Where current pharmacological therapies fall short in COPD: symptom control is not enough

Chronic obstructive pulmonary disease (COPD) is a common, heterogeneous and progressive condition with airflow limitation that is not fully reversible and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, most notably those arising from cigarette smoke [1]. COPD is a major public health problem. It is currently the fourth leading cause of death in the world, and both the prevalence and mortality associated with COPD are expected to rise in coming decades [1]. COPD is the most rapidly rising cause of death in individuals >65 yrs of age, the fastest growing segment of the population in developed countries [2]. Disability from COPD is expected to rise through to 2020 with aging of the population and the associated increase in the prevalence of chronic diseases. By that time, it will be the third most common cause of death [3].

Patients with COPD present with a variety of clinical findings, including respiratory and nonrespiratory manifestations. The most characteristic respiratory symptoms include abnormal shortness of breath, chronic cough and excessive sputum production [1]. The latter two symptoms precede airflow limitation in many COPD patients [1] but they do not independently predict its occurrence, once tobacco smoking is taken into account [4]. Patients with COPD may also present with so-called “systemic” symptoms that may result from the chronic inflammatory nature of the disease [5]. Extrapulmonary manifestations that have been associated with COPD include systemic inflammation, nutritional depletion and weight loss, skeletal muscle dysfunction, cardiovascular disease, osteoporosis, anaemia and depression [5–7]. The relationship between COPD and cardiovascular disease may be particularly important since, in some studies, >50% of patients with COPD die from cardiovascular-related disease [5]. The pulmonary and extrapulmonary effects of COPD result in a wide range of deleterious effects on clinical outcomes, including decreased exercise tolerance, impairment to the ability to carry out daily activities, reduced life expectancy and decreased quality of life [1, 8].

The present article considers the possibility of a central mechanism, i.e. inflammation, underlying both the pulmonary and extrapulmonary symptoms of COPD. Such a mechanism would be a relevant target for treatments aimed at altering disease progression. The present article also discusses how disease modification should be defined and how current and future pharmacological treatments could achieve this goal.

INFLAMMATION AS A UNIFYING CONCEPT IN COPD

There is now a large body of evidence indicating that both pulmonary and systemic inflammation are present in patients with stable COPD [5]. The article by Rennard [9] in the present issue of the European Respiratory Review (ERR) extensively describes the characteristics of airway inflammation, repair and remodelling in patients with COPD. For instance, several inflammatory markers have been shown to be elevated in the lungs or airways of smokers and patients with COPD, including interleukin (IL)-6, IL-8, IL-1β, macrophage chemoattractant protein (MCP)-1, transforming growth factor-β and matrix metalloproteinase (MMP)-9 [10, 11].

A systematic review of results from studies available in 2004 also indicated that patients with chronic airflow limitation had significantly elevated levels of circulating C-reactive protein, fibrinogen, leukocytes and tumour necrosis factor (TNF)-α. This was true for both current and ex-smokers [5].

Systemic inflammation is also thought to play a key role in many comorbid conditions associated with COPD. This observation has prompted the suggestion of an individual predisposition to develop abnormal systemic inflammation in response to environmental aggressions (mainly tobacco smoke), where this response represents a common disease process in both COPD and its related comorbid conditions (fig. 1⇓). Inhaled corticosteroids are the only currently available anti-inflammatory agents that have some efficacy on clinical outcomes in COPD (discussed further later) [12]. However, the magnitude of observed benefits is relatively limited, which may relate to some degree of molecular resistance to their effects on transcription, as a consequence of oxidative stress. These considerations suggest the need for new therapies that specifically target the inflammatory processes that characterise COPD, and for monitoring their effects on both the lungs and other organ systems [13].

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FIGURE 1.

Inflammation as a unifying factor in the respiratory and systematic manifestations of chronic obstructive pulmonary disease (COPD). A combination of genetic and environmental (e.g. tobacco smoke) factors lead to airflow limitation, hyperinflation, lung destruction and remodelling, which result in COPD symptoms (dyspnoea). This leads to deconditioning, reduced exercise tolerance and handicap. Impaired nutritional status and inflammation contribute to muscle dysfunction. The occurrence of exacerbations amplifies and accelerates all of these processes. Data from [12].

Despite the generally accepted importance of inflammation in COPD [14], it is noteworthy that, to date, no strictly anti-inflammatory therapy evaluated has been definitely demonstrated to alter the natural course of the disease. Animal studies have indicated that airway remodelling can occur in the absence of inflammation, so it is possible that inflammation may be a consequence rather than a cause of COPD.

OVERVIEW OF CURRENT TREATMENT FOR COPD

None of the existing treatments of COPD has been consistently shown to modify the course of the disease, as assessed by lung function decline and mortality. Thus, the remaining aims of current therapy are to decrease symptoms and exercise intolerance, improve activity and health status and reduce the risk for disease complications (e.g. acute exacerbations and chronic respiratory failure leading to cor pulmonale) [1]. Current therapeutic approaches for COPD include as-needed or regular bronchodilator medications (mainly inhaled anticholinergic agents, β₂-agonists, and combinations of these agents) to reduce or prevent symptoms [1], inhaled corticosteroids (ICS) combined with long-acting β₂-agonists, pulmonary rehabilitation, long-term oxygen therapy (LTOT) and, in highly selected patients, surgery [1].

Inhaled bronchodilators are central to the symptomatic treatment of patients with COPD and their use has been shown to decrease airflow limitation and static and dynamic hyperinflation, leading to lessened respiratory constraints and work of breathing. In this way, COPD-related dyspnoea and functional impairment are reduced, while exercise tolerance and patient activity increase. Bronchodilators also reduce the risk for acute exacerbations. In combination, these effects lead to improvements in quality of life [1, 15].

The purpose of using ICS in COPD is to decrease the severity of COPD symptoms and the frequency of exacerbations, and to improve health status [16]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends that ICS treatment should be used in addition to bronchodilators in patients with severe or very severe COPD (forced expiratory volume in one second (FEV₁) <50% predicted) who have repeated exacerbations [1]. However, practice surveys found that in COPD, ICS are frequently prescribed in situations that do not fit this indication [17]. Finally, long-term treatment with oral glucocorticosteroids is not recommended for the treatment of patients with COPD: no obvious beneficial effect has been described with these agents, which can have many deleterious consequences, including impairments in bone density, nutritional status and peripheral muscle function, aggravation of comorbid diseases, lessening of the efficacy of pulmonary rehabilitation and even decreased survival [1, 18].

DISEASE-MODIFYING THERAPY IN COPD: THE CONSERVATIVE VIEW

A “conservative” view is that, to be considered as a “disease modifier”, a treatment should decrease either the rate of lung function decline or mortality. Such effects are widely accepted for a few measures only, namely smoking cessation, LTOT and, most recently, the combination of ICS and a long-acting β₂-agonist.

Smoking cessation

It is well established that smoking cessation can alter the course of disease in patients with COPD. The Lung Health Study (LHS) was a randomised clinical trial of smoking cessation and regular administration of an inhaled bronchodilator (ipratropium bromide) in 5,887 middle-aged smokers (35–60 yrs old at study entry) who had airway obstruction but no other serious illness. In the LHS, smoking cessation significantly decreased the rate of lung function decline [19]. Further follow-up of these patients 11 yrs after the start of the study showed that 38% of continuing smokers but only 10% of sustained quitters had an FEV₁ <60% pred [20]. Assessment of mortality at 14.5 yrs of follow-up indicated that smoking cessation decreased the risk of dying from the two leading causes of mortality, i.e. cancer and coronary heart disease (fig. 2⇓) [21].

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FIGURE 2.

Mortality rates by cause at 14.5 yrs in the Lung Health Study. Only a small percentage of patients with chronic obstructive pulmonary disease die as a result of respiratory disease. Lung cancer and the combination of coronary heart disease (CHD) and cardiovascular disease (CVD) are the most common causes of death in these patients. □: sustained quitter; ▒: intermittent quitter; ▪: continuing smoker. Data from [21].

Bronchodilators

The long-acting anticholinergic agent tiotropium (one dose = 18 µg·day⁻¹) has been demonstrated to improve lung function in a combined analysis of two identical placebo-controlled trials that included a total of 921 patients with stable COPD (mean age 65.2 yrs). The primary spirometric outcome was trough FEV₁, i.e. FEV₁ measured 23 h after the last treatment dose. Treatment for 1 yr resulted in an ∼12% increase over baseline in trough FEV₁ and a 22% increase in mean FEV₁. Further analysis of results from these studies showed that the mean decline in trough FEV₁ between days 8 and 344 was 58 mL·yr⁻¹ in the placebo group versus only 12 mL·yr⁻¹ in the tiotropium group (fig. 3⇓) [26]. The results of this analysis support the view that tiotropium has the potential to reduce the rate of decline in FEV₁ in patients with COPD and thus modify the course of this disease. However, longer-term trials specifically designed to study this effect are required to confirm this observation. Such an evaluation is currently being carried out in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study, a large multicentre 4-yr trial, which is investigating the effects of tiotropium on lung function in up to 6,000 patients with COPD. The first results should be available in 2008.

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FIGURE 3.

Mean change in trough forced expiratory volume in one second (FEV₁) (mL·yr⁻¹) in tiotropium-treated (–––––; n = 518) and placebo-treated (– – –; n = 328) patients from 8 to 344 days after the beginning of treatment. The results are from a post hoc analysis of data from 921 ambulatory COPD patients participating in two 1-yr, double-blind tiotropium versus placebo-controlled trials. Serial spirometry was obtained at baseline (before the first dose of study drug), on day 8, at 6 weeks and at 3, 6, 9 and 12 months after the start of the study. The mean decline in trough FEV₁ between days 8 and 344 was 58 mL·yr⁻¹ in the placebo group and 12 mL·yr⁻¹ in the tiotropium group (p = 0.005 versus placebo (mean regression slopes)). Reproduced and modified from [26] with permission from the publisher.

DISEASE-MODIFYING THERAPY IN COPD: WIDENING THE PERSPECTIVE

The previously mentioned conservative definition of disease modification in patients with COPD could be too narrow, since survival and FEV₁ may remain unchanged despite relevant and durable improvements in clinically important outcomes, such as symptoms, time to LTOT, overall decline in health status, exacerbations (frequency, duration and severity), and the course of COPD-associated systemic manifestations. Thus, focusing on lung function and mortality may ignore critical factors in the overall health of patients with COPD; assessing the benefit of therapy also requires accurate assessment of the effects on dyspnoea, fatigue, activities of daily living, work productivity, exacerbations and quality of life [32]. This is emphasised by the observation that, in patients with COPD, health status relates much more closely to physical function than to FEV₁; in addition, the systemic manifestations associated with COPD may be more important determinants of disability and overall health than pulmonary function in many individuals [33]. Finally, lung function may not be the most appropriate end-point to assess the anti-inflammatory effects of treatment that may be key to slowing or stopping disease progression.

Major issues when assessing the disease-modifying potential of a treatment are the required length of follow-up and number of patients, given the slowly progressive nature of the disease. Attempts to use “acute” response to treatments to predict patients’ long-term effects have been unsuccessful [34]. In addition, corresponding measurements were dominated by FEV₁, which is a robust measure but correlates poorly with clinical outcomes [35]. Other lung function variables reflecting hyperinflation or avoiding dynamic airways expiratory compression have been proposed. However, although they do indeed correlate better than FEV₁ with, for example, dyspnoea, the correlation is not sufficiently strong to be used at the individual level [36, 37].

Therefore, biological (or possibly radiological) markers related to disease progression may be useful for the assessment of potentially disease-modifying therapies in patients with COPD. Useful biomarkers must be sensitive to therapeutic interventions, predictive of clinical outcomes and, if possible, responsive relatively quickly. At present, no such marker is available but several candidates are being studied, including markers of inflammation, protease–antiprotease balance and oxidative stress [38]. It is also crucial that candidate markers can be collected noninvasively, which explains the growing interest in exhaled gases and breath condensates or induced sputum. However, given the complexity of COPD pathophysiology, demonstrating biological effects on one or even several markers does not mean that a treatment will be clinically effective. Therefore, formal validation of the predictive potential of biomarkers is needed, which requires long-term clinical studies. Before such studies are completed, biomarkers can only be used for screening, which is already an important step in the development of new products.

EFFECT OF CURRENT PHARMACOLOGICAL TREATMENTS ON CLINICALLY IMPORTANT OUTCOMES IN COPD

Results from recent studies have suggested that several treatments may have the potential to alter some clinical aspects of the natural history of COPD. In the placebo-controlled trials mentioned previously, tiotropium was shown to reduce exacerbation rate and dyspnoea, thereby improving quality of life [39]. As described later, similar results were found with long-acting β₂-agonists, ICS and their combination.

The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) trial was carried out to assess the effect of long-term ICS (500 μg b.i.d. fluticasone propionate) on pulmonary function, exacerbations and health status in 751 patients with moderate-to-severe COPD (mean FEV₁ 50% pred). At the end of the 3-yr follow-up, there was no significant benefit of ICS versus placebo with respect to the annual rate of decline in FEV₁. However, the mean exacerbation rate was reduced by 25%, from 1.32·yr⁻¹ on placebo to 0.99·yr⁻¹ with fluticasone propionate. Similarly, health status deteriorated by 3.2 units·yr⁻¹ on placebo versus 2.0 units on fluticasone propionate (fig. 4⇓). In addition, withdrawals from the study due to nonmalignant respiratory diseases occurred more often in the placebo group than with ICS (25 versus 19%) [40]. Thus, while ICS did not slow the rate of decline of FEV₁ in the long-term ISOLDE study, it did significantly improve respiratory and overall health versus placebo. However, the relatively limited magnitude of improvements led to the question of whether the addition of a long-acting β₂-agonist could improve the results, as a consequence of molecular interactions between these products [41]. The TRial of Inhaled STeroids ANd long-acting β₂-agonists (TRISTAN) compared the efficacy of the combination of a long-acting β₂-agonist (50 μg salmeterol b.i.d.) and an ICS (500 μg fluticasone propionate b.i.d.) to the effects of either of the agents alone, in 1,465 patients with COPD. The primary outcome was FEV₁ at the end of 12 months of therapy. All active treatments improved lung function, symptoms and health status, and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pre-treatment FEV₁ significantly more than placebo, salmeterol or fluticasone. Perhaps more importantly, it was also significantly more effective than either single agent in improving health status [42]. Again, benefits were more obvious in patients with FEV₁ <50% pred. Similar results were found in 1-yr trials with the combination of budesonide and formoterol [43, 44].

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FIGURE 4.

Effects of fluticasone propionate 500 μg b.i.d. or placebo on decline in health status indicated by increasing total scores on the St George's Respiratory Questionnaire (SGRQ; mean±95% confidence interval). The number at each assessment indicates the number of patients for whom measurements of health status were available at that visit. The study included 751 males and females aged 40–75 yrs with a mean forced expiratory volume in one second of 50% of the predicted normal. Health status deteriorated by 3.2 units·yr⁻¹ on placebo and 2.0 units·yr⁻¹ on fluticasone propionate (p = 0.0043). ○: placebo; •: fluticasone propionate. Reproduced and modified from [40] with permission from the publisher.

Finally, in the TORCH trial, patients receiving the combined treatment had a St George's Respiratory Questionnaire score that was on average 3.1 units lower than those receiving placebo, 2.2 units lower than those receiving salmeterol monotherapy and 1.2 units lower than those receiving fluticasone monotherapy. Combined treatment was also associated with 25% fewer exacerbations than placebo, 12% fewer than salmeterol and 9% fewer than fluticasone [30].

Thus, even if their effects on the “conservatively defined” natural history of the disease can be debated, several pharmacological agents demonstrated their ability to provide clinically significant benefits in COPD patients. However, these effects remain of a relatively limited magnitude, making new, more effective treatments desirable and leading to consideration of the benefit/risk ratio of existing therapies before reaching a conclusion as to their interest.

SAFETY ISSUES WITH CURRENT PHARMACOLOGICAL TREATMENTS OF COPD

The combination of ICS and a long-acting β₂-agonist has demonstrated significant benefit in the management of patients with COPD, but there are still safety concerns about the long-term use of these treatments in this disease. A recent meta-analysis of safety results for ICS administered in the setting of clinical trials indicated negligible risk with these agents [16]. For example, pooled discontinuation rates did not differ significantly between ICS and placebo [16]. However, observational evidence suggests a dose-related risk of cataract and open-angle glaucoma in patients receiving ICS [16]. Results that address the possibility of an association between ICS and osteoporosis (which is also favoured by age, tobacco smoking and COPD itself) are mixed. A meta-analysis of randomised trials found no evidence of increased risk of loss of bone mineral density or fractures [16]. However, findings from two case–control studies suggested a relationship between ICS use and osteoporosis [16].

Recent results from patients treated in the Salmeterol Multi-centre Asthma Research Trial (SMART) have raised concerns about the safety of long-acting β₂-agonists. This study was discontinued because patients taking salmeterol (42 μg b.i.d.) had increased risk for mortality [45]. However, the increase in mortality was observed mainly in African-Americans. Thus, it may reflect a lower access to healthcare resources, poorer compliance to ICS treatment or a genetic susceptibility, rather than a general intrinsic toxicity of long-acting β₂-agonists. While it is not clear whether these findings can be generalised to individuals with COPD, they may raise some concern, since several of these patients suffered from cardiovascular comorbidities. However, a systematic review of the cardiovascular safety of salmeterol in COPD patients has provided reassuring results [46].

EMERGING THERAPIES

There has been great interest in the development of new therapies for COPD. COPD is characterised by chronic inflammation of the respiratory tract with increased numbers of macrophages, neutrophils and cytotoxic T-lymphocytes in airways and the lung parenchyma. The central role of inflammatory processes in COPD and its comorbidities has focused research on mediators involved in recruitment and activation of inflammatory cells (most often neutrophils). Treatments aimed at inhibiting these inflammatory processes include phosphodiesterase 4 inhibitors (considered in the article by McIvor [47] in the present issue of the ERR), nuclear factor-κB inhibitors, adhesion molecule inhibitors, IL-10 and analogues, p38 mitogen-activated protein kinase inhibitors, phosphoinositide-3 kinase γ-inhibitors and immunomodulators [48]. Other new COPD treatments with potential anti-inflammatory properties currently in development include leukotriene B₄ antagonists, 5′-lipoxygenase inhibitors, IL-8 antagonists, MCP antagonists, TNF-α inhibitors, antioxidants and inducible nitric oxide synthase inhibitors. Treatments aimed at reducing oxidative stress in COPD have also been a focus of attention.

Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and MMP inhibitors to prevent lung destruction and the development of emphysema [12, 49]. Finally, “repairing” agents, such as retinoic acid receptor agonists or stem cells, are also being studied.

CONCLUSIONS

At present, there is a large number of symptomatic treatments for COPD and these medications have been shown to significantly improve dyspnoea, exercise tolerance, activity, the rate of exacerbations and quality of life in patients with this disease. However, these agents may have limited efficacy in some patients, which is exacerbated by the fact that they are often used late in the course of disease, when the likelihood of reversible lesions may be reduced. Therapies that alter the course of COPD, as measured by survival and lung function decline, include smoking cessation, LTOT, and the combination of fluticasone propionate and salmeterol. However, the definition of a therapy that modifies the natural history of COPD may need to be revisited and more precisely defined in terms of markers and clinical outcomes indicative of progression, including the risks for comorbid extrarespiratory diseases. It is reasonable to suggest that early diagnosis and treatment of patients with COPD might be the first and potentially most important disease-modifying intervention, since it would result in the application of existing treatments at the time when they are most likely to provide their greatest benefits. This remains to be formally demonstrated.

Nevertheless, treatments with a more favourable long-term benefit/risk ratio are warranted. Their development will probably require more specific targeting of the local and systemic inflammatory processes that give rise to the pulmonary and extrapulmonary manifestations of chronic obstructive pulmonary disease.

Statement of interest

N. Roche has received fees for speaking or consulting, funds for attendance at congresses, and fees for organising education or research from GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Altana, Chiesi, Novartis and AstraZeneca.