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The Proceedings of the American Thoracic Society 3:624-629 (2006)
© 2006 The American Thoracic Society
doi: 10.1513/pats.200603-096SS
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Pharmacotherapy for Mortality Reduction in Chronic Obstructive Pulmonary Disease

Don D. Sin and S. F. Paul Man

The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital; and the Department of Medicine, Division of Respirology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Don D. Sin, M.D., The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 368A, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: dsin{at}mrl.ubc.ca

ABSTRACT

Despite rapid advances in our understanding of its pathophysiology, chronic obstructive pulmonary disease (COPD) remains incurable. Although bronchodilators and theophyllines are commonly used to treat symptoms of dyspnea and cough and to acutely improve lung function, they do not modify the long-term decline in FEV1. The principal goals of current COPD pharmacotherapy are to reduce exacerbations, improve health status, and prolong survival. There is strong evidence, including data from randomized clinical trials, that indicates inhaled corticosteroids alone, or in combination with a long-acting ß2-adrenoceptor agonist, improve patient symptoms, reduce morbidity, and perhaps even prolong survival in COPD. A recent individual patient–based meta-analysis of randomized, placebo-controlled trials of inhaled corticosteroids in COPD indicated that mortality over 3–4 yr was 27% lower in the group that received inhaled corticosteroids compared with the group that received placebo. Several short-term follow-up trials have also suggested a reduction in mortality with a combination of long-acting ß2-agonist and inhaled corticosteroids, and a large, long-term study that is currently ongoing (the Toward a Revolution in COPD Health [TORCH] study) will provide data on the effects of fluticasone propionate and salmeterol in combination on all-cause mortality. This article reviews some of the relevant epidemiologic and pathophysiologic processes that affect mortality in COPD and critically examines the effect of current COPD therapies on mortality.

Key Words: chronic obstructive pulmonary disease • inhaled corticosteroids • mortality • therapy

Chronic obstructive pulmonary disease (COPD) affects over 5% of the adult population, and is the only major cause of mortality that is increasing worldwide (1). Over the past 30 yr, age-adjusted mortality rate from all causes has decreased by 32%, whereas over the same period of time, the age-adjusted mortality rate for COPD has increased by 102% (2). Even the most optimistic models predict that, over the next 15 years, worldwide COPD mortality rates will increase by 20% (3). This bleak outlook reflects not only the expected increase in the worldwide prevalence of COPD in the coming years, but also the dismal prognosis of patients once they become affected by this disorder. Indeed, nearly half of all patients with American Thoracic Society stage III COPD are likely to die within 4–5 yr, and no more than 50% of patients are alive beyond 3 yr after hospitalization for an exacerbation (4). Thus, there is an urgent need to develop new therapies that can reduce mortality in COPD.

Over the past 20 yr, pharmacotherapy for COPD has been targeted largely for symptomatic relief. Bronchodilators have been the mainstay of treatment because they improve breathlessness, reduce exacerbations, and improve lung function (5). However, they have little or no impact on lung inflammation, which is believed to be at the heart of COPD pathophysiology (6). Inhaled corticosteroids, on the other hand, reduce lung inflammation in COPD (7), although they do not appear to modify the long-term decline in lung function (8). Whether any of these medications affects mortality in COPD is unclear. This article reviews some of the relevant epidemiologic and pathophysiologic processes that affect mortality in COPD and critically examines the effect of current COPD therapies on mortality.

PATIENTS WITH COPD DIE NOT JUST OF RESPIRATORY FAILURE: THE LINK BETWEEN COPD, FEV1, AND CARDIOVASCULAR EVENTS

Patients with COPD die from causes other than respiratory failure. Indeed, in patients with mild to moderate COPD, lung cancer and cardiovascular complications are the leading causes of mortality (9). The Lung Health Study (LHS) evaluated over 5,800 patients with mild to moderate COPD and followed these patients for up to 14.5 yr (10). There were 731 deaths during this period of follow-up. Lung cancer accounted for 33% and cardiovascular diseases accounted for 22% of all deaths (10). Surprisingly, fewer than 8% of the deaths occurred as a result of respiratory failure. The data on hospitalization were even more striking. In the first 5 yr of follow-up, approximately 20% of the LHS participants were hospitalized (9, 11). Cardiovascular events accounted for 42% of all first hospitalizations and 48% of all second hospitalizations. In contrast, only 14% of the patients were hospitalized for exacerbations of COPD. In general, the LHS investigators found that, for every 10% decrease in FEV1, all-cause mortality increased by 14%, cardiovascular mortality increased by 28%, and nonfatal coronary events increased by almost 20% (9, 11). Even in more advanced COPD (i.e., GOLD [Global Initiative for Chronic Lung Disease] class 3 and 4), cardiovascular events were still important, accounting for 15–25% of all deaths (12–14). However, in these patients, mortality rates from cancer were much lower (10–20% of deaths), whereas mortality rates from respiratory failure were much higher (50–75% of deaths) compared to those in patients in GOLD stages 0–2 (12–14). Cardiovascular events, therefore, represent an important source of morbidity and mortality for patients with COPD, regardless of severity.

The relationship between COPD and cardiovascular diseases are further supported by data from large population-based studies. For example, in the First National Health Nutrition and Health Examination Survey Follow-Up Study, individuals with an average FEV1 of 63% predicted were over 3.5 times more likely to experience cardiovascular mortality compared with individuals with normal lung function (an average FEV1 of 109% predicted) (15). The risk of mortality from ischemic heart diseases was even higher (relative risk 5.6). Other population-based studies have shown similar results (15). The contributions of COPD and reduced FEV1 to deaths from ischemic events are not trivial; they are quite substantial. Hole and colleagues calculated the percent attributable risk of deaths related to ischemic heart disease according to common risk factors for atherosclerosis (16). They found that cigarette smoking was responsible for 32–37% of all deaths from ischemic heart disease, and hypertension was responsible for 33–40% of the deaths. Strikingly, reduced FEV1 (<= 73–75% predicted) was responsible for 24–26% of all deaths related to ischemic heart disease, a figure that was comparable to the risk imposed by hypercholesterolemia. These data indicate that COPD is a powerful, independent risk factor for cardiovascular morbidity and mortality, and cardiovascular diseases may account for 25% of all deaths and 40–50% of all hospitalizations in patients with mild to moderate COPD. Accordingly, therapies that aim to reduce all-cause mortality and hospitalizations in COPD must have salutary effects on the cardiovascular system. Conversely, compounds that have negative effects on the cardiovascular system are unlikely to reduce mortality in COPD. Why patients with COPD develop cardiovascular diseases remains largely a mystery. Recent studies, however, have implicated systemic inflammation as a potential mechanism for the linkage.

THE ROLE OF INFLAMMATION IN COPD

COPD is an inflammatory disorder of the lungs, caused mainly, but not exclusively, by cigarette smoking (6). A detailed description of the inflammatory process is beyond the scope of this review, and the reader is referred elsewhere for excellent synopses (17, 18). Briefly, cigarette smoke and toxic environmental irritants incite lung inflammation. Once inflammation becomes firmly established in the airways, the inflammatory process persists even after smoking cessation (6). With disease progression, the inflammatory process intensifies and becomes more widespread. The inflammatory process is not confined to the lungs, however. Patients with COPD demonstrate systemic inflammation (19). As with lung inflammation, systemic inflammation intensifies with COPD progression, and is related to increased prevalence of ischemic heart disease (20). The molecular pathways linking lung with systemic inflammation in COPD have not yet been elucidated. In COPD, systemic inflammation may play a very important role in the systemic and local complications of COPD. Systemic inflammation, for example, has been linked with cardiovascular events, cachexia, muscle wasting, disease progression, and even lung cancer (21–27). One way to quantify systemic inflammation in COPD is to measure serum or plasma C-reactive protein (CRP). In patients with COPD, there is a severity-dependent increase in CRP levels (20, 26), which directly parallels the intensity of lung inflammation (6). Whereas inflammation is the body's defensive response to infection and injury, it is now recognized that it may be associated with complications, such as cancer, Alzheimer's disease, and cardiovascular diseases. Therefore, inflammation may be the key to COPD and its link with cardiovascular events, and represents an important potential target of therapies.

REVIEW OF CURRENT COPD PHARMACOTHERAPY WITH PARTICULAR REFERENCE TO MORTALITY

Bronchodilators
For individuals who are symptomatic, short-acting ß2-adrenoreceptor agonists (e.g., salbutamol) and short-acting anticholinergics (e.g., ipratropium) are the mainstay of therapy for symptomatic management (28). Although airflow obstruction in COPD is largely fixed and irreversible, bronchodilators improve patient symptoms and exercise tolerance. They also appear to reduce exacerbations and frequency of health service utilization (5). However, they do not modify the long-term decline in FEV1, and their effect on mortality is uncertain. There are some preliminary reports of (potential) increased cardiovascular mortality associated with certain bronchodilators. Au and colleagues, for example, showed that, compared with patients with COPD who did not fill a prescription for a short-acting ß2-adrenoceptor agonist, patients who did fill such a prescription in the 3 mo before their index date were approximately 70% more likely to experience an acute coronary event. New users of ß2-adrenoceptor agonists had a sevenfold increase in the risk of cardiovascular events (29). A recent systematic review and meta-analysis showed that a single dose of a ß2-agonist caused an increase in heart rate of 9 beats/min and reduced serum potassium by 0.36 mmol/L compared with placebo (30). In long-term trials, treatment with short-acting ß2-adrenoceptor agonists was associated with a 2.5-fold increase in the risk of adverse cardiovascular events, which included ventricular tachycardia, myocardial infarction (MI), and sudden deaths (30).

Some studies have also implicated inhaled anticholinergics with increased mortality, especially deaths related to cardiovascular events. Ringbaek and colleagues showed that the use of ipratropium bromide was associated with a 60% increase in adjusted mortality compared with nonusers in 827 patients with COPD (31). In the LHS (9), 5,887 patients with mild to moderate COPD were randomized to ipratropium bromide, a short-acting anticholinergic agent, or placebo, over a 5-yr period. In the first year of treatment, there was an improvement in FEV1 with ipratropium relative to placebo. However, over the full 5 yr, those assigned to ipratropium had a 3.7-fold increase in the risk of arrhythmias, a 26% increase in the risk of cardiovascular events, and a 2.6-fold increase in fatal cardiovascular events compared with placebo (p < 0.05) (11). Although this study was underpowered to detect cardiovascular events, these data raised concerns that ipratropium may increase the overall risk of cardiovascular complications in COPD by 10–20%. In the 1-yr clinical trials of tiotropium, the risk of heart rate and rhythm disturbance disorders, such as arrhythmias, atrial fibrillation, and tachycardia, were about twofold higher in those assigned to tiotropium (n = 550 patients) compared with those assigned to placebo (n = 371). However, these events were rare, occurring in only 4.4% of this carefully selected group of patients with COPD (32). Why ß2-adrenoreceptor agonists and anticholinergics might lead to increased cardiovascular morbidity and mortality is uncertain. There is evidence that patients with COPD have a perturbed neurohumoral regulatory system, leading to excess sympathetic nervous activity relative to vagal tone (33). Accordingly, patients with COPD have raised resting heart rates and have an increased risk of rhythm disturbances and ectopic beats (34). It is plausible that bronchodilators in certain susceptible patients may further dysregulate autonomic tone on the heart. Intriguingly, in one study, co-adminstration of inhaled corticosteroids with a long-acting ß2-adrenoceptor agonist attenuated the rise in heart rate related to ß2-agonists, raising the possibility that inhaled corticosteroids may (to a certain extent) protect against autonomic dysregulation related to certain bronchodilators (35).

Inhaled Corticosteroids in COPD
Although there is some controversy, the totality of evidence indicates that the long-term use of inhaled corticosteroids reduces lung inflammation (Figure 1) (7), attenuates bronchial responsiveness (36), improves patient symptoms (36), decreases exacerbations rates (37), and enhances health status in COPD (38).


Figure 1
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  		Figure 1. Changes in cell counts in sputum of patients with COPD receiving inhaled corticosteroids compared with control subjects (7). For each study, the standardized mean difference was derived by dividing the mean change in the inflammatory cell concentration at follow-up visit from the baseline visit between intervention and control groups by a pooled SD of the mean change. A negative standardized mean difference indicated that the participants assigned to inhaled corticosteroids had lower cell counts compared with those receiving placebo at the end of the study phase, whereas a positive number denoted increased cell count relative to the control group.

 
Inhaled corticosteroids not only reduce lung inflammation, but may also appear to attenuate systemic inflammation. In healthy volunteers, fluticasone has been demonstrated to prevent the increase in serum IL-6, a marker of systemic inflammation, in response to organic dust (i.e., endotoxin) exposure compared with placebo (39). Similarly, in patients with COPD, use of inhaled corticosteroids has been associated with reduced circulating levels of CRP (24, 40).

Another characteristic feature of COPD is bronchial hyperresponsiveness, affecting 60–80% of patients (36). In the general population, bronchial hyperresponsiveness has been associated with increased COPD mortality by up to 15-fold compared with normal bronchial reactivity (41). In the LHS-2 trial, therapy with an inhaled corticosteroid, triamcinolone, significantly decreased bronchial responsiveness to methacholine compared with placebo (36).

Several studies have shown that inhaled corticosteroids reduce exacerbations by about 25% when given for a minimum of 6 mo in patients with stable COPD (37). They may also reduce the rate of hospitalization for respiratory problems. In the LHS-2, there was a trend toward a 53% reduction in the rate of hospitalization for respiratory problems in the group that received triamcinolone compared with the group that received placebo over an average follow-up of 40 mo (p = 0.07) (36). Finally, the ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) study demonstrated that inhaled corticosteroids reduced the annual rate of decline in health status by approximately 25% compared to the placebo group (38).

The Effect of Inhaled Corticosteroids on Survival
Inhaled corticosteroids reduce both lung and systemic inflammation and improve COPD-related and general health, but do they improve survival? Results of a population-based cohort study in Canada indicated that patients with COPD who received inhaled corticosteroids on hospital discharge had 24% fewer repeat hospitalizations and were 26% less likely to die in the year after discharge than patients who did not receive inhaled corticosteroids (42). Soriano and colleagues reported that regular use of fluticasone propionate alone or in combination with salmeterol is associated with increased survival of patients with COPD managed in primary care (43). However, there have been some dissenting observational studies (44, 45), reflecting the enormous difficulty of accurately adjusting for confounding factors and avoiding methodologic biases in observational studies.

Data from randomized controlled trials, on the other hand, are much more reliable than those from observational studies, as the former are much less susceptible to confounding than the latter. The Inhaled Steroid Effects Evaluation in COPD (ISEEC) study (46) combined individual patient data from seven large, randomized, placebo-controlled trials investigating the effects of inhaled corticosteroids in COPD. The analysis included more than 5,000 patients with stable COPD (mean FEV1 was 59% predicted) randomized to either inhaled corticosteroids or placebo and followed for between 12 and 48 months. Overall, the mortality rate was 27% lower in patients with COPD assigned to inhaled corticosteroids compared with those assigned to placebo (adjusted hazard ratio = 0.73; 95% confidence interval = 0.55–0.96). The clinical relevance requires benchmarking of these data with well established life-preserving therapies in other diseases. One such therapy that can be benchmarked against COPD therapies is the use of statins for the management of patients with ischemic heart disease after acute coronary events. The Scandinavian Simvastatin Survival Study (4S) was a landmark study that determined the role of statins in the secondary prevention of cardiovascular disease, and is seen as one of the benchmarks in mortality protection (47, 48). Comparing the ISEEC data with those from the 4S, inhaled corticosteroids provided at least as much protection over 3 yr as did simvastatin (Figure 2). Most of this decreased mortality was seen in patients with moderate to severe COPD.


Figure 2
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  		Figure 2. Effect of simvastatin on survival: the Scandinavian Simvastatin Survival Study (4S)—a benchmark for survival in COPD? Survival curves are compared between ISEEC (Inhaled Steroid Effects Evaluation in COPD) study, which evaluated clinical trials of inhaled corticosteroids versus placebo (46) and the 4S, which evaluated effects of simvastatin versus placebo on all-cause mortality in patients with established coronary heart disease (48).

 
Low-dose inhaled corticosteroids may also have a protective effect on the risk of acute MI in patients with COPD. Huiart and colleagues studied 371 patients and 1,864 control subjects between 1990 and 1997 and found that users of inhaled corticosteroids had a nonsignificant 18% reduction in the risk for acute MI (49). Most of the benefit came from a subgroup that used, on average, 50–200 µg/d of inhaled beclomethasone or equivalent. Remarkably, this subgroup experienced a 32% relative reduction in the risk for acute MI (p < 0.05). Macie and colleagues recently reported similar findings from a cohort of patients with COPD during 1996–2000 who received inhaled corticosteroids for 3 mo after hospital discharge for an exacerbation. A 25% reduction in all-cause mortality was noted among those receiving inhaled corticosteroids compared with control subjects, driven largely by the 38% reduction in cardiovascular deaths (50). Most recently, investigators of the EUROSCOP (European Respiratory Society Study on Chronic Obstructive Pulmonary Disease) trial reported that patients with COPD assigned to inhaled corticosteroids had an approximately 40% reduction in the rate of cardiovascular events (angina and MI) compared with those assigned to placebo over a 3-yr period (51).

Combination of Inhaled Corticosteroids and Long-Acting ß2-Agonists
Treatment with the combination of a long-acting ß2-agonists and an inhaled corticosteroid has been shown to improve outcomes in patients with COPD, improving lung function, symptoms, and health status, over and above each therapy alone. Intriguingly, a recent biopsy and induced-sputum study has shown that the salmeterol/fluticasone propionate combination has broad-spectrum antiinflammatory effects, a finding that has not been reported previously with inhaled corticosteroids alone (52). Although the mechanisms are not entirely clear, there is emerging evidence to suggest that ß2-agonists and corticosteroids attenuate different, but complementary, components of the inflammatory cascade related to COPD (53). Moreover, long-acting ß2-agonists and corticosteroids may beneficially interact to increase the translocation of the glucocorticoid receptor to the nucleus and stimulate ß2-receptor transcription and expression, thereby amplifying the antiinflammatory activity of the combination (54).

Regardless of the mechanism, several large, high-quality, randomized controlled clinical trials indicate that combination therapy of long-acting ß2-agonists with inhaled corticosteroids improves patient symptoms and reduces exacerbations by one third (compared to placebo) (55–57). More importantly, combination therapy produces superior health outcomes than monotherapy with inhaled corticosteroids or long-acting ß2-agonists, suggesting added clinical benefits of these two compounds in COPD, and an important advance in COPD therapy.

Evidence from three large, randomized controlled trials suggests that the combination of a long-acting ß2-agonist and inhaled corticosteroid may reduce mortality (58). A pooled analysis of the three trials showed the relative risk of mortality to be 0.62 (95% confidence interval = 0.33–1.18), although the low number of deaths limited the power of any analysis. The reduction was numerically greater with the long-acting ß2-agonist/inhaled corticosteroids combination than with either component alone.

Key Ongoing Trials
The long-term effects of inhaled corticosteroid, in particular on mortality, will be clarified by the TORCH (Toward a Revolution in COPD Health) study, which has been designed to determine the impact of the long-acting ß2-agonist, salmeterol, and inhaled corticosteroid, fluticasone propionate, (alone and in combination) on mortality in patients with COPD (59). It is a 3-yr, multicenter, randomized, double-blind, parallel-group, placebo-controlled study of over 6,000 patients with moderate to severe COPD from 42 countries. The primary end-point is all-cause mortality, comparing salmeterol/fluticasone propionate with placebo, with secondary endpoints including COPD morbidity relating to rate of exacerbations and health status. Results from TORCH are expected to be reported in 2006.

The UPLIFT (Understanding Potential Long-Term Impacts on Function with Tiotropium) study, another large, multicenter, long-term trial, is investigating the long-term impact of tiotropium on lung function in up to 6,000 patients with COPD (60). The primary objective is to determine whether tiotropium reduces the rate of lung function decline (as measured by FEV1) over time. Other outcome measures include quality of life, exacerbations, and mortality. The first UPLIFT results are expected in 2008.

CONCLUSIONS

Despite advances in understanding the pathophysiology of COPD, it remains a largely incurable disease. The management of COPD with bronchodilators is limited, and cannot be expected to modify the natural disease course. The paradigm shift in our view of pathophysiology of COPD, from a disease of airway obstruction to an inflammatory disorder involving both local lung and systemic inflammation, suggests that therapies must not only attenuate airway obstruction, but also suppress the underlying inflammatory process. A large body of evidence, including data from observational and randomized clinical trials, indicates that inhaled corticosteroids alone and in combination are likely to reduce morbidity and mortality in COPD, a not unexpected finding given the central role of inflammation in COPD pathophysiology. Current evidence indicates that inhaled corticosteroids reduce all-cause mortality by about 25%, attenuate airway inflammation, decrease airway hyperresponsiveness, and may also reduce systemic inflammation. Combination therapy with inhaled corticosteroids and a long-acting ß2-agonist may provide additional benefit. This will be confirmed or refuted by the results of TORCH, which are expected in early 2006, and will throw further light on this combination treatment approach for this most insidious of diseases.

FOOTNOTES

Conflict of Interest Statement: D.D.S. has received honoraria for speaking engagements from AtraZeneca in 2004 ($3,000) and in 2005($11,000), and from GlaxoSmithKline (GSK) in 2004 ($8,000), 2005 ($6,500), and 2006 ($10,000). He has also received unrestricted research funding as either the principal investigator or co–principal investigator from GSK in 2004 for $1.5 million, and has also received $3,500 from GSK for consultancy work in 2004. As co–principal investigator, S.F.P.M. received a medical school grant from GSK ($140,000) and from Merck ($2.45 million) until 2003, and a medical school grant has been approved by GSK (as co–principal investigator); he was also invited to speak at an AstraZeneca-sponsored scientific meeting in April 2004.

(Received in original form March 27, 2006; accepted in final form April 12, 2006)

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Where current pharmacological therapies fall short in COPD: symptom control is not enough
Eur. Respir. Rev., September 1, 2007; 16(105): 98 - 104.
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