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Is COPD Really a Cardiovascular Disease? FREE TO VIEW

Don D. Sin, MD, FCCP
Author and Funding Information

Don D. Sin, MD, FCCP, James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 368A, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6; e-mail: dsin@mrl.ubc.ca

Dr. Sin is Associate Professor of Medicine, Canada Research Chair in COPD, University of British Columbia, and a Michael Smith Foundation for Health Research Senior Scholar.


The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(2):329-330. doi:10.1378/chest.09-0808
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Published online

It is now well established that COPD is a chronic inflammatory condition with significant extrapulmonary manifestations.1 In patients with mild-to-moderate COPD, the leading cause of morbidity and mortality is cardiovascular disease. In the Lung Health Study,2 which examined nearly 6,000 smokers whose FEV1 was between 55% and 90% predicted, cardiovascular diseases were the leading cause of hospitalization, accounting for nearly 50% of all hospital admissions, and the second leading cause of mortality, accounting for a quarter of all deaths. Subsequent studies3 have confirmed that, on average, patients with COPD have two to three times the risk of hospitalization for cardiovascular conditions (including ischemic heart disease, stroke, and heart failure) compared to those patients without COPD. However, in more severe stages of disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 3 and 4), the clinical relevance of cardiovascular disease is less certain. The conventional wisdom is that in these groups of patients “lung failure” is the predominant driver of morbidity and mortality, and that other “comorbidities,” including cardiovascular disease, play less important roles. This notion is supported by large-scale COPD studies such as that by Celli et al,4 which reported that 61% of patients with predominantly GOLD 3 and 4 stage disease died from respiratory failure; whereas, only 14% died from myocardial ischemia.4 In a more recent study, the Towards a Revolution in COPD Health (or TORCH) investigators5 demonstrated that 35% of predominantly GOLD 3 and 4 patients died from respiratory failure; whereas only 10% died of a clear cut cardiovascular event such as myocardial ischemia, heart failure, or stroke. Although the Towards a Revolution in COPD Health study5 and other studies2,4,6 went to extreme measures to ensure the accuracy of the reporting of the underlying causes of death, there were nevertheless some important limitations. In most cases, investigators relied on death certificates or medical records of events that led to the patient's demise for attributing causality. However, even with detailed documentation, assigning a cause of mortality based on these sources can be problematic and fraught with significant misclassification errors.7 Autopsies, on the other hand, are less susceptible to this type of error and are a more accurate means of attributing causality. However, previous autopsy studies8 of patients dying with COPD have produced heterogeneous results owing largely to selection bias of cases included in each of the series. This is not surprising given that only a very select (and biased) sample of cases go on to autopsies.8

In this issue of CHEST (see page 376), Zvezdin and colleagues9 overcome this major limitation of previous studies by reporting on an autopsy series of 43 consecutive patients who were admitted to the hospital for an acute exacerbation and died within 24 h of hospitalization. Because the local jurisdiction mandates that all patients who die within this 24 h window undergo an autopsy, these investigators were able to evaluate all decedents, thus avoiding selection bias. Although the study was small, there were several notable findings. First, they found that the leading cause of death was, surprisingly, not respiratory failure but cardiac failure, accounting for 37% of all deaths, followed by pneumonia and thromboembolic events, each contributing 28% and 21%, respectively, to total mortality. Only 14% of the deaths could be primarily attributed to respiratory failure secondary to COPD. Interestingly, there were six patients, who were (incidentally) found to have carcinoma at autopsy, but all of them died from another cause. Second, because a majority of these patients were smokers and had multiple comorbid conditions, none of the routinely collected demographic or clinical data, including patient symptoms, and the findings of general blood tests, chest radiographs, and ECGs, could reliably predict the causes of death before the terminal event. It is plausible that the wider use of more sensitive instruments such as CT scanning or blood tests including serum troponin or brain natriuretic peptide levels may have increased the diagnostic yield of these terminal events. Third, a majority of patients in this study died of causes that were potentially modifiable but only if they had been diagnosed early and treated promptly. In this study, although all patients received appropriate therapies for their lung disease,1 only one-third of patients who eventually died from thromboembolic disease received anticoagulant therapy (likely due to delayed diagnosis). It is unclear how many of the patients who died from cardiac failure had received anti-heart failure medications, including diuretics, statins, angiotensin-converting enzyme inhibitors, or β-blockers, which are life preserving even in patients with COPD,10,11 but based on prior literature on COPD,10,11 it is likely that very few of these patients would have received these medications. This begs the following question: could some of these deaths have been averted had the diagnosis of thromboembolic disease or cardiac failure been made earlier in the course of their illness? Clinical intuition, along with prior clinical studies,12,13 suggest that this is likely.

There were limitations to the study by Zvezdin et al,9 including small sample size and the lack of information regarding COPD deaths after the first 24 h of hospitalization. Notwithstanding these shortcomings, the study by Zvezdin and colleagues9 adds a critical piece of information that enhances our understanding of COPD. Contrary to the conventional paradigm that most patients with an acute exacerbation of COPD die simply from progressive respiratory failure secondary to their underlying lung disease, the study by Zvezdin et al9 indicates that these patients die from a complex web of interconnected comorbidities, including cardiac failure, pneumonia, and thromboembolism. The clinical implication of this new knowledge is that when physicians are confronted by a patient experiencing a COPD exacerbation, they must resist the “knee-jerk” reaction of instituting anti-COPD interventions without adequately considering other possibilities for the patients worsening “respiratory” status. We now have sophisticated and accurate laboratory and imaging techniques and decision rules to diagnose thromboembolic disease, pneumonia, and cardiac failure in COPD patients, which can facilitate the prompt diagnosis and early institution of treatment for these conditions.1416 Hopefully, by doing so, we can curb the growing morbidity and mortality that results from COPD, which in just 10 years will be the third leading cause of death worldwide.1

References

Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-555. [PubMed] [CrossRef]
 
Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA. 1994;272:1497-1505. [PubMed]
 
Sidney S, Sorel M, Quesenberry CP Jr, et al. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest. 2005;128:2068-2075. [PubMed]
 
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005-1012. [PubMed]
 
McGarvey LP, John M, Anderson JA, et al. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;62:411-415. [PubMed]
 
Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554. [PubMed]
 
Jensen HH, Godtfredsen NS, Lange P, et al. Potential misclassification of causes of death from COPD. Eur Respir J. 2006;28:781-785. [PubMed]
 
Janssens JP, Herrmann F, MacGee W, et al. Cause of death in older patients with anatomo-pathological evidence of chronic bronchitis or emphysema: a case-control study based on autopsy findings. J Am Geriatr Soc. 2001;49:571-576. [PubMed]
 
Zvezdin B, Milutinov S, Koijicic M, et al. A post-mortem analysis of major causes of early death in patients hospitalized with chronic obstructive pulmonary disease. Chest. 2009;136:376-380. [PubMed]
 
Mancini GB, Etminan M, Zhang B, et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;47:2554-2560. [PubMed]
 
van Gestel YR, Hoeks SE, Sin DD, et al. Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis. Am J Respir Crit Care Med. 2008;178:695-700. [PubMed]
 
Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med. 1997;157:2317-2321. [PubMed]
 
Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA. 1997;278:2080-2084. [PubMed]
 
Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144:390-396. [PubMed]
 
Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294:1944-1956. [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250. [PubMed]
 

Figures

Tables

References

Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-555. [PubMed] [CrossRef]
 
Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA. 1994;272:1497-1505. [PubMed]
 
Sidney S, Sorel M, Quesenberry CP Jr, et al. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest. 2005;128:2068-2075. [PubMed]
 
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005-1012. [PubMed]
 
McGarvey LP, John M, Anderson JA, et al. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;62:411-415. [PubMed]
 
Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554. [PubMed]
 
Jensen HH, Godtfredsen NS, Lange P, et al. Potential misclassification of causes of death from COPD. Eur Respir J. 2006;28:781-785. [PubMed]
 
Janssens JP, Herrmann F, MacGee W, et al. Cause of death in older patients with anatomo-pathological evidence of chronic bronchitis or emphysema: a case-control study based on autopsy findings. J Am Geriatr Soc. 2001;49:571-576. [PubMed]
 
Zvezdin B, Milutinov S, Koijicic M, et al. A post-mortem analysis of major causes of early death in patients hospitalized with chronic obstructive pulmonary disease. Chest. 2009;136:376-380. [PubMed]
 
Mancini GB, Etminan M, Zhang B, et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;47:2554-2560. [PubMed]
 
van Gestel YR, Hoeks SE, Sin DD, et al. Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis. Am J Respir Crit Care Med. 2008;178:695-700. [PubMed]
 
Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med. 1997;157:2317-2321. [PubMed]
 
Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA. 1997;278:2080-2084. [PubMed]
 
Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144:390-396. [PubMed]
 
Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294:1944-1956. [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250. [PubMed]
 
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