Review
Chronic obstructive pulmonary disease and comorbidities Marc Decramer, Wim Janssens
Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensinconverting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of socalled spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic antiinflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive debilitating disease with high prevalence. It is the fourth most prevalent cause of death and is responsible for very high expenditures in the health-care system. Global economic costs generated by COPD amount to US$2·1 trillion and are expected to increase to $4·8 trillion by 2030.1 A considerable proportion of these costs is due to the fact that this is a complex disease associated with several serious comorbidities.2 Many comorbidities are associated with COPD, and those for which there are the most data include cardiovascular and cerebrovascular disease, lung cancer, diabetes, muscle weakness, osteoporosis, and anxiety and depression. A randomly selected sample of 1522 patients who were enrolled in a health maintenance organisation in 1997, had on average 3·7 comorbid disorders compared with 1·8 in controls.3 These comorbidities contribute substantially to reduced health status, increased healthcare utilisation, all-cause hospital admission, and mortality.4,5 In fact, patients with COPD are more likely to die from comorbidities than from the disease itself. In a well-designed study in which a panel of senior physicians critically studied and adjudicated the causes of death in patients with COPD, only 40% of deaths were definitely or probably related to COPD, whereas 50% were unrelated to COPD, and 9% were unknown.6 A third of the deaths were due to cardiovascular disease. We will briefly review the evidence for a link between COPD and the major comorbidities of the disease, with a focus on the mechanisms of their association with COPD, and discuss the implications of these links to the treatment of COPD. We only address the major comorbidities, for which mechanistic links with COPD have recently been studied.
Cardiovascular disease Cardiovascular disease is not a clearly defined disorder. It usually encompasses ischaemic heart disease, congestive heart failure, pulmonary vascular disease, coronary artery disease, peripheral vascular disease, and stroke www.thelancet.com/respiratory Vol 1 March 2013
and transient ischaemic attack. It might also include biomarkers of disease such as lipid abnormalities or inflammatory markers of disease. This section will mainly focus on ischaemic heart disease, because recent mechanistic work has focused on this area. The association of COPD with cardiovascular disease is well established.3,7 Progressive respiratory failure only accounts for about a third of COPD deaths, suggesting that many patients with COPD die from other causes.8 In a pooled analysis of two large epidemiological studies— the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS)—including more than 20 000 adults, the prevalence of cardiovascular disease in patients with COPD was 20–22% compared with 9% in people without COPD.7 In the ARIC study, 32% of deaths in people with severe COPD (Global Initiative for Obstructive Lung Disease [GOLD] stage III and IV) were due to respiratory causes, whereas 24% were due to lung cancer and 13% were cardiac-related. This high prevalence of cardiovascular mortality was supported by the adjudicated causes of death reported in the Towards a Revolution in COPD Health (TORCH) study.6 In patients with moderate COPD (GOLD stage II) only 4% of deaths were respiratory-related, 25% were due to lung cancer, and 28% were cardiac-related.9 In a recent review, Sin and colleagues10 compiled evidence for the relation between forced expiratory volume in 1 s (FEV1) and these causes of death (figure 1).10 Taken together, these data show that a substantial proportion of mortality in patients with COPD is due to cardiovascular disease and lung cancer, particularly in patients with mild and moderate disease. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) further corroborated the relation between reduced pulmonary function and cardiovascular mortality. The analysis showed that patients with reduced pulmonary function had increased cardiovascular mortality, even those with small decrements that strictly fell within the normal range.11 This relation was also shown in lifetime nonsmokers, suggesting that exposure to tobacco smoke was not the sole reason for this association.11
Lancet Respir Med 2013; 1: 73–83 Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(12)70060-7 Respiratory Division, University of Leuven, Leuven, Belgium (Prof M Decramer MD, W Janssens MD) Correspondence to: Prof Marc Decramer, Chief Respiratory Division, University Hospital, University of Leuven, Herestraat 49, 3000 Leuven, Belgium [email protected]
73
Review
(1) (2)
80
60 Total mortality (%)
(3)
(4)
Lung cancer Cardiovascular disease Respiratory failure
40
20
0 0
20
40 60 Mean FEV1 (% predicted)
80
100
Figure 1: Relation between lung function and death due to cardiovascular disease, lung cancer, and respiratory failure Data are taken from four large cohorts of patients with COPD based on different mean forced expiratory volume in 1 s (FEV1) values (1–4).10 Reproduced from Sin and colleagues,10 by permission of the European Respiratory Society.
Smoking Lung oxidative stress inflammation
Airway remodelling and emphysema
Inactivity
Poor diet
Systemic oxidative stress inflammation
Ageing Genetics
Endothelial dysfunction and vascular inflammation
COPD
Arteriosclerosis
Exacerbations
Plaque rupture
Arterial hypertension Obesity Diabetes Hypercholesterolaemia
AMI/stroke
Figure 2: Associations between COPD and cardiovascular disease Ageing and genetics are inherent processes (pink box) that affect all the other mechanisms, whereas smoking, inactivity, poor diet, and exacerbations are modifiable environmental factors (purple boxes). Green boxes represent the diseases (COPD or comorbidities of COPD). COPD=chronic obstructive pulmonary disease. AMI=acute myocardial infarction.
Findings from several studies further support the links between COPD and incidence of cardiovascular disease. First, results of a large population-based study showed an increased relative risk of comorbid cardiovascular disease and subsequent myocardial infarction and stroke in patients with COPD.12 Second, arterial stiffness, measured non-invasively as aortic pulse wave velocity, is a known marker of cardiovascular events and mortality in the general population. Patients with COPD have been shown to have increased arterial stiffness13 compared with age-matched and smoking-matched controls, and this arterial stiffness was associated with the extent of airflow obstruction and CT-quantified emphysema.14 Third, findings from two studies showed a relation between COPD and either previous cerebrovascular events15 or incidence of acute stroke.12 74
Finally, COPD was shown to be associated with diseases that enhance the cardiovascular risk profile. In the previously mentioned combined analysis of the ARIC and CHS population-based studies, the odds ratio for having hypertension compared with healthy people was 1·4 in patients with GOLD stage II COPD, and 1·6 in those with GOLD stage III and IV COPD.7 Most studies did not find associations between COPD and dyslipidaemia or metabolic syndrome.16 Several studies reported an enhanced prevalence of diabetes in patients with COPD,7,9,12,16,17 but the odds ratio of patients with COPD having diabetes was reduced in those older than 65 years.12 An association between COPD and diabetes, however, was not noted in another meta-analysis.18 The mechanistic links between COPD and cardiovascular disease are complex, multifactorial, and not entirely understood (figure 2). The observed association between both diseases is to a large extent explained by the presence of common risk factors. Within these factors distinction can be made between environmental risk factors, most of them being largely modifiable (lifestyle), and inherent risk factors that predispose individuals to disease, but which cannot be changed. Of all combined risk factors, smoking is by far the most important, but the risk attributable to inactivity and unhealthy diet should not be underestimated. Genetic predisposition and ageing are inherent factors, but still poorly understood. By contrast with COPD, for which the amount of pack-years smoked is an important risk determinant,19 cardiovascular risk is known to steeply increase with very low levels of smoke exposure and to flatten out with high exposure levels.20 Small inhaled particles (particulate matter [PM] 2·5, diameter
Chronic obstructive pulmonary disease and comorbidities Marc Decramer, Wim Janssens
Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensinconverting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of socalled spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic antiinflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive debilitating disease with high prevalence. It is the fourth most prevalent cause of death and is responsible for very high expenditures in the health-care system. Global economic costs generated by COPD amount to US$2·1 trillion and are expected to increase to $4·8 trillion by 2030.1 A considerable proportion of these costs is due to the fact that this is a complex disease associated with several serious comorbidities.2 Many comorbidities are associated with COPD, and those for which there are the most data include cardiovascular and cerebrovascular disease, lung cancer, diabetes, muscle weakness, osteoporosis, and anxiety and depression. A randomly selected sample of 1522 patients who were enrolled in a health maintenance organisation in 1997, had on average 3·7 comorbid disorders compared with 1·8 in controls.3 These comorbidities contribute substantially to reduced health status, increased healthcare utilisation, all-cause hospital admission, and mortality.4,5 In fact, patients with COPD are more likely to die from comorbidities than from the disease itself. In a well-designed study in which a panel of senior physicians critically studied and adjudicated the causes of death in patients with COPD, only 40% of deaths were definitely or probably related to COPD, whereas 50% were unrelated to COPD, and 9% were unknown.6 A third of the deaths were due to cardiovascular disease. We will briefly review the evidence for a link between COPD and the major comorbidities of the disease, with a focus on the mechanisms of their association with COPD, and discuss the implications of these links to the treatment of COPD. We only address the major comorbidities, for which mechanistic links with COPD have recently been studied.
Cardiovascular disease Cardiovascular disease is not a clearly defined disorder. It usually encompasses ischaemic heart disease, congestive heart failure, pulmonary vascular disease, coronary artery disease, peripheral vascular disease, and stroke www.thelancet.com/respiratory Vol 1 March 2013
and transient ischaemic attack. It might also include biomarkers of disease such as lipid abnormalities or inflammatory markers of disease. This section will mainly focus on ischaemic heart disease, because recent mechanistic work has focused on this area. The association of COPD with cardiovascular disease is well established.3,7 Progressive respiratory failure only accounts for about a third of COPD deaths, suggesting that many patients with COPD die from other causes.8 In a pooled analysis of two large epidemiological studies— the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS)—including more than 20 000 adults, the prevalence of cardiovascular disease in patients with COPD was 20–22% compared with 9% in people without COPD.7 In the ARIC study, 32% of deaths in people with severe COPD (Global Initiative for Obstructive Lung Disease [GOLD] stage III and IV) were due to respiratory causes, whereas 24% were due to lung cancer and 13% were cardiac-related. This high prevalence of cardiovascular mortality was supported by the adjudicated causes of death reported in the Towards a Revolution in COPD Health (TORCH) study.6 In patients with moderate COPD (GOLD stage II) only 4% of deaths were respiratory-related, 25% were due to lung cancer, and 28% were cardiac-related.9 In a recent review, Sin and colleagues10 compiled evidence for the relation between forced expiratory volume in 1 s (FEV1) and these causes of death (figure 1).10 Taken together, these data show that a substantial proportion of mortality in patients with COPD is due to cardiovascular disease and lung cancer, particularly in patients with mild and moderate disease. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) further corroborated the relation between reduced pulmonary function and cardiovascular mortality. The analysis showed that patients with reduced pulmonary function had increased cardiovascular mortality, even those with small decrements that strictly fell within the normal range.11 This relation was also shown in lifetime nonsmokers, suggesting that exposure to tobacco smoke was not the sole reason for this association.11
Lancet Respir Med 2013; 1: 73–83 Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(12)70060-7 Respiratory Division, University of Leuven, Leuven, Belgium (Prof M Decramer MD, W Janssens MD) Correspondence to: Prof Marc Decramer, Chief Respiratory Division, University Hospital, University of Leuven, Herestraat 49, 3000 Leuven, Belgium [email protected]
73
Review
(1) (2)
80
60 Total mortality (%)
(3)
(4)
Lung cancer Cardiovascular disease Respiratory failure
40
20
0 0
20
40 60 Mean FEV1 (% predicted)
80
100
Figure 1: Relation between lung function and death due to cardiovascular disease, lung cancer, and respiratory failure Data are taken from four large cohorts of patients with COPD based on different mean forced expiratory volume in 1 s (FEV1) values (1–4).10 Reproduced from Sin and colleagues,10 by permission of the European Respiratory Society.
Smoking Lung oxidative stress inflammation
Airway remodelling and emphysema
Inactivity
Poor diet
Systemic oxidative stress inflammation
Ageing Genetics
Endothelial dysfunction and vascular inflammation
COPD
Arteriosclerosis
Exacerbations
Plaque rupture
Arterial hypertension Obesity Diabetes Hypercholesterolaemia
AMI/stroke
Figure 2: Associations between COPD and cardiovascular disease Ageing and genetics are inherent processes (pink box) that affect all the other mechanisms, whereas smoking, inactivity, poor diet, and exacerbations are modifiable environmental factors (purple boxes). Green boxes represent the diseases (COPD or comorbidities of COPD). COPD=chronic obstructive pulmonary disease. AMI=acute myocardial infarction.
Findings from several studies further support the links between COPD and incidence of cardiovascular disease. First, results of a large population-based study showed an increased relative risk of comorbid cardiovascular disease and subsequent myocardial infarction and stroke in patients with COPD.12 Second, arterial stiffness, measured non-invasively as aortic pulse wave velocity, is a known marker of cardiovascular events and mortality in the general population. Patients with COPD have been shown to have increased arterial stiffness13 compared with age-matched and smoking-matched controls, and this arterial stiffness was associated with the extent of airflow obstruction and CT-quantified emphysema.14 Third, findings from two studies showed a relation between COPD and either previous cerebrovascular events15 or incidence of acute stroke.12 74
Finally, COPD was shown to be associated with diseases that enhance the cardiovascular risk profile. In the previously mentioned combined analysis of the ARIC and CHS population-based studies, the odds ratio for having hypertension compared with healthy people was 1·4 in patients with GOLD stage II COPD, and 1·6 in those with GOLD stage III and IV COPD.7 Most studies did not find associations between COPD and dyslipidaemia or metabolic syndrome.16 Several studies reported an enhanced prevalence of diabetes in patients with COPD,7,9,12,16,17 but the odds ratio of patients with COPD having diabetes was reduced in those older than 65 years.12 An association between COPD and diabetes, however, was not noted in another meta-analysis.18 The mechanistic links between COPD and cardiovascular disease are complex, multifactorial, and not entirely understood (figure 2). The observed association between both diseases is to a large extent explained by the presence of common risk factors. Within these factors distinction can be made between environmental risk factors, most of them being largely modifiable (lifestyle), and inherent risk factors that predispose individuals to disease, but which cannot be changed. Of all combined risk factors, smoking is by far the most important, but the risk attributable to inactivity and unhealthy diet should not be underestimated. Genetic predisposition and ageing are inherent factors, but still poorly understood. By contrast with COPD, for which the amount of pack-years smoked is an important risk determinant,19 cardiovascular risk is known to steeply increase with very low levels of smoke exposure and to flatten out with high exposure levels.20 Small inhaled particles (particulate matter [PM] 2·5, diameter
