Chronic Obstructive Pulmonary Disease - ATS Journals

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Mar 27, 2006 - Department of Respiratory Medicine, Royal Devon and Exeter Hospital, ..... patients still die directly or indirectly of COPD and its complica-.
Chronic Obstructive Pulmonary Disease The Disease and Its Burden to Society David M. G. Halpin and Marc Miravitlles Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, United Kingdom; and Department of Pneumology, Clinical Institute of Thorax (IDIBAPS), Hospital Clinic, Barcelona, Spain

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease with inflammation at its core, and a major cause of morbidity and mortality. It represents a substantial economic and social burden throughout the world. Currently, COPD is the fifth leading cause of death worldwide, and despite advances in management, mortality is expected to increase in the coming decades, in marked contrast to other chronic diseases, such as heart disease and stroke, where there have been considerable decreases in mortality. On a patient level, the burden of COPD to patients and their families and carers is high, both in terms of health-related quality of life and health status. Health care providers and patients often underestimate the substantial morbidity associated with COPD; the condition is also frequently underdiagnosed and undertreated, which further compromises morbidity. Reducing the burden of COPD requires better evaluation and diagnosis, as well as improved management of chronic symptoms. As exacerbations and hospitalizations represent an important driver of the cost and morbidity of COPD, high priority should be given to interventions aimed at delaying the progression of disease, preventing exacerbations, and reducing the risk of comorbidities to alleviate the clinical and economic burden of disease. Keywords: burden of disease; chronic obstructive pulmonary disease; cost; epidemiology; management

Chronic obstructive pulmonary disease (COPD) is a common, treatable, and preventable disease with substantial morbidity and mortality, and one of the most important long-term conditions facing society (1). Despite this, many patients remain undiagnosed, experience high levels of symptoms, and their quality of life is often poor. Consultation rates in primary care are high and exacerbations of COPD are one of the most common causes of hospital admission. The costs of COPD to health services and society are therefore considerable. Although it is recognized that the burden of COPD is high, the availability of accurate data for COPD prevalence is hampered by underdiagnosis and misdiagnosis. Data from the U.K. General Practice Research Database estimate about 883,200 patients in the United Kingdom have a diagnosis of COPD (2). Mortality data are also likely to underestimate the impact of COPD because many patients suffering from COPD do not have this recorded on their death certificate, with inconsistent use of International Classification of Disease codes (3). However, even allowing for this underreporting, it is clear that COPD is one of the most common causes of death. In England and Wales, for example, COPD was recorded as the principal cause of death in 23,204 people in 2004 (12,487 males and 10,717 females) (4). On the basis of these figures, COPD is the fifth leading cause of death in the United Kingdom after ischemic heart disease,

(Received in original form March 27, 2006; accepted in final form April 17, 2006 ) Correspondence and requests for reprints should be addressed to Dr. David Halpin, Ph.D., F.R.C.P., Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon, EX2 5DW UK. E-mail: [email protected] Proc Am Thorac Soc Vol 3. pp 619–623, 2006 DOI: 10.1513/pats.200603-093SS Internet address: www.atsjournals.org

stroke, lung cancer, and pneumonia. In England, in 2002/2003, COPD was recorded as the reason for hospital admission in 109,243 cases and accounted for 1,094,922 bed-days, with a median duration of stay of 6 d (2001/2002 data) (2). Consultation rates in general practice are also high and rise with age from 417 per year per 10,000 patients aged 45 to 64 yr to 1,032 per year per 10,000 patients aged 75 to 84 yr (5).

EPIDEMIOLOGY OF COPD Data from the Quality and Outcomes Framework, in which every primary care practice in England was required to record the number of patients with spirometrically confirmed COPD, indicate a COPD prevalence of 1.4%, which compares with prevalences of 3.6% for coronary heart disease, 1.5% for stroke, 3.3% for diabetes, 0.5% for cancer, and 5.8% for asthma (6). However, it is likely that this represents a substantial underestimate of the true prevalence of COPD. Between 45 and 65% of patients with COPD are not formally diagnosed because many accept breathlessness and limited exercise tolerance as features of aging and regard their smoker’s cough as normal. In Spain, 9% of adults aged between 40 and 70 yr are affected by COPD (7), although only 22% are diagnosed and receive some kind of treatment for their disease (8). In the “Confronting COPD in North America and Europe” survey (9), attempts were made to overcome such problems by collecting data on symptoms suggestive of COPD as well as recording doctor-diagnosed COPD. On the basis of these criteria, the prevalence of COPD in smokers was shown to be consistent across many countries (ranging from 5.4% in the Netherlands and 4.5% in the United States and Canada to 3.2% in France). However, the survey did not use spirometry to confirm the presence of airflow limitation and also found that significant numbers of nonsmokers met the definition of COPD. In studies where spirometry has been used to confirm diagnosis, the overall prevalence of COPD has been estimated at 4 to 10% (10) (Table 1). What is most striking about the epidemiology of COPD has been the change in prevalence in women over the last decade. As a result of the change in demographics of smoking in the postwar years, COPD in the United Kingdom was as prevalent in women by the end of the 1990s as it had been in men at the beginning of the decade (11). This effect is similar to that seen in the United States with respect to female mortality (12) and is expected to be reflected in other European countries in the near future. Although the prevalence of COPD among women in Spain is fourfold lower compared with men, women with COPD remain less likely to be diagnosed and treated (8). General practitioners, in particular, consider the diagnosis of COPD less frequently in women despite presenting with the same risk factors and clinical symptoms as men (13). Few data are available on the incidence of COPD. There is evidence of a higher incidence in smokers than nonsmokers, as shown by follow-up data from the Copenhagen City Heart Study, in which 27% of patients who continued to smoke over 25 yr developed Global Initiative for Chronic Obstructive Lung Disease

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TABLE 1. COMPARATIVE PREVALENCE OF SPIROMETRICALLY CONFIRMED CHRONIC OBSTRUCTIVE PULMONARY DISEASE Country

Study

Diagnostic Criteria

FEV1/FVC ⬍ 70%, FEV1 ⬍ 60% predicted FEV1 ⬍ fifth centile plus reversibility test Clinical examination plus spirometry Clinical examination plus spirometry FEV1/FVC ⭐ 69% Italy Viegi and colleagues (63) ERS spirometric criteria Norway Gulsvik (64) Clinical examination plus spirometry Bakke and colleagues (65) Symptoms plus spirometry FEV1/FVC ⬍ 70%, FEV1 ⬍ 80% predicted Spain Marco Jorda´n and colleagues (66) FEV1/FVC ⬍ 70%, FEV1 ⬍ 80% predicted Pen ERS spirometric criteria plus reversibility test ˜ a and colleagues (7) United States Mueller and colleagues (67) FEV1/FVC ⬍ 60% Mannino and colleagues (68) FEV1/FVC ⬍ 70%, FEV1 ⬍ 80% predicted Denmark England Finland

Lange and colleagues (59) Dickinson and colleagues (60) Isoaho and colleagues (61) von Hertzen and colleagues (62)

COPD Prevalence (% ) Ages (yr) Overall Males Females 20–90 60–75 ⭓ 65 ⭓ 30 ⭓ 30 ⭓ 25 16–69 18–70 18–70 40–60 40–69 20–69 ⭓ 17

3.7 9.9

11.0 4.1 5.4 4.5 6.8 9.1 13 2 6.8

12.5 22.1 11 12.5 3.7 5.6 4.8

3.0 7.2 5.2 11.8 4.6 5.2 4.2

14.3

3.9

Definition of abbreviations: COPD ⫽ chronic obstructive pulmonary disease; ERS ⫽ European Respiratory Society. Based on data from Reference 10.

(GOLD) stage II–IV COPD, compared with 5.7% of nonsmokers (14). COPD mortality is also increasing, despite advances in the management of COPD over the past 30 yr, in marked contrast to other chronic diseases, such as heart disease, stroke, and cancer (15), where there have been considerable decreases in mortality. Most patients are not diagnosed until their mid-50s and overall 5-yr survival from diagnosis is 78% in men and 72% in women, and 30 and 24%, respectively, in severe disease (11). There are surprisingly few data on the causes of death in patients with COPD. In a study of 215 patients on long-term oxygen therapy, 38% died of acute-on-chronic respiratory failure, 13% of heart failure, 11% of pulmonary infection, 10% of pulmonary embolism, 8% of a cardiac arrhythmia, and 7% of lung cancer (16). In a study of 312,664 patients in the United Kingdom where obstructive lung disease, but not asthma, was entered on the death certificate, either as the primary cause of death or as a comorbidity, only 57% of cases had COPD recorded as the primary cause of death. Approximately 7% of patients died as a result of acute myocardial infarction, 9% died as a result of other ischemic heart disease, 2% of heart failure, and 6% of other cardiac causes. Approximately 3% died of lung cancer, 2% of pneumonia, and 4% from other cancers (17). The coexistence of cardiac disease, particularly coronary artery disease, in patients with COPD might be expected because smoking is the main etiologic factor in both diseases. In addition, there is increasing evidence that systemic inflammatory mediators, such as C-reactive protein (CRP), present in elevated concentrations in patients with COPD, may reflect cardiovascular pathology. A study by Curkendall and coworkers (18) using the Saskatchewan longitudinal database found a significantly increased risk of death from arrhythmia (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.64–1.89), acute myocardial infarction (OR, 1.61; 95% CI, 1.14–2.01), congestive cardiac failure (OR, 3.84; 95% CI, 3.56–4.14), stroke (OR, 1.11; 95% CI, 1.02– 1.21), and pulmonary embolism (OR, 5.46; 95% CI, 4.25–7.02) in individuals with COPD and elevated CRP, compared with ageand sex-matched control subjects. Increased CRP and fibrinogen levels, circulating inflammatory cells, proinflammatory cytokines, and oxidative stress are also associated with muscle wasting and osteoporosis (19).

BURDEN OF COPD The burden to the patient with COPD is high, both in terms of health-related quality of life and health status. Patients experience poor physical functioning and live with distressing symptoms that

require frequent hospital admission as the disease progresses. They are frequently unable to work and may become socially isolated and often depressed. In the Confronting COPD survey (9), 80% of patients had two or more symptoms on most or all days, such as breathlessness (45%), cough (46%), and sputum production (40%). Just over two-thirds of patients were breathless when walking up a flight of stairs and one-third were breathless getting washed or dressed. In addition, 39% of patients woke due to their symptoms at least a few nights each week. Thus, COPD also takes a toll on the patient’s spouse, carer, and family. As well as living with the daily symptoms of stable disease, patients live with the fear of exacerbations, which are common for all levels of lung disease. Exacerbations are associated with significant mortality, lead to frequent hospitalization, and are a major determinant of COPD costs. Recovery from exacerbations is slow and often incomplete, and recurrent exacerbations lead to step-wise decline in lung function and physical status. Data from the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that exacerbations were more common in patients with greater lung function impairment, with an annual exacerbation rate in patients with an FEV1 of less than 1.25 L more than double that in patients with an FEV1 of more than 1.54 L (2.6 vs. 1.2) (20). Data from the East London Cohort Study (21) show that, in the prodrome of an exacerbation, symptoms worsen over a few days, and in many patients symptoms remain worse up to 28 d or longer after the onset of an exacerbation. This increase in symptom severity has a dramatic impact on quality of life; even after 1 mo, the percentage of patients who remain housebound is increased (22). A multicenter 2-yr followup study in Spain demonstrated that repeated exacerbations result in a permanent negative impact on health status (23). Exacerbations are therefore a driving force in a downward spiral of decline in lung function, increased symptoms and frequency of exacerbations, worsening quality of life and increased risk of hospitalization, and, ultimately, death. Exacerbations remain a significant problem as reflected by data on hospital admission rates for COPD in England and Wales, which show a steady increase over the period 1991–1999 (24).

MANAGEMENT OF COPD The GOLD initiative defines a number of objectives for COPD management involving both pharmacologic and nonpharmacologic interventions (Table 2) (25). Current pharmacologic options include drugs used to assist smoking cessation, short- and long-acting ␤2-agonists, short- and long-acting anticholinergics, inhaled corticosteroids, theophylline, N-acetyl cysteine and other

Halpin and Miravitlles: The Burden of COPD TABLE 2. OBJECTIVES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE MANAGEMENT Prevent disease progression Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat exacerbations Prevent and treat complications Reduce mortality Minimize side effects from treatment Based on data from Reference 22.

mucolytics, oxygen, and dietary supplements. Increasingly, multiple drugs are used in combination to provide better symptom control and exacerbation reduction. Smoking cessation is one of the most important aspects of COPD management (2, 25). Stopping smoking reduces the rate of decline of FEV1, symptoms, exacerbation rates, and all-cause mortality (26). Short-acting ␤2-agonists (e.g., salbutamol) and short-acting anticholinergics (e.g., ipratropium), used alone or in combination, are the mainstay of therapy for breathlessness in “mild” disease. Long-acting ␤2-agonists, such as salmeterol or formoterol, and the long-acting anticholinergic tiotropium have quantitatively and qualitatively greater benefits than short-acting drugs (2). As well as reducing breathlessness more effectively, they improve exercise capacity and health status and reduce exacerbation frequency. They may be used alone or in combination with inhaled corticosteroids, and emerging data show additional benefit when combined with long-acting anticholinergic therapy (27). Although data from four large long-term clinical trials showed that inhaled corticosteroids did not affect the rate of decline in FEV1 (20, 28–30), these agents do have a very important effect in reducing exacerbation rates, although there remain uncertainties relating to optimum dose. Inhaled corticosteroids are generally used in combination with long-acting ␤2-agonists; in combination, improvements in exacerbation rates are greater than those seen with the single components alone (2). Theophylline remains a useful bronchodilator and the related phosphodiesterase-4 inhibitors, currently in clinical development, offer the potential of antiinflammatory actions, although their use may be limited by side effects, particularly nausea and diarrhea. The mechanism of action of N-acetyl cysteine is unclear as it may act as a mucolytic or antioxidant; this and other mucolytics may improve cough symptoms in some patients and appear to reduce exacerbation frequency (2). Although the only interventions shown to reduce mortality in clinical trials are smoking cessation (26), long-term oxygen therapy when indicated (31, 32), and dietary supplements in nonobese patients (33), analysis of prescribing databases has suggested that the use of inhaled corticosteroids and combinations of inhaled corticosteroids and long-acting ␤2-agonists may also reduce mortality (34–36). Further information is required from randomized intervention studies such as TORCH (TOward a Revolution in COPD Health), a study involving over 6,000 patients designed to investigate the effect of salmeterol/fluticasone propionate on all-cause mortality compared with placebo (37), to determine whether this effect is real or represents bias in prescribing practice.

THE COST OF COPD COPD generates a high societal and economic cost. The major drivers of the direct cost of COPD (i.e., the cost associated with health care provision and drug costs) are hospital care, medication,

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and oxygen therapy (Table 3) (38), with the magnitude of these costs correlated with disease severity (39), health status, age, and the specialty of the treating physician (38, 40). According to the U.S. National Heart, Lung, and Blood Institute, the estimated direct medical costs of COPD in 1993 were greater than $15.5 billion, with hospitalization accounting for $6.1 billion (39). In Europe, the total annual cost of COPD is estimated at €38.7 billion ($51.2 billion) (41). However, up to 60% of the total costs of COPD may be attributable to indirect costs (38). In Europe, a total of 28.5 million workdays are lost due to COPD (41). In the United Kingdom, COPD is responsible for 9% of certified sickness absence (i.e., 24 million working days lost), with social security costs and the cost of lost productivity estimated at £600 million and £1.5 billion per year, respectively (42). Among the factors that incur indirect costs, mortality is the least rigorously investigated component. Economic analysis of the Confronting COPD in North America and Europe survey (43) estimated the total cost (direct and indirect costs) of COPD at up to $4,119 per patient per year, with just over half of the average direct costs (54%) due to hospitalization and a further 6% attributable to other unscheduled care. Drugs accounted for only 16% of the average annual costs, whereas oxygen accounted for 3% and investigations for 5% (44). The cost of COPD management also varies according to the severity of disease and whether patients are managed in hospital or at home. In a study in Spain of 1,510 patients with COPD monitored over 1 yr, the mean annual cost per patient was $1,876. Hospital costs represented 43% of this cost; drugs, 40%; and consultations and complementary tests, the remaining 17% (45). In comparison, direct health costs based on a cohort of 413 United States’ patients with COPD ranged from $1,681 for patients in stage I disease, $5,037 for patients in stage II, and $10,812 for those in stage III (39). The higher costs in the latter study are mainly due to patients being selected from a population with COPD registered at their hospital, whereas the Spanish study included patients who had consulted their primary care physician.

THE COST OF COPD EXACERBATIONS Exacerbations and hospitalizations constitute the most important direct health care cost associated with COPD. Currently, there is no universally accepted definition, diagnostic test, or biomarker of exacerbation of COPD, and therefore diagnosis is based on clinical criteria. Clearly, there is a need for a standardized definition to enable comparison among different interventions in different settings (46). An exacerbation definition based on resource utilization would seem to be the most relevant. Regardless of which clinical definition of exacerbation is used (20, 47, 48), it is clear that a high proportion of costs in COPD are attributed to exacerbations, from 40 to 57% of the total direct costs (39, 45, 49, 50), and as high as 63% in severely affected patients. The mean cost of hospital admission in a cohort of United States’ patients with severe COPD was estimated to be $7,100 (51). Although the use of interventions to reduce exacerbations is an investment in health, what remains unanswered is how much society is willing to pay for a given reduction in exacerbations.

CONCLUSIONS Despite considerable advances in the management of COPD over recent years, there remain a number of outstanding issues. These include the fact that patients continue to endure disabling symptoms, which worsen as the disease progresses, and many patients still die directly or indirectly of COPD and its complications. The burden of the disease to society is high, and the societal

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TABLE 3. COMPARISON OF THE COSTS PUBLISHED ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN DIFFERENT COUNTRIES Reference

Country

Costs

Cost/Patient/yr

Morera Prat, 1992 (52)

Spain

Direct and indirect €959

Hilleman and colleagues, 2000 (39)

United States

Direct

Jacobson and colleagues, 2000 (53) Wilson and colleagues, 2000 (54)

Sweden

Direct and indirect

United States

Direct

Rutten-van Mo¨lken and colleagues, 2000 (49) Dal Negro and colleagues, 2001 (55)

The Netherlands Direct Italy

Strassels and colleagues, United States 2001 (56) Jansson and colleagues, 2002 (57) Sweden Miravitlles and colleagues, Spain 2003 (45) Masa and colleagues, 2004 (58)

Spain

Stage I ⫽ $1,681 Stage II ⫽ $5,037 Stage III ⫽ $10,812

Emphysema, $1,341 Chronic bronchitis, $816 $876

Global Cost/yr Direct, €319 M Indirect, €541 M

Direct, €109 M Indirect, €541 M $14,500 M

Stage I ⫽ €151 Stage II ⫽ €3,001 Stage III ⫽ €3,912 Direct Total cost $6,469 of which 25% is COPD related ($1,617) Direct and indirect $1,284 $871 Direct Stage I ⫽ €1,185 €427 M Stage II ⫽ €1,640 Stage III ⫽ €2,333 Direct €909.5 €238.8 M

Direct

Definition of abbreviations: COPD ⫽ chronic obstructive pulmonary disease; M ⫽ million.

costs of patients with severe COPD are 4 to 17 times higher than those of patients with mild disease. Patients with comorbid conditions (accounting for 30–57% of patients in different countries) are also costly to society. Although current drug therapy has not been shown to have any significant effect on the accelerated loss of lung function, it does produce significant improvements in symptoms and health status, and reduces the frequency of exacerbations. Reducing the burden of COPD requires better evaluation and diagnosis, as well as improved management of chronic symptoms. A high priority should be given to interventions aimed at delaying the progression of disease, preventing exacerbations, and reducing the risk of comorbidities, to alleviate the clinical and economic burden of COPD. The goal of modern COPD management is the development of therapies that affect the natural history of the disease and, in particular, reduce mortality.

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Conflict of Interest Statement : D.M.G.H. has received sponsorship to attend international meetings and honoraria for lecturing, attending advisory boards, and preparing educational materials from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer. M.M. received $2,500 in 2004 and $ 2,000 in 2005 for serving on an advisory board for GlaxoSmithKline

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