REVIEW URRENT C OPINION
Chronic obstructive pulmonary disease: getting it right. Does optimal management of chronic obstructive pulmonary disease alter disease progression and improve survival? Richard E. Russell
Purpose of review We live in a world where people live longer lives. The standardized mortality rate for many diseases is decreasing. Chronic obstructive pulmonary disease (COPD) is not following this trend. Over the last 10 years, interventions for COPD have been developed, but have any changed the prognosis or trajectory of this modern epidemic? We review the most recent and classical literature in order to answer this question. Recent findings Recent analyses of data have clarified which interventions are effective in COPD and which are not. New studies have defined what is achievable with the current therapies. Only two interventions have been demonstrated to improve survival: smoking cessation and long-term oxygen therapy. Other treatments do reduce exacerbations, improve lung function and improve the patient’s quality of life, but do not affect physiological disease progression or mortality. Summary There is much work to do, not only to improve the treatments we have for this disease, but also to diagnose it early, intervene at the right time, reduce the treatment side-effects and most importantly understand the pathophysiology better. Moreover, we are duty bound to look at each patient and review what we are trying to achieve for each one through appropriate phenotyping as well as sometimes taking a more palliative approach. Keywords COPD, efficacy, prognosis, therapy
INTRODUCTION Are we winning the war against chronic obstructive pulmonary disease (COPD)? A recently published review of mortality due to COPD in Spain [1] demonstrated a sustained reduction in standardized mortality rate, leading to the comment that the epidemic might be over [2]. This data is not yet a cause for celebration or for us to take our eyes off the goal of significant and sustained reductions in prevalence of COPD, reduced exacerbation rates, lower levels of morbidity and if possible mortality reduction. Maybe as Churchill said, we are at the ‘end of the beginning’ [3]. It is true that the standardized mortality ratios for COPD have been declining in the Western world since the 1970s, but overall all-cause mortality is still increasing in COPD patients and especially so in female patients [4,5].
In both the scientific world and the clinical world, there is much to do. This review will focus on what our current management does achieve and the ways in which we can improve what we do to reduce mortality and disease progression. Firstly, we must reflect on what might be achievable and whether the goals of a reduction in mortality and disease progression will ever be within our reach. No therapy (yet) has significantly affected disease progression as measured by lung Heatherwood and Wexham NHS Foundation Trust, Slough, Berkshire and Imperial College, London, UK Correspondence to Dr Richard E. Russell, Consultant Respiratory Physician, Chest Clinic, King Edwards VII Hospital, St Leonards Road, Windsor, Berks, 01753 636458, UK. E-mail: [email protected] Curr Opin Pulm Med 2014, 20:127–131 DOI:10.1097/MCP.0000000000000030
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases &
KEY POINTS The prevalence of COPD is increasing worldwide, leading to an increased burden of disease, which affects the whole of society and not just the elderly. There are few interventions which change the prognosis in COPD: smoking cessation, pulmonary rehabilitation and long-term oxygen therapy. Pharmacological interventions are effective in reducing the symptom burden and exacerbation rate, but have not been shown to improve prognosis. Given the underlying nature of COPD, it is unlikely that there will be a therapy in the foreseeable future that will radically affect the disease progression. Each new or more effective therapy should be seen as a small step forward which will add up to a significant change for patients both now and in the future. Until we have more effective therapies, our focus should be on the individual patients and helping them to live as well as possible for as long as possible.
function. We have no treatment which can repair the injured lungs. Survival with COPD is inextricably linked with significant co-morbidities as much as isolated lung disease. It is somewhat satisfying to reflect that our patients are getting older. They are surviving the earliest presentations of their primary and co-morbid conditions, and presenting with compound manifestations later in life [6]. This in itself might be seen as a success. Can we prevent our patients dying of respiratory or cardiovascular failure [7]? Eventually not, but we can prevent premature death and try to improve the quality of life until their bell is finally tolled. Carefully conducted prospective research has led to a clear understanding of the prognostic factors in COPD. Much of our focus when treating this disease is on modifying these factors, which may lead to an improvement in prognosis. These factors have been combined into a multidimensional assessment tool [BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) score]; however, this is not easily used in a basic primary care setting [8]. The BODE score is more predictive of mortality risk than spirometry alone. The factors that have a high prognostic significance in COPD include forced expiratory volume in 1 s (FEV1, litres), diffusion capacity of lungs for carbon monoxide (DLCO, as measured during full-lung function testing) [9], MRC breathlessness score, exacerbation frequency, BMI, exercise capacity, arterial oxygen concentration (PaO2, kPa) and the presence of cor pulmonale [10 ]. Research is ongoing into which is the best &
128
www.co-pulmonarymedicine.com
physiological predictor of mortality [11 ], and new biomarkers are being developed which hold some promise [12].
SO WHAT CAN WE ACHIEVE BASED UPON THE CURRENT BEST EVIDENCE? Optimal management of COPD begins with an early diagnosis. This has been recommended now in both UK and global guidelines on COPD (http://www.nice.org.uk/nicemedia/live/13029/ 49425/49425.pdf; http://www.goldcopd.org/guide lines-global-strategy-for-diagnosis-management. html). All healthcare practitioners should be aware of the possibility of a COPD diagnosis when anyone over 35 years old and who is a smoker gets any significant respiratory symptom (http://www.nice.org. uk/nicemedia/live/13029/49425/49425.pdf). Spirometry demonstrates the airways obstruction, and appropriate clinical and investigational assessment completes the severity scoring process. It is outside the scope of this article to comment on this and the author recommends following national or local recommendations. Effective treatments can then be prescribed.
SMOKING Smoking cessation is the most cost-effective medical intervention [13]. The current literature demonstrates that we still have so much to do and that again women are more at risk than men [14 ]. We do have effective therapeutic aids to smoking cessation and often we need to take a multidimensional approach to each patient to achieve the best chance of success. With careful management, support and the right medications, sustained quit rates of up to 50% have been achieved [15,16]. Moreover, our approach to patients must always be supportive rather than either patronizing or punitive. Patients with COPD feel guilty about their disease and smoking. &
PHARMACOLOGICAL INTERVENTIONS Drug therapies for COPD are effective, although individual therapies often result in small benefits. It is hoped that there will be incremental benefit from adding therapies together, leading to a larger and eventually a step change in disease manifestation and progression. Most therapy for COPD is administered by the inhaled route. Inhaled steroids were the first class of medications to be extensively studied in COPD [17–19]. Their effects on this disease seem limited to patients with an FEV1 of less than 50% predicted [17] and Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Chronic obstructive pulmonary disease: getting it right Russell
have no effect in mild or early disease [18,19]. They reduce exacerbation rates in severe disease by up to 25%; however, they have no effect on the rate of decline of lung function [17]. A recent Cochrane review concluded that the use of inhaled steroids must be balanced for individual patients against the risk of side-effects [20 ]. Long-acting beta agonists (LABAs) have been shown to improve lung function (FEV1), reduce symptom scores and perhaps more significantly reduce the exacerbation rate by up to 20% [21,22]. The currently available compounds are given twice a day. Newly developed LABA medications can now be given once a day, which will hopefully lead to improved compliance as well as allowing combination with other once-daily drugs for COPD [23,24]. Long-acting muscarinic antagonists (LAMAs) are a growing class of drugs, which have been developed specifically for COPD. The first-in-class medication (tiotropium) has been used in a large number of long-term trials and has demonstrated comparable effects to LABA on lung function, symptom scores and exacerbation rates [24,25]. There are now two further compounds in clinical use which have been shown to be effective to a similar degree [26 ]. Currently, their data is limited to studies of 1 year duration, although long-term data will follow. Adding these classes of medication together makes pharmacological and physiological sense. Although this approach is recommended in patients with severe illness, the quality of evidence which at present supports a multidrug approach is poor. There is a need for much more research in this area [27,28]. The use of any medication raises the issue of adherence. This is complicated when using the inhaled route as not only has the patient to take the medication at the correct time and dose, but also they must be able to effectively use the inhaler device specific for that medication [28]. This is an under-investigated area, although there is recent convincing evidence that poor adherence leads to a worse outcome. Data on device use is often poor, short term and small scale. Moreover, we must improve our ability as prescribers to understand the patient’s preference [29]. Preventing exacerbations is a key goal of current therapy, as there is clearly a close link between exacerbations and mortality [30 ]. Unfortunately, none of our currently available medications changes the rate of decline of lung function or any other long-term marker of decline of the health and well being of our patients. Mucolytic therapies have been used more extensively in the last 2 years than before. They have been &
&
&&
shown to have a minor effect on exacerbation frequency and increase the time to next exacerbation. They too have no effect on mortality [31]. There has been a recent explosion of interest in the role of macrolide antibiotics in the management of airway disease. COPD has been studied extensively using these medications and there is good evidence that the use of long-term macrolide antibiotics does reduce the exacerbation rate [32,33 ,34]. The mechanism of action of these compounds is poorly understood, but is likely to involve a direct antimicrobial action as well as an immunemodulatory effect. Oxygen is one of the most expensive and poorly prescribed drugs in the world. The use of oxygen long term for more than 15 h a day in patients with significant hypoxia (PaO2
Chronic obstructive pulmonary disease: getting it right. Does optimal management of chronic obstructive pulmonary disease alter disease progression and improve survival? Richard E. Russell
Purpose of review We live in a world where people live longer lives. The standardized mortality rate for many diseases is decreasing. Chronic obstructive pulmonary disease (COPD) is not following this trend. Over the last 10 years, interventions for COPD have been developed, but have any changed the prognosis or trajectory of this modern epidemic? We review the most recent and classical literature in order to answer this question. Recent findings Recent analyses of data have clarified which interventions are effective in COPD and which are not. New studies have defined what is achievable with the current therapies. Only two interventions have been demonstrated to improve survival: smoking cessation and long-term oxygen therapy. Other treatments do reduce exacerbations, improve lung function and improve the patient’s quality of life, but do not affect physiological disease progression or mortality. Summary There is much work to do, not only to improve the treatments we have for this disease, but also to diagnose it early, intervene at the right time, reduce the treatment side-effects and most importantly understand the pathophysiology better. Moreover, we are duty bound to look at each patient and review what we are trying to achieve for each one through appropriate phenotyping as well as sometimes taking a more palliative approach. Keywords COPD, efficacy, prognosis, therapy
INTRODUCTION Are we winning the war against chronic obstructive pulmonary disease (COPD)? A recently published review of mortality due to COPD in Spain [1] demonstrated a sustained reduction in standardized mortality rate, leading to the comment that the epidemic might be over [2]. This data is not yet a cause for celebration or for us to take our eyes off the goal of significant and sustained reductions in prevalence of COPD, reduced exacerbation rates, lower levels of morbidity and if possible mortality reduction. Maybe as Churchill said, we are at the ‘end of the beginning’ [3]. It is true that the standardized mortality ratios for COPD have been declining in the Western world since the 1970s, but overall all-cause mortality is still increasing in COPD patients and especially so in female patients [4,5].
In both the scientific world and the clinical world, there is much to do. This review will focus on what our current management does achieve and the ways in which we can improve what we do to reduce mortality and disease progression. Firstly, we must reflect on what might be achievable and whether the goals of a reduction in mortality and disease progression will ever be within our reach. No therapy (yet) has significantly affected disease progression as measured by lung Heatherwood and Wexham NHS Foundation Trust, Slough, Berkshire and Imperial College, London, UK Correspondence to Dr Richard E. Russell, Consultant Respiratory Physician, Chest Clinic, King Edwards VII Hospital, St Leonards Road, Windsor, Berks, 01753 636458, UK. E-mail: [email protected] Curr Opin Pulm Med 2014, 20:127–131 DOI:10.1097/MCP.0000000000000030
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases &
KEY POINTS The prevalence of COPD is increasing worldwide, leading to an increased burden of disease, which affects the whole of society and not just the elderly. There are few interventions which change the prognosis in COPD: smoking cessation, pulmonary rehabilitation and long-term oxygen therapy. Pharmacological interventions are effective in reducing the symptom burden and exacerbation rate, but have not been shown to improve prognosis. Given the underlying nature of COPD, it is unlikely that there will be a therapy in the foreseeable future that will radically affect the disease progression. Each new or more effective therapy should be seen as a small step forward which will add up to a significant change for patients both now and in the future. Until we have more effective therapies, our focus should be on the individual patients and helping them to live as well as possible for as long as possible.
function. We have no treatment which can repair the injured lungs. Survival with COPD is inextricably linked with significant co-morbidities as much as isolated lung disease. It is somewhat satisfying to reflect that our patients are getting older. They are surviving the earliest presentations of their primary and co-morbid conditions, and presenting with compound manifestations later in life [6]. This in itself might be seen as a success. Can we prevent our patients dying of respiratory or cardiovascular failure [7]? Eventually not, but we can prevent premature death and try to improve the quality of life until their bell is finally tolled. Carefully conducted prospective research has led to a clear understanding of the prognostic factors in COPD. Much of our focus when treating this disease is on modifying these factors, which may lead to an improvement in prognosis. These factors have been combined into a multidimensional assessment tool [BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) score]; however, this is not easily used in a basic primary care setting [8]. The BODE score is more predictive of mortality risk than spirometry alone. The factors that have a high prognostic significance in COPD include forced expiratory volume in 1 s (FEV1, litres), diffusion capacity of lungs for carbon monoxide (DLCO, as measured during full-lung function testing) [9], MRC breathlessness score, exacerbation frequency, BMI, exercise capacity, arterial oxygen concentration (PaO2, kPa) and the presence of cor pulmonale [10 ]. Research is ongoing into which is the best &
128
www.co-pulmonarymedicine.com
physiological predictor of mortality [11 ], and new biomarkers are being developed which hold some promise [12].
SO WHAT CAN WE ACHIEVE BASED UPON THE CURRENT BEST EVIDENCE? Optimal management of COPD begins with an early diagnosis. This has been recommended now in both UK and global guidelines on COPD (http://www.nice.org.uk/nicemedia/live/13029/ 49425/49425.pdf; http://www.goldcopd.org/guide lines-global-strategy-for-diagnosis-management. html). All healthcare practitioners should be aware of the possibility of a COPD diagnosis when anyone over 35 years old and who is a smoker gets any significant respiratory symptom (http://www.nice.org. uk/nicemedia/live/13029/49425/49425.pdf). Spirometry demonstrates the airways obstruction, and appropriate clinical and investigational assessment completes the severity scoring process. It is outside the scope of this article to comment on this and the author recommends following national or local recommendations. Effective treatments can then be prescribed.
SMOKING Smoking cessation is the most cost-effective medical intervention [13]. The current literature demonstrates that we still have so much to do and that again women are more at risk than men [14 ]. We do have effective therapeutic aids to smoking cessation and often we need to take a multidimensional approach to each patient to achieve the best chance of success. With careful management, support and the right medications, sustained quit rates of up to 50% have been achieved [15,16]. Moreover, our approach to patients must always be supportive rather than either patronizing or punitive. Patients with COPD feel guilty about their disease and smoking. &
PHARMACOLOGICAL INTERVENTIONS Drug therapies for COPD are effective, although individual therapies often result in small benefits. It is hoped that there will be incremental benefit from adding therapies together, leading to a larger and eventually a step change in disease manifestation and progression. Most therapy for COPD is administered by the inhaled route. Inhaled steroids were the first class of medications to be extensively studied in COPD [17–19]. Their effects on this disease seem limited to patients with an FEV1 of less than 50% predicted [17] and Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Chronic obstructive pulmonary disease: getting it right Russell
have no effect in mild or early disease [18,19]. They reduce exacerbation rates in severe disease by up to 25%; however, they have no effect on the rate of decline of lung function [17]. A recent Cochrane review concluded that the use of inhaled steroids must be balanced for individual patients against the risk of side-effects [20 ]. Long-acting beta agonists (LABAs) have been shown to improve lung function (FEV1), reduce symptom scores and perhaps more significantly reduce the exacerbation rate by up to 20% [21,22]. The currently available compounds are given twice a day. Newly developed LABA medications can now be given once a day, which will hopefully lead to improved compliance as well as allowing combination with other once-daily drugs for COPD [23,24]. Long-acting muscarinic antagonists (LAMAs) are a growing class of drugs, which have been developed specifically for COPD. The first-in-class medication (tiotropium) has been used in a large number of long-term trials and has demonstrated comparable effects to LABA on lung function, symptom scores and exacerbation rates [24,25]. There are now two further compounds in clinical use which have been shown to be effective to a similar degree [26 ]. Currently, their data is limited to studies of 1 year duration, although long-term data will follow. Adding these classes of medication together makes pharmacological and physiological sense. Although this approach is recommended in patients with severe illness, the quality of evidence which at present supports a multidrug approach is poor. There is a need for much more research in this area [27,28]. The use of any medication raises the issue of adherence. This is complicated when using the inhaled route as not only has the patient to take the medication at the correct time and dose, but also they must be able to effectively use the inhaler device specific for that medication [28]. This is an under-investigated area, although there is recent convincing evidence that poor adherence leads to a worse outcome. Data on device use is often poor, short term and small scale. Moreover, we must improve our ability as prescribers to understand the patient’s preference [29]. Preventing exacerbations is a key goal of current therapy, as there is clearly a close link between exacerbations and mortality [30 ]. Unfortunately, none of our currently available medications changes the rate of decline of lung function or any other long-term marker of decline of the health and well being of our patients. Mucolytic therapies have been used more extensively in the last 2 years than before. They have been &
&
&&
shown to have a minor effect on exacerbation frequency and increase the time to next exacerbation. They too have no effect on mortality [31]. There has been a recent explosion of interest in the role of macrolide antibiotics in the management of airway disease. COPD has been studied extensively using these medications and there is good evidence that the use of long-term macrolide antibiotics does reduce the exacerbation rate [32,33 ,34]. The mechanism of action of these compounds is poorly understood, but is likely to involve a direct antimicrobial action as well as an immunemodulatory effect. Oxygen is one of the most expensive and poorly prescribed drugs in the world. The use of oxygen long term for more than 15 h a day in patients with significant hypoxia (PaO2
