is not appropriate to pretend that everyone falls in that middle group, since this would not allow us to aim the correct treatment at the correct patients. While there will always be people with components of both asthma and COPD, I do not think that these are the majority of COPD patients.
BOURBEAU: We have to ask ourselves, what exactly is our question or intent in these studies. If we are trying to understand COPD as a complex disease in an epidemiological study, we may be interested in looking at different populations including the nonsmoker. But if you want to test an intervention, it is best to define a population of patients who most likely have COPD, so then it should be related to smoking.
HAGAN: Another factor to consider is the perspective of pharmaceutical industry. When we are designing randomised clinical trials (RCTs), we have to abide by the criteria requested by Regulatory Agencies. For example, forced expiratory volume in one second reversibility criteria are getting more and more stringent because we have to prove that these are pure COPD patients. But, in the real world, most COPD patients do not have pure COPD.
MAPEL: When wrestling with this issue of how to define COPD, there are three areas in our end-points that are problematic. First, in spirometry itself, we tend to fixate solely on airway obstruction and ignore dynamic hyperinflation. In a population of female smokers that we brought in for testing with no diagnosis, we performed complete lung volumes and we found that a large population of female smokers had normal spirometry but remarkably elevated residual volumes. The first change in objective measures with smokers is increased residual volumes. However, we missed that completely when we used spirometry as an end-point. Spirometry is really an illogical end-point. Most of the people in a study are still smoking. If you do not get away from exposure, then disease will progress. So we need to expand the end-points. Exacerbations and hospitalisation rates, for example, are important and exciting end-points that are starting to be used. Pathological end-points are also important. The Hattatua study focused on chronic bronchitis patients without an asthma component (pure COPD) and found significant reductions in subepithelial mast cells. There are probably some inflammatory mechanisms in COPD that will be affected by corticosteroids. However, even in the pathological studies, we are seeing null results because they are looking at the wrong end-points. The truth is that we know remarkably little about the pathology of the disease.
HAGAN: It is interesting to note that the Hattatua study in patients with pure COPD used exactly the same entry criteria as the Inhaled Steroids in Obstructive Lung Disease in Europe trial. That does provide some pathological basis for selection criteria that we use in industry when selecting patients for COPD studies.
ERNST: But, I hope that we are not sending a message that we should use poorly reproducible surrogate end-points, such as mast cells or residual volumes. I would hope that we would be going towards outcomes such as hospitalisations and exacerbations that actually have an impact.
VIEGI: I think we need to go back to the basic issues. We cannot still use reference equations that were collected 40 yrs ago. Although there are attempts to standardise, there is still high technical and population variability. We cannot just use one reference equation. We need to recognise that when we start to measure lung function, we should check which is the best reference equation for our clinic setting and population.
FABBRI: The Global Initiative for Obstructive Lung Disease (GOLD) guidelines are becoming increasingly evidence-based. If you want to issue recommendations for treatment based on evidence, you should specify the entry criteria of the study you cite. And the entry criteria of most of the studies I presented excluded atopy, history of asthma, etc. However, you still may have the problem of the mixed population. But, we need studies of that mixed population, too.
BOURBEAU: In trying to make a diagnosis of COPD as epidemiologists, we will not be able to do better than what our current understanding is of the disease. We have a poor understanding of the phenotyping of COPD. There are many phenotypes of the disease, but it is too early to distinguish what they are. We should try to distinguish what is an asthma population, a COPD population and the in-between questionable population. When we are doing a pharmacoepidemiological study, we should probably look at these populations of patients differently and try to validate (what we have done very little of in pharmacoepidemology studies so far) from the different administrative databases what is asthma and what is COPD and then, in our conclusions, we should be able to speak the same language. This will evolve over the next 10 yrs as our understanding of the disease increases and we hope that pharmacoepidemiology studies will also evolve with that understanding.
PRICE: L. Fabbri said that the guidelines are becoming increasingly evidence-based and that recommendations will have to be made based on RCTs. Yet, the challenge from the industry perspective is that to meet regulatory requirement they will have to study patients from narrower and narrower groups. The industry is trying to produce more generalisable data and more pragmatic trials with different populations in spite of having to produce more regimented trials for registration purposes. We just had a new evidence-based asthma guideline produced in the UK. One of the challenges of the evidence-based hierarchy as it has been implemented in our asthma guidelines is that if you have a discrepancy between an observational database and an RCT, the RCT wins, rather than viewing the evidence as complementary and trying to look at understanding why the discrepancies may occur. In COPD, it will be particularly important that we look for generalisability, and we need to have a way of handling within the guidelines that breadth of data rather than a straight evidence-based hierarchy. Are there plans to encompass these kinds of data as complementary within the hierarchy or will they stay as inferior?
FABBRI: When we discussed the criteria for grading evidence within the GOLD Scientific Committee, there was a strong suggestion to downregulate Cochrane reviews, post hoc analyses, and meta-analyses, with the understanding that these studies may help to generate hypotheses but do not provide evidence and that the evidence is provided only by RCTs. The hypotheses generated by post hoc analyses or meta-analyses and Cochrane reviews should then be properly tested in RCTs.
SORIANO: The reality is that we do not know the general epidemiology of COPD within the community. We still do not have a Framingham study in COPD. The majority of COPD patients are managed by general practitioners (GPs) and we know that GPs have been treating COPD patients with asthma drugs for a number of years. Probably, pharmacoepidemiological studies will help define what the outcomes are in COPD patients from the general population.
VOLLMER: We are all aware that individuals who enroll in RCTs are not representative of the general population. Entry criteria are often highly restrictive and participants highly motivated. While I have enormous respect for the value of RCTs, I also have respect for what can be learned from the large databases that we are beginning to collect from real-life experience. The trick with looking at these databases is to figure out the proper analytical methods to use. I am convinced that we need to find a way to marry these two sources of evidence.
WEISS: As chairman of the guidelines development committee for the American College of Physicians, I find myself asking the question, "How do we step away from the RCT, so that we can incorporate these other pieces of data?" We do not want to end up saying that, because of lack of data, it is best left up to the physician's best judgment. What kinds of questions should be addressed in non-RCT databases that won't be addressed in RCTs? Question-asking may be one of the most important ways to begin these discussions.
Methodological issues
PRICE: There may be issues of bias in terms of what analyses are being done and what actually gets published. We can get around that by registering clinical trials and data analysis plans. This is important to capture what was done versus what was reported. Another issue is that of clustering and the effect of centres in RCTs. In the General Practice Research Database, some GPs are much better at using their systems than others.
DAVIS: We can use this as a matching factor.
SUISSA: Matching does not resolve this issue. In certain studies, the drug may not be used appropriately or measurements themselves may be appropriate in some centres but not in others. If you then match on centres, your result will be attenuated towards a null effect, because you will have created all kinds of measurement errors, whereas in the centres where data are well collected, you may be closer to the truth. Therefore, rather than matching on the centre, a stratified analysis by these centres will provide more accurate estimates.
VOLLMER: It is not just measurement error, but variation in practice patterns.
WEISS: This relates to the clustering of effects above the individual level that have to be accounted for and most of those that we perceive right now are in the health system design whether it be in the actual practice of providers, the way they practice as a group, or how this system is financed. So we have to ask, is it important to account for these?
SULLIVAN: What about major health systems changes, like payments to hospitals that can affect the rate of hospitalisations or exacerbations, independent of anything going on with the disease or treatment?
SUISSA: That also speaks to time-related bias. It would be important that a patient in January 2001 gets compared with all patients in the database in January 2001, so that they are all subject to the same rate at that point in time. If the drug will increase or decrease this rate, it will be assessed at the same time point.
BURNEY: But, it is not just time. What about from institution to institution and the way they manipulate the data?
SULLIVAN: You may have local variations in these factors.
SUISSA: Definitely, stratification on the region would then be important.
VOLLMER: You also need to account for in-migration. These individuals have no prior history in the database and could be incorrectly classified as incident cases when they first present for care. This can be partially addressed by treating those who seek care during an initial enrolment period, say 6 months, as having prevalent disease.
STURKENBOOM: Confounding by indication or by contraindication is also a consideration. It is not so much about the severity of COPD but about the severity of all types of comorbidities.
MAPEL: A difficult confounder that we have spent time wrestling with is comorbid illnesses, particularly heart disease. The single most common death in COPD patients has been cardiac arrest. How you deal with that will greatly affect the results. If you use it as an exclusion criterion, you end up wiping out half of your population. But if you use Charlson index or a similar technique to adjust for that, it changes your results.
ERNST: The comorbidity problem is a big problem especially in COPD. We have looked at cause of death in patients in our COPD cohort and the most common cause of death is cardiovascular. Even among those who are hospitalised with a primary diagnosis of COPD, the primary cause of death is cardiovascular. A lot of this represents misclassification.
VOLLMER: Adjusting for severity is also difficult, since we will typically have very imprecise tools for assessing it. Furthermore, the measures that are generally available to us for defining severity are inevitably closely related to the same measures we would use to assess current level of control, which is an outcome. This creates the potential for overadjusting in our analyses.
VIEGI: Besides the time dimension we should also use the space dimension. There is overwhelming evidence coming from recent air pollution epidemiology data. Differential exposures to air pollution can represent an important source of variability when we compare studies on drug efficacy coming from different populations. Another issue comes from the problem of compliance. We know from P. Burney's study that there can be an inverse relationship between the rate of compliance and hospital
