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The Proceedings of the American Thoracic Society 3:635-640 (2006)
© 2006 The American Thoracic Society
doi: 10.1513/pats.200603-094SS
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Chronic Obstructive Pulmonary Disease, Risk Factors, and Outcome Trials

Comparisons with Cardiovascular Disease

Scott D. Ramsey and F. D. Richard Hobbs

University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington; and Department of Primary Care and General Practice, University of Birmingham, Edgbaston, United Kingdom

Correspondence and requests for reprints should be addressed to Professor Richard Hobbs, M.B., F.R.C.G.P., F.R.C.P., F. Med. Sci., Department of Primary Care and General Practice, University of Birmingham, Edgbastan, Birmingham B15 2TT, UK. E-mail: f.d.r.hobbs{at}bham.ac.uk

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a major health problem and now ranks fifth in terms of the global burden of disease. Although COPD is a disease that is characterized by progressive respiratory symptoms and functional decline, exacerbations pose the greatest risk for morbidity and early mortality, have a dramatic effect on quality of life, and are the most significant source of health care expenditure. To improve survival and reduce costs, it is critical to develop effective programs designed to reduce the frequency and severity of exacerbations for these patients. With limited health care resources, efficient and effective management of COPD ideally involves identifying and focusing efforts on individuals at particular risk. In the development of an appropriate multimodal strategy, lessons could be learned from the evolution of guidelines and management of cardiovascular disease, in particular heart failure, which has many parallels with COPD in terms of prevalence, prognosis, and impact on patient quality of life. There is a need for large prospective trials in COPD, based on hard clinical outcomes such as death, which, together with physician and patient education, will help to drive improvements in clinical management.

Key Words: chronic obstructive pulmonary disease • clinical management • exacerbations • risk factors

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. The prevalence of the condition is also increasing, and COPD now ranks fifth in terms of the global burden of disease, measured as disability-adjusted life-years (Table 1) (1), and is the fifth leading cause of premature mortality (2). However, prevalence and mortality data largely underestimate the true burden of COPD because the condition is usually not recognized until is clinically apparent and moderately advanced.


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  		TABLE 1. LEADING CAUSES OF DEATH AND DISABILITY (DISABILITY-ADJUSTED LIFE-YEARS)

 
Although COPD is a disease that is characterized by progressive respiratory symptoms and functional decline, exacerbations pose the greatest risk for morbidity and early mortality, have a dramatic effect on quality of life, and are the most significant driver of healthcare expenditure. To improve survival and reduce costs, it is critical to develop effective programs designed to reduce the frequency and severity of exacerbations for these patients. In particular, clinicians need to be able to identify individuals at high risk for adverse outcomes (functional decline, exacerbations, and premature mortality) in COPD and to identify effective interventions that can lower the risk of such outcomes. In developing new strategies for management of COPD, valuable lessons can be gleaned from the approaches adopted in the management of certain cardiovascular disorders.

IDENTIFYING RISK FACTORS FOR ADVERSE OUTCOMES IN COPD

Functional Decline
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (3) identify six factors associated with functional decline. These factors are grouped into host factors (e.g., {alpha}1-antitrypsin deficiency) and exposures (e.g., tobacco smoke, occupational dusts and chemicals, indoor and outdoor air pollution, infections, and low socioeconomic status).

Smoking is considered by far the most important risk factor associated with functional decline in COPD (4). As well as having more respiratory symptoms, smokers also have a greater annual rate of lung function decline, as assessed by change in FEV1, and are at greater risk of premature mortality due to COPD than nonsmokers (5, 6). In the Lung Health Study (7), middle-aged smokers who continued smoking had an accelerated loss in FEV1 compared with nonsmokers. Stopping smoking can prevent the onset of disability and reduce the rate of functional decline and the risk of premature mortality (5, 6). However, it is likely that previous studies (6) have oversimplified this scenario in assuming that all individuals have 100% FEV1 before the onset of COPD and that all individuals show the same course of deterioration. In addition, individuals with COPD are at increased risk of death from other causes, such as lung cancer and cardiovascular disease, which may complicate this paradigm. Irrespective of such considerations, stopping smoking has positive benefits on functional decline in individuals with COPD. Clinical and economic evidence supporting the value of tobacco cessation is overwhelming (4). A multimodal strategy, including physician counseling, medications, and follow-up, as recommended by a recent U.S. Public Health Report (4), is essential.

Exposure to occupational dusts and chemicals and air pollution are important risk factors and can cause COPD independently of tobacco smoke (8). Such exposure results in inflammation, a key factor in the pathogenesis of COPD. Chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature are hallmarks of the disease process and lead to the pathologic changes characteristic of COPD.

Viral infection, in particular influenza, plays an important role in exacerbation of COPD and associated functional decline. There is clear evidence that influenza vaccines can reduce serious illness and death in patients with COPD by about 50%, irrespective of the severity of disease (9, 10). The evidence supporting pneumococcal vaccine in patients with COPD is relatively weak, indicating a need for large international trials to fully address this issue.

Exacerbations
The progressive course of COPD is complicated by exacerbations. There are many approaches to defining an exacerbation, but to assess their impact on COPD-related costs and patient well-being, a "health services" perspective is useful. This defines an exacerbation as an event of respiratory distress that compels the patient to seek urgent care and may result a change in therapy (e.g., the use of antibiotics and/or oral corticosteroids) and, in some cases, hospitalization. Preventing exacerbations requires a multidimensional approach to prevent further functional decline (which raises the overall risk for exacerbations) and requires identification, for a given functional level, of those particular risk factors for severe respiratory distress.

There are many risk factors for COPD exacerbation that go beyond FEV1 decline and reflect the systemic nature of the disease. Key factors associated with increased risk for COPD exacerbation identified are listed in Table 2. Pulmonary hypertension, hypoxia and hypercapnia, and poor health status are also recognized as risk factors. Foremost of all these factors is previous hospitalization for COPD. With the exception of smoking, these factors are not directly modifiable.


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  		TABLE 2. RISK FACTORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATION

 
From the perspective of the primary care physician, improving the identification of individuals at risk of an exacerbation may optimize appropriate intervention. FEV1 has been proposed as an objective means of identifying individuals at greatest risk in much the same way cholesterol is used to identify cardiovascular risk. Studies suggest that exacerbations among patients with COPD increases among those with an FEV1 < 50% of predicted (11, 12). Furthermore, FEV1 also seems to be influenced by exacerbations, thus creating an interrelated cycle of respiratory decline. In a recent study (13) involving 109 patients with COPD monitored for a 4-yr period, individuals with frequent exacerbations had a significantly faster decline in FEV1 than patients who experienced less frequent exacerbations and were more often admitted to hospital and had a longer duration of stay.

Body weight is also an important factor influencing risk of hospitalization for COPD (14, 15). Low body weight (in particular, body mass index < 20 kg/m2) and weight loss have been shown to be independent risk factors for an acute COPD exacerbation. In one study, low body weight and weight loss increased risk by 22% and 24%, respectively, whereas no significant association was shown for FEV1, sex, age, or cigarette pack-years (14). Body mass index was also likely to identify patients at increased risk of hospitalization for a COPD exacerbation (15). These data indicate the importance of monitoring weight changes and nutritional status in patients with at least moderately severe COPD, something that is feasible in the primary practice setting.

Approximately 25% of patients with stable COPD are positive for potentially pathogenic micoorganisms, and prevalence is higher in patients with more severe COPD. In addition to lung function impairment, a high bacterial load may be an independent risk factor for an exacerbation (16). Furthermore, certain types of organisms further increase this risk, particularly Haemophilus influenzae and Pseudomonas aeruginosa. It is possible that the extent of microbial colonization is a marker of disease severity; when defense mechanisms are overcome, the increased microbial load and colonization with P. aeruginosa may result in the development of an inflammatory response that may clinically manifest as a COPD exacerbation.

Quality-of-life data derived from respiratory questionnaires can also be used as predictors of the risk of COPD exacerbation. Fan and colleagues have modeled data from patients with severe emphysema randomized to medical therapy (about 600 patients) in the National Emphysema Treatment Trial and showed that a low score for every specific quality-of-life measure assessed (e.g., University of California, San Diego Shortness of Breath Questionnaire, St. George's Respiratory Questionnaire, or the 6-min walk test), independently predicted the likelihood of exacerbation. However, the most important predictors of risk were prior COPD hospitalization or emergency department visit, and hypoxia (17).

The emergency (casualty) department is an important setting for the management of moderate to severe COPD exacerbations (18). A substantial proportion of patients with COPD experience relapse (i.e., urgent clinic or emergency department visit for worsening COPD) after treatment; one in five experiences relapse requiring repeat emergency department treatment within 2 wk (19). Such information could be used in predicting the risk of COPD exacerbation by the primary care physician, although, as for myocardial infarction (MI) and coronary heart disease (CHD), this predictor relates to more severe or advanced disease and is therefore much less desirable than the risk factors previously discussed.

Mortality
Risk factors for early mortality are much the same as those for risk for exacerbations. Among patients who are hospitalized, risks for in-hospital mortality include PaO2/FIO2 ratio, APACHE (Acute Physiology and Chronic Health Status Evaluation) II score on admission, low serum albumin (a measure of nutritional status), the presence of cor pulmonale, poor exercise capacity, and long-term oral steroid use (Table 3). Indices of several respiratory and systemic risk factors seem to have better predictive capacity than the individual factors themselves (20). Hospitalization carries a substantial risk for mortality (21) and often indicates a rapid course toward death. Postdischarge survival is of the same order as that reported for heart failure, with an estimated 5-yr survival of 35 to 45% (22) (Figure 1). Risk factors for mortality postdischarge are similar to those during hospitalization (Table 3). Duration of hospital stay is a predictor, reflecting the severity of illness and increased risk of nosocomial infection during hospitalization. Long-term oral steroid use in patients with emphysema should be avoided (22); this message needs to be reemphasized among the primary care community.


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  		TABLE 3. RISK FACTORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE MORTALITY

 

Figure 1
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  		Figure 1. Postdischarge survival in patients hospitalized with chronic obstructive pulmonary disease exacerbation. Modified by permission from Reference 19.

 
In addition to careful pharmacologic management, oxygen therapy and pulmonary rehabilitation are beneficial in reducing the risk of mortality (22) and the risk of readmission for an exacerbation (23). Although hospital admission for COPD exacerbation is recognized as a risk factor for premature mortality by primary care physicians, the benefits of getting patients into a pulmonary rehabilitation program and reducing their risk for further hospitalization are less well known and should therefore be emphasized within primary practice.

HOW CAN CLINICAL TRIALS IMPROVE THE MANAGEMENT OF COPD? LESSONS FROM CARDIOVASCULAR TRIALS

Because COPD is an increasingly prevalent condition associated with increased premature mortality, poor quality of life for patients, and increasing health care resource use, COPD has many parallels with cardiovascular disease, in particular heart failure. However, the impact of clinical trials on the management of COPD has been markedly less than clinical trials in cardiology. Moreover, there are no major health system targets for the management of COPD, unlike cardiovascular disease. Are there lessons from cardiovascular disease about conducting trials that can affect clinical practice?

Epidemiologic Evidence as Rationale for Clinical Trials
Over the last decade, most notably over the last 5 yr, epidemiologic evidence has increasingly been used to provide the rationale for clinical trials in cardiovascular disease, reflecting clinicians' growing awareness of the importance of risk factors in clinical management. Epidemiologic data provided the novel concept that risk factors clustered in individuals and that the effects of these risk factors were multiplicative rather than additive. Moreover, data from the INTERHEART study (24), a global study involving 52 countries, confirmed that the traditional nine risk factors explained over 90% of the attributable population risk for MI. Thus, the findings from the INTERHEART study reemphasized the importance of assessing and managing these key risk factors to reduce cardiovascular risk. These data led to the development of risk-scoring systems for predicting cardiovascular events in people in the primary prevention setting. In other words, funding with health care systems was justified because physicians were able to target individuals at increased risk on the basis of a predefined risk score. This approach to cardiovascular disease management has become accepted within most health care systems in Europe and the United States.

Not only do physicians want to understand which risk factors are important so that they can intervene to prevent the development of cardiovascular disease but they also want to know which treatments are most effective. In the planning of clinical trials, there has been a focus on conducting clinical trials with adequate statistical power and using hard outcomes, such as death, to evaluate treatment effects and translate findings to clinical practice.

The Importance of Large, Outcome-based Clinical Studies: The Statin Story
The early introduction of the statins was associated with extensive negative concern, particularly regarding their safety profile, which persisted until the early 1990s. What changed clinical opinion and practice was the Scandinavian Simvastatin Survival Study (4S) (25), the first of the landmark studies that assessed treatment effects on hard outcomes, such as total mortality, CHD death, and nonfatal MI. The 4S was specifically designed to evaluate the effect of simvastatin therapy (20 or 40 mg once daily titrating to a total cholesterol target of 3–5.2 mmol/L) on predefined major clinical outcomes in 4,444 high-risk patients with established CHD and, at that stage, modest cholesterol levels. Safety assessment was also a priority in 4S. The rationale for 4S was provided by epidemiologic evidence that predicted that coronary events would be reduced by statin therapy.

The 4S study demonstrated a highly significant risk reduction in terms of overall mortality and major coronary events at 6 yr. Subgroup analyses showed that these results were consistent across the different sexes and age groups, irrespective of concomitant medication and comorbidities. After 4S, there was a succession of statin studies in secondary and primary prevention settings. The largest of these was the Heart Protection Study (26), which showed that statins have as big an impact on stroke prevention as they do on CHD. These studies demonstrated consistent findings (Figure 2) and when analyzed together confirmed a 21 to 23% risk reduction (dependent on outcome) for every 1-mmol/L reduction in low-density lipoprotein cholesterol (27). Evidence from these large trials affected treatment guidelines, permitting definitive recommendations about when treatment should be started (cholesterol thresholds) and on target cholesterol levels. Data from the Heart Protection Study suggested that the statins remain effective irrespective of baseline cholesterol levels (26). Subsequent major studies (28, 29) have contributed to the consensus on target levels, with the most recent indicating that further reducing target low-density lipoprotein cholesterol levels (from < 2.6 to 1.8 mmol/L [< 100–70 mg/dl]) in stable post-MI patients with aggressive statin therapy further reduced the risk of major coronary events and led to a reevaluation of treatment guidelines in the United States (30) and in the United Kingdom (31). Thus, landmark trials based on hard outcomes such as mortality are rapidly driving guideline recommendations and are rapidly being updated on the basis of outcome data from new clinical trials, leading to increased prescribing in clinical practice.


Figure 2
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  		Figure 2. Impact of statin trials on the development and evolution of treatment guidelines for cardiovascular disease prevention. Definition of abbreviations: NCEP = National Cholesterol Education Program; JBS = Joint British Societies; Eur Joint = Joint European Societies; ATV = atovastatin; LDL-C = low-density lipoprotein; PRA = Pravastatin; Rx = treatment; plac = placebo; HPS = Heart Protection Study; CARE = Cholesterol and Recurrent Events Trial; LIPID = Long-term interevention with Pravastatin in ischaemic Disease; 4S = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study; PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; TNT = Treating to New Targets; ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial. Modified by permission from Reference 41.

 
Trials in Heart Failure
The heart failure trials perhaps provide a better example in terms of messages for COPD. As for COPD, heart failure is common and increasingly becoming more so, although (as for COPD) prevalence rates tend to be underestimated (32). Moreover, the prognosis of heart failure (as for COPD) is poor, with estimated 5-yr mortality ranging from 40% (in patients with unrecognized heart failure) to 70% (New York Heart Association [NYHA] class III–IV) (33). Heart failure is also the second most expensive single condition to treat after stroke in the United States and Europe. Like COPD, what creates and drives this expense are hospital admissions. Finally, there are obvious parallels between all grades of heart failure and COPD in terms of impact on quality of life. However, because clinical trials have focused predominantly on outcome data related to mortality, there has been less emphasis on the importance of quality of life in patients with heart failure, the reverse probably of what is perceived for COPD.

As in other areas of vascular medicine, guidelines and management of heart failure have been largely driven by large outcome trials (Figure 3). Trials with the angiotensin-converting enzyme (ACE) inhibitors (34), lately in combination with ß-blockers, showed similar and predictive risk reductions in mortality (35–37). These trials also reported large reductions in the number of patients hospitalized and the duration of hospital stay, an important outcome for health care systems, which had a rapid impact on guidelines. The ß-blocker trials also demonstrated that not all ß-blockers were the same (i.e., a class effect could not be imputed) because at least one trial was negative (38). Most recently, the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial program, composed of three concurrent, randomized, double-blind trials that compared the effect of the angiotensin II antagonist candesartan and placebo in a total of 7,601 patients with symptomatic heart failure, provided clear evidence of the efficacy of candesartan in the management of chronic heart failure in patients receiving an ACE inhibitor and a ß-blocker (39), in patients previously intolerant to an ACE inhibitor (40), and in patients with left ventricular function heart failure. Largely as a result of CHARM, revised European guidelines for the management of patients with chronic heart failure recommend triple therapy (ACE inhibitor, angiotensin II antagonist, and ß-blocker) in patients with chronic heart failure (41).


Figure 3
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  		Figure 3. The impact of clinical trials on improving survival in heart failure. Definition of abbreviations: SOLVO = Studies Of Left Venticular Dysfunction; CIBIS-II = Cardiac Insufficiency Bisoprolol Study II; MERIT-HF = Metoprolol CR/XL Randomised Intervention Trial in Heart Failure; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; CHARM-Added = Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Added; RRR = relative risk reduction; ACEI = angiotensin converter enzyme inhibitors. Data from References 35–39 and 43.

 
The evolution of cardiovascular disease management, in particular the management of chronic heart failure, provides important lessons for COPD management. The development of guidelines has been driven largely by findings from large trials based on hard clinical outcomes, with the rationale of such trials provided by the epidemiology and etiology of cardiovascular disease. Moreover, there is increasing evidence that these data are not only driving guideline recommendations but are also being rapidly translated into clinical practice.

CONCLUSIONS

A complex and interrelated set of risk factors influences functional decline, exacerbations, and early mortality in patients with COPD. Most cases of COPD are due to environmentally related disease. Unlike cardiovascular disease in which 90% of the population attributable risk is due to nine conventional risk factors (22), in the case of COPD, about 80% of the population-attributable disease is due to smoking, and 15% is due to work-related conditions. This message can empower clinicians in justifying the cost of treating COPD, a public disease, to policy makers and governments.

With limited health care resources, efficient and effective management of COPD ideally involves identifying and focusing efforts on individuals who are at particular risk. It is essential that there is some way of identifying individuals at risk to be able to optimize appropriate intervention. Although FEV1 has been mooted as an objective means of identifying individuals at greatest risk for exacerbations and early mortality, in much the same way cholesterol is used in cardiology, a more sophisticated risk profile beyond the measurement of FEV1 is required. The body-mass index, airflow obstruction dyspnea, and exercise capacity (BODE) index is a useful step in this direction (20). In the development of an appropriate multimodal strategy, lessons could be learned from the evolution of guidelines and management of cardiovascular disease, in particular heart failure, which has many parallels with COPD in terms of prevalence, prognosis, and impact on patient quality of life.

The cardiovascular trials also demonstrate that there are many obstacles when translating trial findings to clinical practice. Education of clinicians and their patients is essential. For example, despite extensive trial evidence that convincingly demonstrated the efficacy and safety of the statins to clinicians, patients may be less well informed and convinced, which may affect compliance. This can also be seen for COPD; compliance can be an issue with inhaled corticosteroids because patients cannot usually detect immediate treatment-associated benefit. Side effects can also deter clinicians from using treatments shown to be effective in large clinical trials. For example, the ß-blocker trials showed that it was necessary to titrate very slowly after initiation of treatment due to problems with tolerability. However, this influenced the perception of the tolerability of ß-blockers in practice, reducing uptake of an effective therapy.

There is a need for large prospective trials in COPD, based on hard clinical outcomes, such as death, to drive improvements in clinical management. The TOward a Revolution in COPD Health (TORCH) trial is the largest study to date in COPD, comparing the effect of salmeterol/fluticasone propionate with placebo, in which the primary outcome is total mortality. The TORCH trial is the first major outcome trial in COPD, and it will be interesting to observe whether its impact on guideline recommendations and hence clinical practice is similarly dramatic to the major cardiovascular disease outcome trials.

FOOTNOTES

Conflict of Interest Statement: S.D.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.D.R.H. has received fees on one occasion from GlaxoSmithKline as an external speaker at an international COPD advisory board.

(Received in original form March 27, 2006; accepted in final form April 17, 2006)

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